ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The following clinically significant adverse reactions are described elsewhere in the labeling:Mucocutaneous reactions [see Warnings and Precautions (5.1)] Hepatitis 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)] Mucocutaneous reactions [see Warnings and Precautions (5.1)] Hepatitis 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 fatigueDLBCL: 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.. 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 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 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 full dose of 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 doses (i.e., total of doses in combination with chemotherapy), or as monotherapy for up to 12 doses (maintenance treatment). In the MabEase study patients with DLBCL received full dose of 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 doses (i.e., up to total of doses). In the SAWYER study patients with CLL on part received full dose of rituximab product by intravenous infusion, followed by RITUXAN HYCELA (1,600 mg rituximab/26,800 Units hyaluronidase human) for up to doses, in combination with fludarabine and cyclophosphamide (i.e., total of 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 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 m2), 89% versus 93% (1.73 BSA <= 1.92 m2), and 94% versus 94% (BSA 1.92 m2). The overall incidence of adverse reactions for rituximab versus RITUXAN HYCELA in CLL was 89% versus 100% (BSA <= 1.81 m2), 97% versus 88% (1.82 BSA <= 1.99 m2), and 88% versus 93% (BSA 2.00 m2). Summary of Clinical Trial Experience in Follicular Lymphoma (FL)The data in Table were obtained in the SABRINA study, 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 rituximab product by intravenous infusion (375 mg/m2; n=210), both in combination with CHOP or CVP followed by maintenance treatment with RITUXAN HYCELA or rituximab product by intravenous infusion.The majority of patients completed all 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 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 and population were otherwise balanced in regard to baseline demographics, characterized by 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 m2 (1.80 and 1.84 m2 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. 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 and 6, 12 patients (7%) at Cycle 7, and 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 patients (14%) overall. Grade 1-2 ARRs constituted 96% of the overall ARRs. Grade ARRs were reported during the first administration of RITUXAN HYCELA at Cycle by patients. Of the reported ARRs, local cutaneous reactions with RITUXAN HYCELA were reported in 32 patients. These events resolved within median of days from the onset (range to 37 days). Majority of these reactions were Grade and and were observed in 31 patients (16%). Table 1:Incidence of Adverse Reactions in >= 5% of Patients with Previously Untreated Follicular Lymphoma Receiving RITUXAN HYCELA or Rituximab in Combination with CHOP or CVP and as Monotherapy for Maintenance Treatment Body System/Adverse ReactionsRITUXAN HYCELA (n=197)Rituximab (n=210)All Grades%Grade 3-4%All Grades%Grade 3-4%Gastrointestinal Disorders Nausea310220 Constipation25026< Diarrhea18216< Abdominal Pain14012< Vomiting14012< Dyspepsia8070 Stomatitis6050 Abdominal Pain Upper5050General Disorders and Administration Site Conditions Fatigue20018< Asthenia171130 Pyrexia15< 116< Injection Site Erythema13000 Injection Site Pain8000 Chills8090 Chest Pain6130 Edema Peripheral5< 160 Mucosal Inflammation516< Influenza Like Illness3060Infections Upper Respiratory Tract Infection15< 1100 Pneumonia11542 Nasopharyngitis100100 Bronchitis8< 18< Urinary Tract Infection8114< Sinusitis7< 140 Conjunctivitis5050 Influenza406< 1Blood and Lymphatic System Disorders Neutropenia32262721 Anemia155130 Febrile Neutropenia8766 Leukopenia64112Musculoskeletal and Connective Tissue Disorders Arthralgia13< 1100 Bone Pain10< 180 Pain In Extremity10050 Back Pain9< 112< Muscle Spasms8030 Myalgia8050Nervous System Disorders Paresthesia160120 Headache13090 Neuropathy Peripheral12214< Dizziness7070Skin and Subcutaneous Tissue Disorders Alopecia14< 110< Pruritus10012< Rash10070 Erythema9050Respiratory, Thoracic and Mediastinal Disorders Cough23013< Dyspnea11182 Oropharyngeal Pain9080Psychiatric Disorders Insomnia9090Vascular Disorders Hypertension6160. Summary of Clinical Trial Experience in Diffuse Large B-Cell Lymphoma (DLBCL)The data in Table were obtained in the MabEASE study, comparative, randomized, parallel-group, multicenter study to investigate the efficacy of RITUXAN HYCELA (1,400 mg rituximab and 23,400 Units hyaluronidase human; n=369) versus 375 mg/m2 rituximab product by intravenous infusion (n=203) both in combination with CHOP (R-CHOP) in previously untreated patients with CD20-positive DLBCL.Eighty two percent of patients receiving RITUXAN HYCELA or rituximab completed all cycles of study treatment. In both RITUXAN HYCELA and rituximab treatment groups, patients experienced 4.9 months median duration of rituximab exposure in each arm.The demographic characteristics were balanced. Most patients were White (79%) and 54% were male. The median was 64 years and median BSA was 1.83 m2.The incidences of adverse reactions of any grade (RITUXAN HYCELA [94%] vs. rituximab [92%]) (Table 2), Grade 3-4 adverse reactions (RITUXAN HYCELA [63%] vs. rituximab [57%]), and serious adverse reactions (RITUXAN HYCELA [42%] vs. rituximab [37%]) were generally comparable between the two treatment groups. The common adverse reactions (occurring in >= 20% of patients in any treatment group) were neutropenia, alopecia, nausea, and anemia.A total of 91 patients (16%) died, including 58/369 patients (16%) in RITUXAN HYCELA and 33/203 patients (16%) in rituximab. Of these patients, 44 patients (29 patients RITUXAN HYCELA [8%] vs. 15 patients rituximab [7%]) died due to adverse reactions and 35 patients (22 patients RITUXAN HYCELA [6%] vs. 13 patients rituximab [6%]) died due to disease progression. Pneumonia (4 patients RITUXAN HYCELA vs. patient rituximab), septic shock (2 patients RITUXAN HYCELA vs. patients rituximab), and cardiac arrest (1 patient RITUXAN HYCELA vs. patients rituximab) were the most common adverse reactions leading to death. The incidence of administration-related reactions was balanced between the RITUXAN HYCELA and rituximab groups (28% vs. 29%). Grade 1-2 ARRs constituted 97% of the overall ARRs for the RITUXAN HYCELA arm and 80% for the rituximab arm. Of the reported ARRs, local cutaneous reactions with RITUXAN HYCELA were reported in 17 patients. These events resolved within median of days from the onset (range to 32 days). Majority of these reactions were Grade and and were observed in 16 patients (4%).Table 2:Incidence of Adverse Reactions in >= 5% of Patients with Previously Untreated DLBCL Receiving RITUXAN HYCELA or Rituximab in Combination with CHOPBody System/Adverse ReactionsRITUXAN HYCELA CHOP(n=369)Rituximab CHOP(n=203)All Grades%Grade 3-4%All Grades%Grade 3-4%Gastrointestinal Disorders Nausea22< 124< Constipation15< 117< Diarrhea141101 Vomiting11< 18< Abdominal Pain7< 17< Stomatitis6< 150 Dyspepsia5070General Disorders and Administration Site Conditions Fatigue191151 Pyrexia13< 1130 Asthenia11< 112< Mucosal Inflammation8< 181 Edema Peripheral8< 140Infections Pneumonia7342Blood and Lymphatic System Disorders Neutropenia31252919 Anemia235214 Febrile Neutropenia14141211 Leukopenia7373 Lymphopenia5163Investigations Neutrophil Count Decreased14111411 White Blood Cell Count Decreased7475 Weight Decreased8< 14< Lymphocyte Count Decreased5232Metabolism and Nutrition Disorders Decreased Appetite8< 19< 1Nervous System Disorders Neuropathy Peripheral12< 1120 Paresthesia9< 160 Headache6070Skin and Subcutaneous Tissue Disorders Alopecia240240Respiratory, Thoracic and Mediastinal Disorders Cough11< 190 Dyspnea604< 1Psychiatric Disorders Insomnia7< 16< 1. Summary of Clinical Trial Experience in Chronic Lymphocytic LeukemiaThe data in Table were obtained in part of the SAWYER study, two-part, comparative, randomized, parallel-group, multicenter study of RITUXAN HYCELA versus rituximab product by intravenous infusion both in combination with fludarabine and cyclophosphamide (FC) chemotherapy in patients with previously untreated CLL.The safety analysis population in part of the study included 85 patients receiving RITUXAN HYCELA (1,600 mg rituximab/26,800 Units hyaluronidase human) and 89 patients receiving 500 mg/m2 rituximab. In both RITUXAN HYCELA and rituximab groups, patients had similar median duration of rituximab exposure (4.9 vs. 4.7 months). The majority of patients received all cycles of study treatment (86% RITUXAN HYCELA vs. 81% rituximab).The patient population was predominantly White (96%) and male (65%), with median age of 60 years and median BSA of 1.9 m2 (1.97 and 1.86 m2 for the RITUXAN HYCELA and intravenous rituximab groups, respectively). Overall, the treatment groups were balanced with respect to demographic characteristics, with the exception of more males in the RITUXAN HYCELA arm (71% RITUXAN HYCELA vs. 60% rituximab). Baseline disease characteristics were similar between the two groups. Over half of the patients (62%) had Binet Stage disease and the majority had typical CLL characterizations (93%), with median time from first CLL diagnosis to randomization being 18.5 months.The incidences of adverse reactions were balanced between the two treatment groups (96% RITUXAN HYCELA vs. 91% rituximab), and the common adverse reactions (occurring in >= 20% of patients in any arm) were infections, neutropenia, nausea, thrombocytopenia, pyrexia, anemia, vomiting, and injection site erythema. The incidences of Grade 3-4 adverse reactions were also balanced between the two treatment groups (69% RITUXAN HYCELA vs. 71% rituximab). The incidence of serious adverse reactions was 29% for RITUXAN HYCELA and 33% for rituximab. The incidence of administration-related reactions was 44% for RITUXAN HYCELA and 45% for rituximab). Of the reported ARRs, local cutaneous reactions with RITUXAN HYCELA were reported in 15 patients. These events resolved within median of days from the onset (range to 29 days). Majority of these reactions were Grade and and were observed in 14 patients (16%).A total of patients (5%) died, including patients in the RITUXAN HYCELA group and patients in the rituximab group. In the RITUXAN HYCELA group, patient died due to herpes zoster infection, patient died as result of progressive multifocal leukoencephalopathy (PML) (considered by the investigator as related to rituximab), and patients died due to disease progression. In the rituximab group, patients died due to diarrhea and listeriosis and patients died due to disease progression. Table 3:Incidence of Adverse Reactions in >= 5% of Patients with Previously Untreated CLL Receiving RITUXAN HYCELA or Rituximab in Combination with FCBody System/Adverse ReactionsRITUXAN HYCELA FC(n=85)Rituximab FC(n=89)All Grades%Grade 3-4%All Grades%Grade 3-4%Gastrointestinal Disorders Nausea381350 Vomiting212221 Diarrhea120113 Abdominal Pain9060 Constipation8080General Disorders and Administration Site Conditions Pyrexia325251 Injection Site Erythema26200 Injection Site Pain16100 Chills130101 Fatigue110100 Asthenia81172Infections Upper Respiratory Tract Infection130121 Respiratory Tract Infection8141 Bronchitis7060 Urinary Tract Infection2081 Pneumonia2262Blood and Lymphatic System Disorders Neutropenia65565852 Thrombocytopenia246269 Leukopenia19141612 Anemia135249 Febrile Neutropenia11888Musculoskeletal and Connective Tissue Disorders Arthralgia9010 Pain In Extremity7120 Bone Pain6020Nervous System Disorders Headache7090Skin and Subcutaneous Tissue Disorders Erythema15070 Rash120101 Pruritus8040Respiratory, Thoracic and Mediastinal Disorders Cough130110 Oropharyngeal Pain6030 Dyspnea4081Psychiatric Disorders Insomnia1070Vascular Disorders Hypotension1071 Hypertension0061. 6.2Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to RITUXAN HYCELA and rituximab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading.In the SABRINA study, where previously untreated patients with follicular lymphoma were treated with RITUXAN HYCELA or rituximab in combination with CVP or CHOP, the incidence of treatment-induced/enhanced anti-rituximab antibodies in the RITUXAN HYCELA group was similar to that observed in the rituximab group (2.0% RITUXAN HYCELA vs. 1.9% rituximab). The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 15% in the RITUXAN HYCELA group compared with 8% in the rituximab group, and the overall proportion of patients found to have anti-recombinant human hyaluronidase antibodies remained generally constant over the follow-up period in both cohorts. All patients who tested positive for anti-recombinant human hyaluronidase antibodies at any point during the study were negative for neutralizing antibodies.In the SAWYER study, where previously untreated patients with CLL were treated with RITUXAN HYCELA or rituximab in combination with FC, the incidence of treatment-induced/enhanced anti-rituximab antibodies was 12% in the RITUXAN HYCELA group and 15% in the rituximab group. The incidence of treatment-induced/enhanced anti-recombinant human hyaluronidase antibodies was 11% in the RITUXAN HYCELA treatment arm. None of the patients who tested positive for anti-recombinant human hyaluronidase antibodies tested positive for neutralizing antibodies. The clinical relevance of the development of anti-rituximab or anti-recombinant human hyaluronidase antibodies after treatment with RITUXAN HYCELA is not known. 6.3Postmarketing Experience. The following adverse reactions have been identified during post-approval use of rituximab-containing products. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3-4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstroms macroglobulinemia, prolonged hypogammaglobulinemia Cardiac: fatal cardiac failure Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and reported increased incidence of Grade and infections Neoplasia: disease progression of Kaposis sarcoma. Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation).Gastrointestinal: bowel obstruction and perforation.Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease.. Hematologic: prolonged pancytopenia, marrow hypoplasia, Grade 3-4 prolonged or late-onset neutropenia, hyperviscosity syndrome in Waldenstroms macroglobulinemia, prolonged hypogammaglobulinemia Cardiac: fatal cardiac failure Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and reported increased incidence of Grade and infections Neoplasia: disease progression of Kaposis sarcoma. Skin: severe mucocutaneous reactions, pyoderma gangrenosum (including genital presentation).. Gastrointestinal: bowel obstruction and perforation.. Pulmonary: fatal bronchiolitis obliterans and fatal interstitial lung disease.

BOXED WARNING SECTION.

WARNING: SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY. WARNING: SEVERE MUCOCUTANEOUS REACTIONS, HEPATITIS VIRUS REACTIVATION and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHYSee full prescribing information for complete boxed warning.Severe mucocutaneous reactions, some with fatal outcomes (5.1).Hepatitis virus reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death 5.2).Progressive multifocal leukoencephalopathy resulting in death (5.3).. Severe mucocutaneous reactions, some with fatal outcomes (5.1).. Hepatitis virus reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death 5.2).. Progressive multifocal leukoencephalopathy resulting in death (5.3).. Severe Mucocutaneous ReactionsSevere, including fatal, mucocutaneous reactions can occur in patients receiving rituximab-containing products, including RITUXAN HYCELA [see Warnings and Precautions (5.1)]. Hepatitis Virus (HBV) ReactivationHBV reactivation can occur in patients treated with rituximab-containing products, including RITUXAN HYCELA, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with RITUXAN HYCELA. Discontinue RITUXAN HYCELA and concomitant medications in the event of HBV reactivation [see Warnings and Precautions (5.2)].. Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving rituximab-containing products, including RITUXAN HYCELA [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN HYCELA or rituximab, or to determine potential effects on fertility in males or females. RITUXAN HYCELA contains hyaluronidase human. Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase human. In addition, when hyaluronidase human was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is 90 times higher than the human dose, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Rituximab is monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days. Hyaluronidase human increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase human in RITUXAN HYCELA acts locally.The effects of hyaluronidase human are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.Hyaluronidase human has been shown to increase the absorption rate of rituximab product into the systemic circulation when given in the subcutis of Gottingen Minipigs.. 12.2 Pharmacodynamics. Peripheral B-cell counts declined to levels below normal following dose of rituximab by intravenous infusion. In patients treated with rituximab for hematological malignancies, cell recovery began within months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer.. Follicular Lymphoma (FL)Peripheral B-cell counts decline to levels below normal following the first cycle of rituximab and are maintained during treatment with RITUXAN HYCELA. After stopping RITUXAN HYCELA treatment, B-cell repletion followed similar kinetics to that of rituximab with B-cell repletion beginning after months of stopping treatment, although in some patients this may take longer.. Chronic Lymphocytic Leukemia (CLL) Following the first cycle of treatment of rituximab, B-cells begin to deplete, with 28% of patients B-cell depleted at pre-dose Cycle in the SAWYER study. An increase in the proportion of B-cell depleted patients was observed with subsequent cycles of RITUXAN HYCELA and by Cycle 6, 96% of patients were depleted. Patients remained B-cell depleted until the month follow-up visit, where signs of repletion were seen.. 12.3 Pharmacokinetics. The geometric mean rituximab exposures are provided in Table 4. The pharmacokinetic properties of rituximab following the administration of RITUXAN HYCELA in the approved indications are provided in Table 5. The elimination of rituximab was characterized by time-dependent process that occurred early in therapy and time-independent process.Table 4:Rituximab Exposure Values following Subcutaneous Administration of RITUXAN HYCELAPharmacokinetic parameters are presented as geometric mean unless otherwise specified. StudyFor study design information, see Clinical Studies (14). CycleRituximab FLRITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) Cmax, mcg/mL (CV%)SABRINA7237 (29.4)18156 (24.7)Based on predicted values Ctrough, mcg/mL (CV%)7122.2 (55.3)1845.5 (53.6) AUCTAU, mcgday/mL (CV%)73779 (33.7)185000 (34.3) CLLRITUXAN HYCELA 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) Cmax, mcg/mL (CV%)SAWYER6202 (36.1)Ctrough, mcg/mL (CV%)597.5 (42.6)AUCTAU, mcgday/mL (CV%)54088 (34.2)In the SABRINA study, the geometric mean Ctrough in the RITUXAN HYCELA arm was higher than in the rituximab arm with geometric mean ratio (Ctrough, RITUXAN HYCELA/Ctrough, rituximab) of 1.52 (90% CI: 1.36, 1.70) at Cycle [see Clinical Studies (14.1)].In the SAWYER study, the geometric mean Ctrough in the RITUXAN HYCELA arm was higher than in the rituximab arm with an adjusted geometric mean ratio of 1.53 (90% CI: 1.27-1.85) at Cycle [see Clinical Studies (14.3)].Table 5:Pharmacokinetic Parameters of Rituximab following Subcutaneous Administration of RITUXAN HYCELAParameters represented as geometric mean (%CV) unless otherwise specified FLCLLAbsorption Absolute BioavailabilityCompared to rituximab product administered intravenously 0.646 (0.634-0.65995% CI)0.634 (0.602-0.665) Distribution Volume of Central compartment (L)4.06 (26)4.80 (18) Apparent Volume of Distribution at steady stateVolume of central compartment and peripheral compartment (L)8.09 (19)8.52 (13)Elimination Terminal Half-life (days)34.1 (27)32 (24) Clearance (L/day)0.18 (34)0.204 (31). Specific PopulationsThe pharmacokinetics of rituximab and hyaluronidase human in children and adolescents is unknown. The effect of either renal or hepatic impairment on the pharmacokinetics of rituximab and hyaluronidase human is unknown.. Drug Interaction StudiesThe drug interaction potential of rituximab and hyaluronidase human is unknown.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. 14.1Follicular Lymphoma. The SABRINA study [NCT01200758] was randomized, two-stage, open-label, multicenter study that enrolled total of 410 patients with previously untreated, CD20-positive follicular lymphoma of Grade 1, or 3a requiring therapy. The study design is identical in stage and 2. Patients were randomized (1:1) to receive either rituximab product by intravenous infusion 375 mg/m2 for cycles or cycle of rituximab product by intravenous infusion 375 mg/m2 followed by cycles of RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) both every weeks in combination with total of 6-8 cycles of CHOP or cycles of CVP chemotherapy. Patients underwent interim staging after cycles. Patients who received R-CHOP and achieved CR, CRu, PR or SD at the interim assessment could receive either more cycles of R-CHOP or cycles of R-CHOP followed by cycles of monotherapy with rituximab product or RITUXAN HYCELA depending on randomization arm (i.e., total of cycles of rituximab product or RITUXAN HYCELA). Patients with at least PR after combination treatment with chemotherapy continued with single agent maintenance treatment administered every weeks for 24 months with rituximab product or RITUXAN HYCELA as per their randomization (i.e., total of 12 cycles of maintenance treatment).Randomization was stratified by: underlying chemotherapy backbone (CHOP vs CVP), Follicular Lymphoma International Prognostic Index (FLIPI) (low-risk vs. intermediate-risk vs. high-risk), and region (Europe and North America vs. South and Central America vs Asia).The main outcome measure for Stage was the estimated ratio of observed rituximab serum Ctrough SC/Ctrough IV at Cycle of combination treatment with chemotherapy every weeks. The main outcome measure for Stage was the investigator-assessed ORR consisting of CR, CRu, and PR at the completion of combination treatment with chemotherapy. Additional outcome measures were CRR (CR and CRu) at the end of completion of combination treatment with chemotherapy, ORR and CRR at the end of completion of maintenance treatment, and time-to-event endpoints (progression-free survival (PFS), and overall survival (OS)).Of all randomized patients, the median age was 57 years (range: 28 to 86), 53% were female, and 86% were White. The median BSA was 1.83 m2. 45% had high risk or 34% had intermediate risk FLIPI score, and 54% had Ann Arbor Stage IV disease. Ninety percent of patients completed all cycles of combination treatment with chemotherapy, and 70% of patients completed 20 cycles of both combination and maintenance treatment. Median treatment duration was 27.1 months in both groups. The median number of cycles received was 20 in both groups.The pharmacokinetic results for the primary endpoint in Stage 1, rituximab Ctrough at Cycle (i.e., 21 days after Cycle rituximab administration), demonstrated that RITUXAN HYCELA 1,400 mg/23,400 Units was non-inferior compared with rituximab at 375 mg/m2 in patients receiving combination treatment with chemotherapy [see Clinical Pharmacology (12.3)]. The efficacy results are presented in Table 6. Table 6:Efficacy in Patients with Previously Untreated Follicular Lymphoma (SABRINA Study)RITUXAN HYCELA N=205Rituximab N=205Overall Response Rate at End of combination treatment with chemotherapyStage main outcome measure was ORR at the end of combination treatment with chemotherapy; however pooled results which were preplanned are presented in this Table.Response rates based on investigator assessment.Response rates at end of maintenance based on patients who received at least one cycle of maintenance treatment (n). Investigator-assessed ORR (comprising CR, CRu and PR). Number of responders (CR/CRu, PR)173174Overall response (CR/CRu, PR) rate (%, [95% CI])84% [79;89]85% [79;90] Difference in overall response ratesDifference in response rates (RITUXAN HYCELA minus rituximab). [95% CI]-0.5% [-7.7;6.8]Number of complete responders (CR/CRu)6665Complete response (CR/CRu) rate (%, [95% CI])32% [26;39]32% [25;39] Difference in complete response rates [95% CI]0.0% [-9.3;9.3]Overall Response Rate at End of MaintenanceNumber of patients treated in maintenance (n)172178Number of responders (CR/CRu, PR)134139Overall response (CR/CRu, PR) rate (%, [95% CI])78% [71;84]78% [71;84] Difference in overall response rates [95% CI]-0.2 [-9.2;8.8]Number of complete responders (CR/CRu)87103Complete response (CR/CRu) rate (%, [95% CI])51% [43;58]58% [50;65] Difference in complete response rates [95% CI] -7.3 [-18.0;3.5]Progression-free survivalAt time of final analysis (median follow-up 4.8 years). Number of patients with event65 (32%)71 (35%)Hazard Ratio [95% CI] (unstratified Cox model)0.90 [0.64;1.26]Overall survivalNumber of patients with event18 (8.8%)26 (12.7%)Hazard Ratio [95% CI] (unstratified Cox model)0.70 [0.38;1.27]. 14.2Diffuse Large B-Cell Lymphoma (DLBCL). The MabEase study [NCT01649856] enrolled total of 576 patients with previously untreated CD20-positive DLBCL. Patients were randomized (2:1) to receive either rituximab product by intravenous infusion, 375 mg/m2 for cycles or cycle of rituximab product by intravenous infusion 375 mg/m2 followed by cycles of RITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human), both in combination with up to 6-8 cycles of CHOP chemotherapy, every 14 (CHOP-14) or 21 days (CHOP-21). Randomization was stratified by: age (< 60 years, >= 60 years), International Prognostic Index (IPI) risk category (low, low-intermediate, high-intermediate, high), and chemotherapy regimen (CHOP-21 or CHOP-14). The main outcome measure was investigator-assessed complete response rate (CR/CRu) at the end of combination treatment with chemotherapy. Additional outcome measures were time-to-event endpoints (PFS and OS).Of all randomized patients, the median age was 64 years (range: 18 to 80 years); 54% were male; and 79% were White. The median BSA was 1.83 m2. 31% low risk or 30% low intermediate risk IPI score, 24% high intermediate risk, or 15% high risk IPI score and 42% of patients had Ann Arbor Stage IV disease. total of 470 patients (82%) received cycles of treatment. Median duration of exposure to treatment was 4.9 months in both treatment groups. The median number of administrations/cycles (RITUXAN HYCELA or rituximab) was in both groups. The efficacy results for are presented in Table 7. The median observation time was approximately 28 months. Table 7:Efficacy in Patients with Previously Untreated DLBCL (MabEase Study)RITUXAN HYCELA N=381Rituximab N=195Complete Response Rate (CR/CRu)Investigator-assessed. Number achieving CR/CRu Four patients in the RITUXAN HYCELA group and patient in the rituximab group had their response downgraded due to their bone marrow data. 17982Cr/CRu rate (%, [95% CI])47% [42;52]42% [35;49] Difference in rates [95% CI]Difference in response rates (RITUXAN HYCELA minus rituximab). 4.9% [-3.6;13.5]Progression-free survivalProgression-free survival is defined as the time from randomization to the first occurrence of disease progression or relapse, or death from any cause. Number of patients with event104 (27%)44 (23%)Hazard Ratio [95% CI] (unstratified Cox model)1.22 [0.85;1.73]Overall survivalOverall survival is defined as the time from randomization until death from any cause. Number of patients with event63 (17%)29 (15%)Hazard Ratio [95% CI] (unstratified Cox model)1.08 [0.70;1.68]. 14.3Chronic Lymphocytic Leukemia (CLL). The SAWYER study [NCT01292603] was randomized, two-part, open-label, multicenter study that enrolled total of 176 patients with previously untreated CLL. Patients were randomized (1:1) to receive either rituximab product by intravenous infusion, 375 mg/m2, in Cycle followed by up to cycles of rituximab, 500 mg/m2, or rituximab, 375 mg/m2, in Cycle followed by subsequent cycles (2-6) of RITUXAN HYCELA 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human), both in combination with fludarabine and cyclophosphamide (FC) chemotherapy. The main outcome measure was the non-inferiority of the pharmacokinetic profile of RITUXAN HYCELA compared to rituximab. An additional outcome measure in Part was investigator-assessed response rate.The median age was 60 years (range: 25 to 78); 65% were males and 96% were White. The median BSA was 1.9 m2, 62% had Binet Stage disease and 93% had typical CLL characterization. The pharmacokinetic results demonstrated that RITUXAN HYCELA 1,600 mg/26,800 Units serum rituximab Ctrough level was non-inferior compared with rituximab at 500 mg/m2 in patients receiving combination treatment with chemotherapy [see Clinical Pharmacology (12.3)]. The efficacy results for Part are presented in Table 8.Table 8: Efficacy in Patients with Previously Untreated CLL (SAWYER Study)Part 2RITUXAN HYCELA (N 88)Rituximab (N 88)ORR Overall Response RateCRR Complete Response RatePFS Progression-Free SurvivalORRAt month follow-up visit (Part 2). Investigator-assessed. Point estimate85.2% (n 75)80.7% (n 71)95% CI[76.1%, 91.9%][70.9%, 88.3%]CRR Point estimate27.3% (n 24)31.8% (n 28)95% CI[18.3%, 37.8%][22.3%, 42.6%]PFSAt time of final analysis (median follow-up 4.4 years). Investigator-assessed. Proportion with PFS event34.1% (n 30)42.0% (n 37)HR 95% CI0.76 [0.47%, 1.23%]. 14.4 Patient Experience. Previously untreated adult patients outside of the United States with CD20+ diffuse large B-cell lymphoma (DLBCL) or CD20+ follicular non-Hodgkins lymphoma (FL) Grades 1, 2, or 3a were randomized to receive standard chemotherapy regimen (CHOP, CVP, or bendamustine) and either RITUXAN HYCELA 1,400 mg/23,400 Units at Cycles 2-4 (after the first cycle with intravenous rituximab) or rituximab product by intravenous infusion at Cycles 1-4. After the fourth cycle, patients were crossed over to the alternative route of administration for the remaining cycles. After Cycle 8, 477 of 620 patients (77%) reported preferring subcutaneous administration of RITUXAN HYCELA over intravenous rituximab and the most common reason was that administration required less time in the clinic. After Cycle 8, 66 of 620 patients (11%) preferred rituximab intravenous administration and the most common reason was that it felt more comfortable during administration. Forty eight of 620 patients (7.7%) had no preference for the route of administration. Twenty nine subjects of 620 (4.7%) received Cycle but did not complete the preference questionnaire.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None. None.

DESCRIPTION SECTION.

11 DESCRIPTION. RITUXAN HYCELA is combination of rituximab and hyaluronidase human. Rituximab is genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kD. Rituximab has binding affinity for the CD20 antigen of approximately 8.0 nM. Rituximab is produced by mammalian cell (Chinese Hamster Ovary) suspension. Recombinant human hyaluronidase is an endoglycosidase used to increase the dispersion and absorption of co-administered drugs when administered subcutaneously. It is produced by mammalian (Chinese Hamster Ovary) cells containing DNA plasmid encoding for soluble fragment of human hyaluronidase (PH20). It is glycosylated single-chain protein with an approximate molecular weight of 61 kD. RITUXAN HYCELA (rituximab and hyaluronidase human) injection is colorless to yellowish, clear to opalescent solution supplied in sterile, preservative-free, single-dose vials for subcutaneous use. RITUXAN HYCELA is supplied as 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL in single-dose vials or 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL in single-dose vials. Each mL of solution contains rituximab (120 mg), hyaluronidase human (2,000 Units), L-histidine (0.53 mg), L-histidine hydrochloride monohydrate (3.47 mg), L-methionine (1.49 mg), polysorbate 80 (0.6 mg), ,-trehalose dihydrate (79.45 mg), and Water for Injection.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For subcutaneous use only (2.1)All patients must receive at least one full dose of 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 minutes.13.4 mL from 1,600 mg/26,800 Units vial over approximately minutes.Observe 15 minutes following administration For subcutaneous use only (2.1). All patients must receive at least one full dose of 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 minutes.13.4 mL from 1,600 mg/26,800 Units vial over approximately minutes.Observe 15 minutes following administration 11.7 mL from 1,400 mg/23,400 Units vial over approximately minutes.. 13.4 mL from 1,600 mg/26,800 Units vial over approximately 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 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 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 rituximab product by intravenous infusion and not switch to RITUXAN HYCELA until full intravenous dose is successfully administered [see Warnings and Precautions (5.4)]. Refer to the prescribing information for 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.. 2.2Recommended Dosage for Follicular Lymphoma (FL). All patients must receive at least one full dose of 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 fixed dose irrespective of patients body surface area according to the following schedules:Relapsed or Refractory, Follicular Lymphoma Administer once weekly for or weeks following full dose of rituximab product by intravenous infusion at week (i.e., or weeks in total).Retreatment for Relapsed or Refractory, Follicular LymphomaAdminister once weekly for weeks following full dose of rituximab product by intravenous infusion at week (i.e., weeks in total).Previously Untreated, Follicular Lymphoma Administer on Day of Cycles 2-8 of chemotherapy (every 21 days), for up to cycles following full dose of rituximab product by intravenous infusion on Day of Cycle of chemotherapy (i.e., up to cycles in total). In patients with complete or partial response, initiate RITUXAN HYCELA maintenance treatment weeks following completion of RITUXAN HYCELA in combination with chemotherapy. Administer RITUXAN HYCELA as single-agent every weeks for 12 doses.Non-progressing, Follicular Lymphoma after first line CVP chemotherapy Following completion of 6-8 cycles of CVP chemotherapy and full dose of rituximab product by intravenous infusion at week 1, administer once weekly for weeks (i.e., weeks in total) at month intervals to maximum of 16 doses.. Relapsed or Refractory, Follicular Lymphoma Administer once weekly for or weeks following full dose of rituximab product by intravenous infusion at week (i.e., or weeks in total).. Retreatment for Relapsed or Refractory, Follicular LymphomaAdminister once weekly for weeks following full dose of rituximab product by intravenous infusion at week (i.e., weeks in total).. Previously Untreated, Follicular Lymphoma Administer on Day of Cycles 2-8 of chemotherapy (every 21 days), for up to cycles following full dose of rituximab product by intravenous infusion on Day of Cycle of chemotherapy (i.e., up to cycles in total). In patients with complete or partial response, initiate RITUXAN HYCELA maintenance treatment weeks following completion of RITUXAN HYCELA in combination with chemotherapy. Administer RITUXAN HYCELA as single-agent every weeks for 12 doses.. Non-progressing, Follicular Lymphoma after first line CVP chemotherapy Following completion of 6-8 cycles of CVP chemotherapy and full dose of rituximab product by intravenous infusion at week 1, administer once weekly for weeks (i.e., weeks in total) at month intervals to maximum of 16 doses.. 2.3Recommended Dosage for Diffuse Large B-Cell Lymphoma (DLBCL). All patients must receive at least one full dose of 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 fixed dose irrespective of patients body surface area in combination with CHOP chemotherapy. Administer RITUXAN HYCELA 1,400 mg/23,400 Units on Day of Cycles 2-8 of CHOP chemotherapy for up to cycles following full dose of rituximab product by intravenous infusion at Day 1, Cycle of CHOP chemotherapy (i.e., up to 6-8 cycles in total). 2.4Recommended Dosage for Chronic Lymphocytic Leukemia (CLL). All patients must receive at least one full dose of 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 fixed dose, irrespective of patients body surface area. Administer RITUXAN HYCELA 1,600 mg/26,800 Units on Day of Cycles 2-6 (every 28 days) for total of cycles following full intravenous dose at Day 1, Cycle (i.e., cycles in total).. 2.5Recommended Premedication and Prophylactic Medications Premedicate with acetaminophen and an antihistamine before each dose of RITUXAN HYCELA. Premedication with 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)]. 2.6Preparation 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.. PreparationUse 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 20 mL syringe, withdraw the required volume from the vial with narrow (e.g., 25-30 gauge) needle of any length.Label the syringe with the provided peel-off label.Change the needle to 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 clear to opalescent and colorless to yellowish liquid. Do not use if particulates or discoloration is present.. AdministrationInject 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 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 minutes.If administration of RITUXAN HYCELA is interrupted, continue administering at the same site, or at 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 administer other medications for subcutaneous use at the same sites as RITUXAN HYCELA.. 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 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 minutes.. StorageUse immediately.If not used immediately store refrigerated at 2C to 8C (36F to 46F) up to 48 hours and subsequently for hours at room temperature up to 30C (86F) in diffuse light.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. RITUXAN HYCELA is colorless to yellowish, clear to opalescent solution for subcutaneous injection: Injection: 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL (120 mg/2,000 Units per mL) in single-dose vial.Injection: 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL (120 mg/2,000 Units per mL) in single-dose vial.. Injection: 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL (120 mg/2,000 Units per mL) in single-dose vial.. Injection: 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL (120 mg/2,000 Units per mL) in single-dose vial.. Injection: (3)1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL (120 mg/2,000 Units per mL) solution in single-dose vial1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL (120 mg/2,000 Units per mL) solution in single-dose vial. 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL (120 mg/2,000 Units per mL) solution in single-dose vial. 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL (120 mg/2,000 Units per mL) solution in single-dose vial.

DRUG INTERACTIONS SECTION.

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

FEMALES & MALES OF REPRODUCTIVE POTENTIAL SECTION.

8.3 Females and Males of Reproductive Potential. Rituximab-containing products can cause fetal harm [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating RITUXAN HYCELA.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of rituximab-containing products, including RITUXAN HYCELA.

GERIATRIC USE SECTION.

8.5 Geriatric Use. Of the total number of subjects in the SABRINA, MabEase, and SAWYER studies, 37% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. RITUXAN HYCELA (rituximab and hyaluronidase human) injection, for subcutaneous use is supplied as sterile preservative-free liquid solution in single-dose vial. The following configurations are available:Individually packaged single-dose vials:RITUXAN HYCELA 1,400 mg/23,400 Units (NDC 50242-108-01) providing 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mLRITUXAN HYCELA 1,600 mg/26,800 Units (NDC 50242-109-01) providing 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL. RITUXAN HYCELA 1,400 mg/23,400 Units (NDC 50242-108-01) providing 1,400 mg rituximab and 23,400 Units hyaluronidase human per 11.7 mL. RITUXAN HYCELA 1,600 mg/26,800 Units (NDC 50242-109-01) providing 1,600 mg rituximab and 26,800 Units hyaluronidase human per 13.4 mL. StorageStore RITUXAN HYCELA vials in the refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light. Do not freeze.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. RITUXAN HYCELA is combination of rituximab, 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 single agentPreviously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapyNon-progressing (including stable disease), follicular lymphoma as 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 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). Follicular Lymphoma (FL) (1.1)Relapsed or refractory, follicular lymphoma as single agentPreviously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapyNon-progressing (including stable disease), follicular lymphoma as single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy Relapsed or refractory, follicular lymphoma as single agent. Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), follicular lymphoma as 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 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) Previously untreated and previously treated CLL in combination with fludarabine and cyclophosphamide (FC). Initiate treatment with RITUXAN HYCELA only after patients have received at least one full dose of 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). 1.1Follicular Lymphoma (FL). RITUXAN HYCELA is indicated for the treatment of adult patients with:Relapsed or refractory, follicular lymphoma as single agent.Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.Non-progressing (including stable disease), follicular lymphoma as single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.. Relapsed or refractory, follicular lymphoma as single agent.. Previously untreated follicular lymphoma in combination with first line chemotherapy and, in patients achieving complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy.. Non-progressing (including stable disease), follicular lymphoma as single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.. 1.2Diffuse 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.. 1.3Chronic 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.. 1.4Limitations of Use Initiate treatment with RITUXAN HYCELA only after patients have received at least one full dose of 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.. Initiate treatment with RITUXAN HYCELA only after patients have received at least one full dose of 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.

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Medication Guide). Severe Mucocutaneous Reactions Advise patients to contact their healthcare provider immediately for symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the lips or mouth, blisters, peeling skin, rash, and pustules [see Warnings and Precautions (5.1)]. Hepatitis Virus Reactivation Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.2)]. Progressive Multifocal Leukoencephalopathy (PML)Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, decreased strength or weakness on one side of the body, or vision problems [see Warnings and Precautions (5.3)]. Hypersensitivity and Other Administration Reactions Inform patients about the signs and symptoms of hypersensitivity and administration-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of administration-related reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, urticaria, angioedema, breathing problems, or chest pain [see Warnings and Precautions (5.4)].. Tumor Lysis Syndrome (TLS) Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea, and lethargy [see Warnings and Precautions (5.5)]. Infections Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or headache, dysuria, cold sores, and painful wounds with erythema [see Warnings and Precautions (5.6)] Cardiovascular Adverse Reactions Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report chest pain and irregular heartbeats. [see Warnings and Precautions (5.7)] Renal Toxicity Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor kidney function [see Warnings and Precautions (5.8)]. Bowel Obstruction and Perforation Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction and perforation, including severe abdominal pain or repeated vomiting [see Warnings and Precautions (5.9)]. Embryo-Fetal Toxicity Advise pregnant women of the potential risk to fetus. Advise femalesof reproductive potential to inform their healthcare provider of known or suspected pregnancy [see Warnings and Precautions (5.11), Use in Specific Populations (8.1, 8.3)]. Advise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of of rituximab-containing products, including RITUXAN HYCELA [see Use in Specific Populations (8.3)].. Lactation Advise women not to breastfeed during treatment with RITUXAN HYCELA and for months after the last dose [see Use in Specific Populations (8.2)].

LACTATION SECTION.

8.2 Lactation. There are no data on the presence of hyaluronidase human in human milk or the effect of rituximab on milk production, and there is limited data on the effect of rituximab on the breastfed child. However, rituximab is detected in the milk of lactating cynomolgus monkeys and maternal IgG is present in human breast milk. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with RITUXAN HYCELA and for months after the last dose due to the potential for serious adverse reactions in breastfed children.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Rituximab is monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab mediates B-cell lysis. Possible mechanisms of cell lysis include complement dependent cytotoxicity (CDC) and antibody dependent cell mediated cytotoxicity (ADCC). Hyaluronan is polysaccharide found in the extracellular matrix of the subcutaneous tissue. It is depolymerized by the naturally occurring enzyme hyaluronidase. Unlike the stable structural components of the interstitial matrix, hyaluronan has half-life of approximately 0.5 days. Hyaluronidase human increases permeability of the subcutaneous tissue by temporarily depolymerizing hyaluronan. In the doses administered, hyaluronidase human in RITUXAN HYCELA acts locally.The effects of hyaluronidase human are reversible and permeability of the subcutaneous tissue is restored within 24 to 48 hours.Hyaluronidase human has been shown to increase the absorption rate of rituximab product into the systemic circulation when given in the subcutis of Gottingen Minipigs.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. No long term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN HYCELA or rituximab, or to determine potential effects on fertility in males or females. RITUXAN HYCELA contains hyaluronidase human. Hyaluronidases are found in most tissues of the body. Long-term animal studies have not been performed to assess the carcinogenic or mutagenic potential of hyaluronidase human. In addition, when hyaluronidase human was administered to cynomolgus monkeys for 39 weeks at dose levels up to 220,000 U/kg, which is 90 times higher than the human dose, no evidence of toxicity to the male or female reproductive system was found through periodic monitoring of in-life parameters, e.g., semen analyses, hormone levels, menstrual cycles, and also from gross pathology, histopathology and organ weight data.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 11.7 mL Vial Carton. Rx onlyNDC 50242-108-01Rituxan Hycela(R) (rituximab and hyaluronidase human) Injection1,400 mg and 23,400 Units/11.7 mL (120 mg and 2,000 Units/mL)For Subcutaneous Use Only. Give the subcutaneous injection over to minutes.Single-Dose Vial. Discard Unused Portion.Attention Pharmacist: Dispense the accompanying Medication Guide to each patient.1 vialGenentech Biogen(R) 10214985. PRINCIPAL DISPLAY PANEL 11.7 mL Vial Carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of RITUXAN HYCELA in pediatric patients have not been established.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Peripheral B-cell counts declined to levels below normal following dose of rituximab by intravenous infusion. In patients treated with rituximab for hematological malignancies, cell recovery began within months of treatment and generally returned to normal levels within 12 months after completion of therapy, although in some patients this may take longer.. Follicular Lymphoma (FL)Peripheral B-cell counts decline to levels below normal following the first cycle of rituximab and are maintained during treatment with RITUXAN HYCELA. After stopping RITUXAN HYCELA treatment, B-cell repletion followed similar kinetics to that of rituximab with B-cell repletion beginning after months of stopping treatment, although in some patients this may take longer.. Chronic Lymphocytic Leukemia (CLL) Following the first cycle of treatment of rituximab, B-cells begin to deplete, with 28% of patients B-cell depleted at pre-dose Cycle in the SAWYER study. An increase in the proportion of B-cell depleted patients was observed with subsequent cycles of RITUXAN HYCELA and by Cycle 6, 96% of patients were depleted. Patients remained B-cell depleted until the month follow-up visit, where signs of repletion were seen.

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The geometric mean rituximab exposures are provided in Table 4. The pharmacokinetic properties of rituximab following the administration of RITUXAN HYCELA in the approved indications are provided in Table 5. The elimination of rituximab was characterized by time-dependent process that occurred early in therapy and time-independent process.Table 4:Rituximab Exposure Values following Subcutaneous Administration of RITUXAN HYCELAPharmacokinetic parameters are presented as geometric mean unless otherwise specified. StudyFor study design information, see Clinical Studies (14). CycleRituximab FLRITUXAN HYCELA 1,400 mg/23,400 Units (1,400 mg rituximab and 23,400 Units hyaluronidase human) Cmax, mcg/mL (CV%)SABRINA7237 (29.4)18156 (24.7)Based on predicted values Ctrough, mcg/mL (CV%)7122.2 (55.3)1845.5 (53.6) AUCTAU, mcgday/mL (CV%)73779 (33.7)185000 (34.3) CLLRITUXAN HYCELA 1,600 mg/26,800 Units (1,600 mg rituximab and 26,800 Units hyaluronidase human) Cmax, mcg/mL (CV%)SAWYER6202 (36.1)Ctrough, mcg/mL (CV%)597.5 (42.6)AUCTAU, mcgday/mL (CV%)54088 (34.2)In the SABRINA study, the geometric mean Ctrough in the RITUXAN HYCELA arm was higher than in the rituximab arm with geometric mean ratio (Ctrough, RITUXAN HYCELA/Ctrough, rituximab) of 1.52 (90% CI: 1.36, 1.70) at Cycle [see Clinical Studies (14.1)].In the SAWYER study, the geometric mean Ctrough in the RITUXAN HYCELA arm was higher than in the rituximab arm with an adjusted geometric mean ratio of 1.53 (90% CI: 1.27-1.85) at Cycle [see Clinical Studies (14.3)].Table 5:Pharmacokinetic Parameters of Rituximab following Subcutaneous Administration of RITUXAN HYCELAParameters represented as geometric mean (%CV) unless otherwise specified FLCLLAbsorption Absolute BioavailabilityCompared to rituximab product administered intravenously 0.646 (0.634-0.65995% CI)0.634 (0.602-0.665) Distribution Volume of Central compartment (L)4.06 (26)4.80 (18) Apparent Volume of Distribution at steady stateVolume of central compartment and peripheral compartment (L)8.09 (19)8.52 (13)Elimination Terminal Half-life (days)34.1 (27)32 (24) Clearance (L/day)0.18 (34)0.204 (31). Specific PopulationsThe pharmacokinetics of rituximab and hyaluronidase human in children and adolescents is unknown. The effect of either renal or hepatic impairment on the pharmacokinetics of rituximab and hyaluronidase human is unknown.. Drug Interaction StudiesThe drug interaction potential of rituximab and hyaluronidase human is unknown.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryBased on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero (see Clinical Considerations). There are no available data on RITUXAN HYCELA use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, intravenous administration of rituximab product to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following dose of grams in humans. Reduced fetal weight and increased fetal lethality were observed following subcutaneous administration of hyaluronidase human in mice at dose 2700 times higher than the human dose. Comparable systemic exposure levels could occur in pregnant patient following accidental intravenous administration of an entire vial of RITUXAN HYCELA (see Data). Advise pregnant women of the potential risk to fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsObserve newborns and infants for signs of infection and manage accordingly. Data. Human DataPostmarketing data indicate that B-cell lymphocytopenia generally lasting less than months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero.. Animal DataRITUXAN HYCELA for subcutaneous injection contains rituximab and hyaluronidase human [see Description (11)]. Rituximab Product: An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following dose of grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue cells.A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of cells and immune function in infants exposed to rituximab in utero. Animals were treated with loading dose of 0, 15, or 75 mg/kg every day for days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within months postpartum. An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following dose of grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue cells.. subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of cells and immune function in infants exposed to rituximab in utero. Animals were treated with loading dose of 0, 15, or 75 mg/kg every day for days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within months postpartum. Hyaluronidase Human: In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase human at dose levels up to 2,200,000 U/kg, which is 2700 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is 450 times higher than the human dose. In peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase human from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is 1,300 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring. In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase human at dose levels up to 2,200,000 U/kg, which is 2700 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is 450 times higher than the human dose. In peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase human from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is 1,300 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration, Preparation and Administration (2.6)06/2021.

SPL MEDGUIDE SECTION.

This Medication Guide has been approved by the U.S. Food and Drug AdministrationRevised: 6/2021MEDICATION GUIDERITUXAN HYCELA(R) [rih-TUKS-an hye-SELL-uh](rituximab and hyaluronidase human)injectionWhat is the most important information should know about RITUXAN HYCELARITUXAN HYCELA can cause serious side effects that can lead to death, including:Severe skin and mouth reactions. Tell your healthcare provider or get medical help right away if you get any of these symptoms at any time during your treatment with RITUXAN HYCELA:painful sores or ulcers on your skin, lips or in your mouth blisterspeeling skinrashpustules Hepatitis virus (HBV) reactivation. Before you receive RITUXAN HYCELA, your doctor will do blood tests to check for HBV infection. If you have had hepatitis or are carrier of hepatitis virus, receiving RITUXAN HYCELA could cause the virus to become an active infection again. Hepatitis reactivation may cause serious liver problems including liver failure, and death. Your healthcare provider will monitor you for hepatitis infection during and for several months after you stop receiving RITUXAN HYCELA.Tell your healthcare provider right away if you get worsening tiredness, or yellowing of your skin or white part of your eyes during treatment with RITUXAN HYCELA.Progressive Multifocal Leukoencephalopathy (PML). PML is rare, serious brain infection caused by virus that can happen in people who receive RITUXAN HYCELA. People with weakened immune systems can get PML. PML can result in death or severe disability. There is no known treatment, prevention, or cure for PML.Tell your healthcare provider right away if you have any new or worsening symptoms or if anyone close to you notices these symptoms:confusion dizziness or loss of balancedifficulty walking or talkingdecreased strength or weakness on one side of your bodyvision problems, such as blurred vision or loss of vision Serious allergic reactions and other severe reactions.Serious allergic reactions, and reactions due to release of certain substances by your body that can lead to death, can happen with rituximab products, including RITUXAN HYCELA.Skin reactions at or near the injection site (local), including injection site reactions, can happen with RITUXAN HYCELA. Symptoms at or near the injection site may include: pain, swelling, hardness, redness, bleeding, itching, and rash. These reactions sometimes happen more than 24 hours after an injection of RITUXAN HYCELA.Tell your healthcare provider or get medical help right away if you get any of these symptoms during or after an injection of RITUXAN HYCELA: hives (red itchy welts) or rashitchingswelling of your lips, tongue, throat or facesudden coughshortness of breath, difficulty breathing, or wheezingweaknessdizziness or feel faintpalpitations (feel like your heart is racing or fluttering)chest painfeverchills or shaking chillsSee What are the possible side effects of RITUXAN HYCELA for more information about side effects.What is RITUXAN HYCELARITUXAN HYCELA is prescription medicine used to treat adults with:Follicular Lymphoma (FL): alone or with certain chemotherapy medicines. Diffuse Large B-Cell Lymphoma (DLBCL): with certain other chemotherapy medicines in people who have not had previous treatment for their DLBCL.Chronic Lymphocytic Leukemia (CLL): with the chemotherapy medicines fludarabine and cyclophosphamide.You can only receive RITUXAN HYCELA after you receive at least full dose of rituximab product by IV infusion. Read the rituximab by IV infusion Medication Guide for more information about severe infusion reactions, which usually happen during the first dose with rituximab product given by IV infusion.RITUXAN HYCELA is not for use to treat medical conditions other than cancers.It is not known if RITUXAN HYCELA is safe and effective in children.Before you receive RITUXAN HYCELA, tell your healthcare provider about all of your medical conditions, including if you:have had severe reaction to rituximab product or RITUXAN HYCELA have history of heart problems, irregular heart beat or chest painhave lung or kidney problemshave an infection or weakened immune systemhave or have had any severe infections including:Hepatitis virus (HBV)Hepatitis virus (HCV)Cytomegalovirus (CMV)Herpes simplex virus (HSV)Parvovirus B19Varicella zoster virus (chickenpox or shingles)West Nile Virus have had recent vaccination or are scheduled to receive vaccinations. You should not receive certain vaccines before or during treatment with RITUXAN HYCELA. are pregnant or plan to become pregnant. RITUXAN HYCELA may harm your unborn baby.Females who are able to become pregnant: Your healthcare provider should check to see if you are pregnant before you receive RITUXAN HYCELA.You should use effective birth control (contraception) during treatment with RITUXAN HYCELA and for 12 months after the last dose of RITUXAN HYCELA. Talk to your healthcare provider about effective birth control.Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with RITUXAN HYCELA. are breastfeeding or plan to breastfeed. RITUXAN HYCELA may pass into your breast milk. Do not breastfeed during treatment and for months after your last dose of RITUXAN HYCELA.Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive RITUXAN HYCELARITUXAN HYCELA is given as an injection under the skin, in the stomach-area (abdomen). RITUXAN HYCELA is injected over or minutes. Your healthcare provider will prescribe medicines before the injection of RITUXAN HYCELA to help reduce side effects such as fever and chills.Your healthcare provider should monitor you for side effects for at least 15 minutes after you receive an injection of RITUXAN HYCELA.If you have CLL, your healthcare provider should prescribe medicines to help prevent certain infections during treatment and for up to 12 months following treatment with RITUXAN HYCELA.Before each injection of RITUXAN HYCELA treatment, your healthcare provider or nurse will ask you questions about your general health. Tell your healthcare provider or nurse about any new symptoms.What are possible side effects of RITUXAN HYCELARITUXAN HYCELA can cause serious side effects, including:See What is the most important information should know about RITUXAN HYCELATumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause you to have:kidney failure and the need for dialysis treatmentabnormal heart rhythmTLS can happen within 12 to 24 hours after an injection of RITUXAN HYCELA. Your healthcare provider may do blood tests to check you for TLS. Your healthcare provider may give you medicine to help prevent TLS. Tell your healthcare provider right away if you have any of the following signs or symptoms of TLS:nauseavomitingdiarrhealack of energySerious infections. Serious infections can happen during and after treatment with RITUXAN HYCELA, and can lead to death. Rituximab products can increase your risk of getting infections and can lower the ability of your immune system to fight infections. Types of serious infections that can happen with RITUXAN HYCELA include bacterial, fungal, and viral infections. After receiving RITUXAN HYCELA, some people have developed low levels of certain antibodies in their blood for long period of time (longer than 11 months). Some of these people with low antibody levels developed infections. Tell your healthcare provider right away if you have any symptoms of infection:fevercold symptoms, such as runny nose or sore throat that do not go awayflu symptoms, such as cough, tiredness, and body achesearache or headachepain during urinationwhite patches in the mouth or throatcuts, scrapes or incisions that are red, warm, swollen or painful Heart problems. RITUXAN HYCELA may cause chest pain, irregular heartbeats, and heart attack. Your healthcare provider may monitor your heart during and after treatment with RITUXAN HYCELA if you have symptoms of heart problems or have history of heart problems. Tell your healthcare provider right away if you have chest pain or irregular heartbeats during treatment with RITUXAN HYCELA.Kidney problems RITUXAN HYCELA can cause severe kidney problems that can lead to death. Your healthcare provider should do blood tests to check how well your kidneys are working.Stomach and serious bowel problems that can sometimes lead to death. Bowel problems, including blockage or tears in the bowel, can happen if you receive RITUXAN HYCELA with chemotherapy medicines. Tell your healthcare provider right away if you have severe stomach-area (abdomen) pain or repeated vomiting during treatment with RITUXAN HYCELA.Your healthcare provider will stop treatment with RITUXAN HYCELA if you have severe, serious or life-threatening side effects.The most common side effects of RITUXAN HYCELA in people with Follicular Lymphoma (FL) include: infections, low white blood cell count, nausea, constipation, cough, and tiredness. The most common side effects of RITUXAN HYCELA in people with Diffuse Large B-cell Lymphoma (DLBCL) include: infections, low white blood cell count, loss of hair, nausea, and low red blood cell count. The most common side effects of RITUXAN HYCELA in people with Chronic Lymphocytic Leukemia (CLL) include: infections, low white blood cell count, nausea, low platelet count, fever, vomiting, and injection site redness.These are not all of the possible side effects with RITUXAN HYCELA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.General information about the safe and effective use of RITUXAN HYCELA.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your pharmacist or healthcare provider for information about RITUXAN HYCELA that is written for health professionals.What are the ingredients in RITUXAN HYCELAActive ingredient: rituximab and hyaluronidase human.Inactive ingredients: L-histidine, L-histidine hydrochloride monohydrate, L-methionine, polysorbate 80, ,-trehalose dihydrate, and Water for Injection.Manufactured by: Genentech, Inc., Member of the Roche Group, DNA Way, South San Francisco, CA 94080-4990U.S. License No.: 1048Jointly marketed by: Biogen and Genentech USA, Inc.RITUXAN HYCELA(R) is registered trademark of Biogen.(C)2021 Biogen and Genentech USA, Inc.For more information, go to www.RITUXANHYCELA.com or call 1-877-436-3683.Representative sample of labeling (see the HOW SUPPLIED section for complete listing):. Severe skin and mouth reactions. Tell your healthcare provider or get medical help right away if you get any of these symptoms at any time during your treatment with RITUXAN HYCELA:painful sores or ulcers on your skin, lips or in your mouth blisterspeeling skinrashpustules painful sores or ulcers on your skin, lips or in your mouth blisters. peeling skin. rash. pustules. Hepatitis virus (HBV) reactivation. Before you receive RITUXAN HYCELA, your doctor will do blood tests to check for HBV infection. If you have had hepatitis or are carrier of hepatitis virus, receiving RITUXAN HYCELA could cause the virus to become an active infection again. Hepatitis reactivation may cause serious liver problems including liver failure, and death. Your healthcare provider will monitor you for hepatitis infection during and for several months after you stop receiving RITUXAN HYCELA.Tell your healthcare provider right away if you get worsening tiredness, or yellowing of your skin or white part of your eyes during treatment with RITUXAN HYCELA.. Progressive Multifocal Leukoencephalopathy (PML). PML is rare, serious brain infection caused by virus that can happen in people who receive RITUXAN HYCELA. People with weakened immune systems can get PML. PML can result in death or severe disability. There is no known treatment, prevention, or cure for PML.Tell your healthcare provider right away if you have any new or worsening symptoms or if anyone close to you notices these symptoms:confusion dizziness or loss of balancedifficulty walking or talkingdecreased strength or weakness on one side of your bodyvision problems, such as blurred vision or loss of vision confusion dizziness or loss of balance. difficulty walking or talking. decreased strength or weakness on one side of your body. vision problems, such as blurred vision or loss of vision. Serious allergic reactions and other severe reactions.Serious allergic reactions, and reactions due to release of certain substances by your body that can lead to death, can happen with rituximab products, including RITUXAN HYCELA.Skin reactions at or near the injection site (local), including injection site reactions, can happen with RITUXAN HYCELA. Symptoms at or near the injection site may include: pain, swelling, hardness, redness, bleeding, itching, and rash. These reactions sometimes happen more than 24 hours after an injection of RITUXAN HYCELA.Tell your healthcare provider or get medical help right away if you get any of these symptoms during or after an injection of RITUXAN HYCELA:. hives (red itchy welts) or rash. itching. swelling of your lips, tongue, throat or face. sudden cough. shortness of breath, difficulty breathing, or wheezing. weakness. dizziness or feel faint. palpitations (feel like your heart is racing or fluttering). chest pain. fever. chills or shaking chills. Follicular Lymphoma (FL): alone or with certain chemotherapy medicines. Diffuse Large B-Cell Lymphoma (DLBCL): with certain other chemotherapy medicines in people who have not had previous treatment for their DLBCL.. Chronic Lymphocytic Leukemia (CLL): with the chemotherapy medicines fludarabine and cyclophosphamide.. have had severe reaction to rituximab product or RITUXAN HYCELA have history of heart problems, irregular heart beat or chest pain. have lung or kidney problems. have an infection or weakened immune system. have or have had any severe infections including:Hepatitis virus (HBV)Hepatitis virus (HCV)Cytomegalovirus (CMV)Herpes simplex virus (HSV)Parvovirus B19Varicella zoster virus (chickenpox or shingles)West Nile Virus Hepatitis virus (HBV). Hepatitis virus (HCV). Cytomegalovirus (CMV). Herpes simplex virus (HSV). Parvovirus B19. Varicella zoster virus (chickenpox or shingles). West Nile Virus. have had recent vaccination or are scheduled to receive vaccinations. You should not receive certain vaccines before or during treatment with RITUXAN HYCELA. are pregnant or plan to become pregnant. RITUXAN HYCELA may harm your unborn baby.Females who are able to become pregnant: Your healthcare provider should check to see if you are pregnant before you receive RITUXAN HYCELA.You should use effective birth control (contraception) during treatment with RITUXAN HYCELA and for 12 months after the last dose of RITUXAN HYCELA. Talk to your healthcare provider about effective birth control.Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with RITUXAN HYCELA. Your healthcare provider should check to see if you are pregnant before you receive RITUXAN HYCELA.. You should use effective birth control (contraception) during treatment with RITUXAN HYCELA and for 12 months after the last dose of RITUXAN HYCELA. Talk to your healthcare provider about effective birth control.. Tell your healthcare provider if you become pregnant or think you may be pregnant during treatment with RITUXAN HYCELA.. are breastfeeding or plan to breastfeed. RITUXAN HYCELA may pass into your breast milk. Do not breastfeed during treatment and for months after your last dose of RITUXAN HYCELA.. RITUXAN HYCELA is given as an injection under the skin, in the stomach-area (abdomen). RITUXAN HYCELA is injected over or minutes. Your healthcare provider will prescribe medicines before the injection of RITUXAN HYCELA to help reduce side effects such as fever and chills.. Your healthcare provider should monitor you for side effects for at least 15 minutes after you receive an injection of RITUXAN HYCELA.. If you have CLL, your healthcare provider should prescribe medicines to help prevent certain infections during treatment and for up to 12 months following treatment with RITUXAN HYCELA.. See What is the most important information should know about RITUXAN HYCELA. Tumor Lysis Syndrome (TLS). TLS is caused by the fast breakdown of cancer cells. TLS can cause you to have:kidney failure and the need for dialysis treatmentabnormal heart rhythmTLS can happen within 12 to 24 hours after an injection of RITUXAN HYCELA. Your healthcare provider may do blood tests to check you for TLS. Your healthcare provider may give you medicine to help prevent TLS. Tell your healthcare provider right away if you have any of the following signs or symptoms of TLS:. kidney failure and the need for dialysis treatment. abnormal heart rhythm. nausea. vomiting. diarrhea. lack of energy. Serious infections. Serious infections can happen during and after treatment with RITUXAN HYCELA, and can lead to death. Rituximab products can increase your risk of getting infections and can lower the ability of your immune system to fight infections. Types of serious infections that can happen with RITUXAN HYCELA include bacterial, fungal, and viral infections. After receiving RITUXAN HYCELA, some people have developed low levels of certain antibodies in their blood for long period of time (longer than 11 months). Some of these people with low antibody levels developed infections. Tell your healthcare provider right away if you have any symptoms of infection:fevercold symptoms, such as runny nose or sore throat that do not go awayflu symptoms, such as cough, tiredness, and body achesearache or headachepain during urinationwhite patches in the mouth or throatcuts, scrapes or incisions that are red, warm, swollen or painful fever. cold symptoms, such as runny nose or sore throat that do not go away. flu symptoms, such as cough, tiredness, and body aches. earache or headache. pain during urination. white patches in the mouth or throat. cuts, scrapes or incisions that are red, warm, swollen or painful. Heart problems. RITUXAN HYCELA may cause chest pain, irregular heartbeats, and heart attack. Your healthcare provider may monitor your heart during and after treatment with RITUXAN HYCELA if you have symptoms of heart problems or have history of heart problems. Tell your healthcare provider right away if you have chest pain or irregular heartbeats during treatment with RITUXAN HYCELA.. Kidney problems RITUXAN HYCELA can cause severe kidney problems that can lead to death. Your healthcare provider should do blood tests to check how well your kidneys are working.. Stomach and serious bowel problems that can sometimes lead to death. Bowel problems, including blockage or tears in the bowel, can happen if you receive RITUXAN HYCELA with chemotherapy medicines. Tell your healthcare provider right away if you have severe stomach-area (abdomen) pain or repeated vomiting during treatment with RITUXAN HYCELA.

SPL UNCLASSIFIED SECTION.

Severe Mucocutaneous ReactionsSevere, including fatal, mucocutaneous reactions can occur in patients receiving rituximab-containing products, including RITUXAN HYCELA [see Warnings and Precautions (5.1)].

STORAGE AND HANDLING SECTION.

StorageStore RITUXAN HYCELA vials in the refrigerator at 2C to 8C (36F to 46F) in the original carton to protect from light. Do not freeze.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise not to breastfeed. (8.2). Lactation: Advise not to breastfeed. (8.2). 8.1 Pregnancy. Risk SummaryBased on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero (see Clinical Considerations). There are no available data on RITUXAN HYCELA use in pregnant women to inform drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, intravenous administration of rituximab product to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following dose of grams in humans. Reduced fetal weight and increased fetal lethality were observed following subcutaneous administration of hyaluronidase human in mice at dose 2700 times higher than the human dose. Comparable systemic exposure levels could occur in pregnant patient following accidental intravenous administration of an entire vial of RITUXAN HYCELA (see Data). Advise pregnant women of the potential risk to fetus. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. All pregnancies have background risk of birth defect, loss, or other adverse outcomes. The estimated background risk in the U.S. general population of major birth defects is 2%-4% and of miscarriage is 15%-20% of clinically recognized pregnancies.. Clinical Considerations. Fetal/Neonatal Adverse ReactionsObserve newborns and infants for signs of infection and manage accordingly. Data. Human DataPostmarketing data indicate that B-cell lymphocytopenia generally lasting less than months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero.. Animal DataRITUXAN HYCELA for subcutaneous injection contains rituximab and hyaluronidase human [see Description (11)]. Rituximab Product: An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following dose of grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue cells.A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of cells and immune function in infants exposed to rituximab in utero. Animals were treated with loading dose of 0, 15, or 75 mg/kg every day for days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within months postpartum. An embryo-fetal developmental toxicity study was performed on pregnant cynomolgus monkeys. Pregnant animals received rituximab via the intravenous route during early gestation (organogenesis period; post coitum days 20 through 50). Rituximab was administered as loading doses on post coitum (PC) Days 20, 21 and 22, at 15, 37.5 or 75 mg/kg/day, and then weekly on PC Days 29, 36, 43 and 50, at 20, 50 or 100 mg/kg/week. The 100 mg/kg/week dose resulted in 80% of the exposure (based on AUC) of those achieved following dose of grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue cells.. subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of cells and immune function in infants exposed to rituximab in utero. Animals were treated with loading dose of 0, 15, or 75 mg/kg every day for days, followed by weekly dosing with 0, 20, or 100 mg/kg dose. Subsets of pregnant females were treated from PC Day 20 through postpartum Day 78, PC Day 76 through PC Day 134, and from PC Day 132 through delivery and postpartum Day 28. Regardless of the timing of treatment, decreased cells and immunosuppression were noted in the offspring of rituximab-treated pregnant animals. The B-cell counts returned to normal levels, and immunologic function was restored within months postpartum. Hyaluronidase Human: In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase human at dose levels up to 2,200,000 U/kg, which is 2700 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is 450 times higher than the human dose. In peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase human from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is 1,300 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring. In an embryo-fetal study, mice have been dosed daily by subcutaneous injection during the period of organogenesis with hyaluronidase human at dose levels up to 2,200,000 U/kg, which is 2700 times higher than the human dose. The study found no evidence of teratogenicity. Reduced fetal weight and increased numbers of fetal resorptions were observed, with no effects found at daily dose of 360,000 U/kg, which is 450 times higher than the human dose. In peri-and post-natal reproduction study, mice have been dosed daily by subcutaneous injection, with hyaluronidase human from implantation through lactation and weaning at dose levels up to 1,100,000 U/kg, which is 1,300 times higher than the human dose. The study found no adverse effects on sexual maturation, learning and memory or fertility of the offspring. 8.2 Lactation. There are no data on the presence of hyaluronidase human in human milk or the effect of rituximab on milk production, and there is limited data on the effect of rituximab on the breastfed child. However, rituximab is detected in the milk of lactating cynomolgus monkeys and maternal IgG is present in human breast milk. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with RITUXAN HYCELA and for months after the last dose due to the potential for serious adverse reactions in breastfed children. 8.3 Females and Males of Reproductive Potential. Rituximab-containing products can cause fetal harm [see Use in Specific Populations (8.1)]. Pregnancy TestingVerify pregnancy status in females of reproductive potential prior to initiating RITUXAN HYCELA.. Contraception. FemalesAdvise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of rituximab-containing products, including RITUXAN HYCELA. 8.4 Pediatric Use. The safety and effectiveness of RITUXAN HYCELA in pediatric patients have not been established.. 8.5 Geriatric Use. Of the total number of subjects in the SABRINA, MabEase, and SAWYER studies, 37% were 65 and over, while 10% were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

WARNINGS AND PRECAUTIONS SECTION.

5 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 fetus and use of effective contraception. (5.11). 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 fetus and use of effective contraception. (5.11). 5.1Severe 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 severe mucocutaneous reaction. The safety of re-administration of rituximab-containing product, including RITUXAN HYCELA, to patients with severe mucocutaneous reactions has not been determined. 5.2Hepatitis Virus Reactivation. Hepatitis 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 rapid increase in serum HBV DNA levels or detection of HBsAg in 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 rituximab-containing product. For patients who show evidence of prior hepatitis infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis regarding monitoring and consideration for HBV antiviral therapy before and/or during treatment with 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.. 5.3Progressive 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 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)].. 5.4Hypersensitivity and other Administration Reactions. Systemic ReactionsPatients must receive at least one full dose of 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 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 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 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 history of pulmonary insufficiency or those with pulmonary tumor infiltration may be at 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 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/mm3) [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. longer period may be appropriate in patients with an increased risk of hypersensitivity reactions. Local Cutaneous ReactionsLocal 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.. 5.5Tumor Lysis Syndrome (TLS). TLS can occur within 12-24 hours after administration of rituximab-containing product, including RITUXAN HYCELA. high number of circulating malignant cells (>= 25,000/mm3) or high tumor burden confers greater risk of TLS. Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated [see Warnings and Precautions (5.8)].. 5.6Infections. Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of therapy with rituximab-containing products, including RITUXAN HYCELA. The incidence of infections with RITUXAN HYCELA vs rituximab was 56% and 49% respectively in patients with CLL, and 46% and 41% respectively in patients with FL/DLBCL in combination with chemotherapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia 11 months after rituximab exposure). New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis and C. Discontinue RITUXAN HYCELA for serious infections and institute appropriate anti-infective therapy [see Adverse Reactions (6.1)].. 5.7Cardiovascular Adverse Reactions. Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur with rituximab-containing products, including RITUXAN HYCELA. Discontinue RITUXAN HYCELA for serious or life threatening cardiac arrhythmias. Perform cardiac monitoring during and after all administrations of RITUXAN HYCELA for patients who develop clinically significant arrhythmias, or who have history of arrhythmia or angina [see Adverse Reactions (6.1)].. 5.8Renal Toxicity. Severe, including fatal, renal toxicity can occur after administration of rituximab-containing products, including RITUXAN HYCELA. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN HYCELA is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RITUXAN HYCELA in patients with rising serum creatinine or oliguria [see Warnings and Precautions (5.5)].. 5.9Bowel Obstruction and Perforation. Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab-containing products, including RITUXAN HYCELA, in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was (range 1-77) days. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur. 5.10Immunization. The safety of immunization with live viral vaccines following rituximab-containing products, including RITUXAN HYCELA, therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.. 5.11Embryo-Fetal Toxicity. Based on human data, rituximab-containing products can cause fetal harm due to B-cell lymphocytopenia in infants exposed to rituximab in-utero. Advise pregnant women of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment with RITUXAN HYCELA and for 12 months after the last dose of rituximab-containing products, including RITUXAN HYCELA [see Use in Specific Populations (8.1, 8.3)].