Rituximab

RITUXAN is a CD20-directed cytolytic antibody indicated for the treatment of: Adult patients with Non-Hodgkin's Lymphoma (NHL) ( 1.1 ). Relapsed or refractory, low grade or follicular, CD20-positive B-cell NHL as a single agent. Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. Previously untreated diffuse large B-cell, CD20-positive NHL in combination with (cyclophosphamide, doxorubicin, vincristine, and prednisone) (CHOP) or other anthracycline-based chemotherapy regimens. Pediatric patients aged 6 months and older with mature B-cell NHL and mature B-cell acute leukemia (B-AL) ( 1.1 ) Previously untreated, advanced stage, CD20-positive, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy. Adult patients with Chronic Lymphocytic Leukemia (CLL) ( 1.2 ). Previously untreated and previously treated CD20-positive CLL in combination with fludarabine and cyclophosphamide (FC). Rheumatoid Arthritis (RA) in combination with methotrexate in adult patients with moderately-to severely-active RA who have inadequate response to one or more TNF antagonist therapies ( 1.3 ). Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) in adult and pediatric patients 2 years of age and older in combination with glucocorticoids ( 1.4 ). Moderate to severe Pemphigus Vulgaris (PV) in adult patients ( 1.5 ).

1.1 Non–Hodgkin's Lymphoma (NHL) RITUXAN is indicated for the treatment of adult patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent. Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy. Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy. Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens. RITUXAN is indicated for the treatment of pediatric patients aged 6 months and older with: Previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy.

1.2 Chronic Lymphocytic Leukemia (CLL) RITUXAN, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL.

1.3 Rheumatoid Arthritis (RA) RITUXAN, in combination with methotrexate, is indicated for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

1.4 Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) RITUXAN, in combination with glucocorticoids, is indicated for the treatment of adult and pediatric patients 2 years of age and older with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).

1.5 Pemphigus Vulgaris (PV) RITUXAN is indicated for the treatment of adult patients with moderate to severe pemphigus vulgaris.

Injection: RITUXAN is a colorless, clear solution for intravenous infusion: 100 mg/10 mL (10 mg/mL) in a single-dose vial 500 mg/50 mL (10 mg/mL) in a single-dose vial Injection: 100 mg/10 mL (10 mg/mL) and 500 mg/50 mL (10 mg/mL) solution in single-dose vials ( 3 )

None. None ( 4 )

Tumor lysis syndrome: Administer aggressive intravenous hydration, anti-hyperuricemic agents, monitor renal function ( 5.5 ). Infections: Withhold RITUXAN and institute appropriate anti-infective therapy ( 5.6 ). Cardiac adverse reactions: Discontinue infusions 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 RITUXAN treatment not recommended ( 5.10 ). Embryo-Fetal toxicity: Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and use of effective contraception ( 5.11 ).

5.1 Infusion-Related Reactions RITUXAN can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. RITUXAN-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA, GPA and MPA, and PV patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. For pediatric patients with mature B-cell NHL/B-AL, administer prednisone as part of chemotherapy regimen prior to RITUXAN during induction and as needed for subsequent cycles [see Dosage and Administration (2.2 and 2.8) ] . Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RITUXAN. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. 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 (greater than or equal to 25,000/mm 3 ) [see Warnings and Precautions (5.7) , Adverse Reactions (6.1) ] .

5.2 Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with RITUXAN. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of RITUXAN exposure. Discontinue RITUXAN in patients who experience a severe mucocutaneous reaction. The safety of re-administration of RITUXAN to patients with severe mucocutaneous reactions has not been determined.

5.3 Hepatitis B Virus (HBV) Reactivation Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including RITUXAN. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive). HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur. Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RITUXAN. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during RITUXAN treatment. 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 therapy. HBV reactivation has been reported up to 24 months following completion of RITUXAN therapy. In patients who develop reactivation of HBV while on RITUXAN, immediately discontinue RITUXAN and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming RITUXAN treatment in patients who develop HBV reactivation. Resumption of RITUXAN treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV.

5.4 Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in RITUXAN-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received RITUXAN in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of RITUXAN. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue RITUXAN and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

5.5 Tumor Lysis Syndrome (TLS) Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12–24 hours after the first infusion of RITUXAN in patients with NHL. A high number of circulating malignant cells ( greater than or equal to 25,000/mm 3 ) or high tumor burden, confers a 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) ] .

5.6 Infections Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of RITUXAN-based therapy. Infections have been reported in some patients with prolonged hypogammaglobulinemia (defined as hypogammaglobulinemia greater than 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 B and C. Discontinue RITUXAN for serious infections and institute appropriate anti-infective therapy [see Adverse Reactions (6.1 , 6.3) ] . RITUXAN is not recommended for use in patients with severe, active infections.

5.7 Cardiovascular Adverse Reactions Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving RITUXAN. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RITUXAN for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina [see Adverse Reactions (6.1) ] . […]

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Infusion-related reactions [see Warnings and Precautions (5.1) ] Severe mucocutaneous reactions [see Warnings and Precautions (5.2) ] Hepatitis B reactivation with fulminant hepatitis [see Warnings and Precautions (5.3) ] Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.4) ] Tumor lysis syndrome [see Warnings and Precautions (5.5) ] Infections [see Warnings and Precautions (5.6) ] Cardiovascular adverse reactions [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 in clinical trials were: NHL (greater than or equal to 25%): infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia ( 6.1 ). Pediatric B-NHL/B-AL with chemotherapy (Grade 3 or higher greater than 15%): febrile neutropenia, stomatitis, enteritis, sepsis, alanine aminotransferase increased and hypokalemia ( 6.1 ). CLL (greater than or equal to 25%): infusion-related reactions and neutropenia ( 6.1 ). RA (greater than or equal to 10%): upper respiratory tract infection, nasopharyngitis, urinary tract infection, and bronchitis (other important adverse reactions include infusion-related reactions, serious infections, and cardiovascular events) ( 6.1 ). GPA and MPA (greater than or equal to 15 %): infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, infusion-related reactions ( 6.1 ). PV (greater than or equal to 15%): infusion-related reactions, depression, upper respiratory tract infection/ nasopharyngitis, headache (other important adverse reactions include infections) ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. B-Cell Malignancies The data described below reflect exposure to RITUXAN in 3092 patients, with exposures ranging from a single infusion up to 2 years. RITUXAN was studied in both single-arm and controlled trials (n=356 and n=2427). The population included 1180 patients with low grade or follicular lymphoma, 927 patients with DLBCL, 676 patients with CLL, and 309 pediatric patients with mature B-cell NHL/B-AL. Most NHL patients received RITUXAN as an infusion of 375 mg/m 2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Pediatric patients received 6 total doses of RITUXAN or a non-U.S. licensed rituximab in combination with chemotherapy. CLL patients received RITUXAN 375 mg/m 2 as an initial infusion followed by 500 mg/m 2 for up to 5 doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of RITUXAN-based therapy. The most common adverse reactions of RITUXAN (incidence greater than or equal to 25%) observed in clinical trials of patients with NHL were infusion-related reactions, fever, lymphopenia, chills, infection, and asthenia. The most common adverse reactions of RITUXAN (incidence greater than or equal to 25%) observed in clinical trials of patients with CLL were: infusion-related reactions and neutropenia. Infusion-Related Reactions In the majority of patients with NHL, infusion-related reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first RITUXAN infusion. Infusion-related reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the RITUXAN infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion-related reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [see Warnings and Precautions (5.1) ] . In adult patients with previously untreated follicular NHL or previously untreated DLBCL, who did not experience a Grade 3 or 4 infusion-related reaction in Cycle 1 and received a 90-minute infusion of RITUXAN at Cycle 2, the incidence of Grade 3-4 infusion reactions on the day of, or day after the infusion was 1.1% (95% CI [0.3%, 2.8%]). For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions on the day of or day after the 90-minute infusion, was 2.8% (95% CI [1.3%, 5.0%]). In pediatric patients, the incidence of grade 3 infusion reactions was 3.4% with the first infusion and 1% for subsequent infusions. One patient experienced a grade 4 infusion reaction with the fifth infusion. [see Warnings and Precautions (5.1) , Clinical Studies (14.4) ] . Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [see Warnings and Precautions (5.6) ] . In randomized, controlled studies where RITUXAN was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received RITUXAN. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received RITUXAN. In pediatric patients with mature B-cell NHL/B-AL, the rate of serious infections was higher, with an incidence of 32%, in those receiving RITUXAN or a non-U.S. licensed rituximab with chemotherapy. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following RITUXAN therapy occurred during the single-arm studies. In studies of monotherapy, RITUXAN-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. In CLL trials, the frequency of prolonged neutropenia and late-onset neutropenia was higher in patients treated with R-FC compared to patients treated with FC. Prolonged neutropenia is defined as Grade 3-4 neutropenia that has not resolved between 24 and 42 days after the last dose of study treatment. Late-onset neutropenia is defined as Grade 3-4 neutropenia starting at least 42 days after the last treatment dose. In patients with previously untreated CLL, the frequency of prolonged neutropenia was 8.5% for patients who received R-FC (n=402) and 5.8% for patients who received FC (n=398). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 14.8% of 209 patients who received R-FC and 4.3% of 230 patients who received FC. For patients with previously treated CLL, the frequency of prolonged neutropenia was 24.8% for patients who received R-FC (n=274) and 19.1% for patients who received FC (n=274). In patients who did not have prolonged neutropenia, the frequency of late-onset neutropenia was 38.7% in 160 patients who received R-FC and 13.6% of 147 patients who received FC. […]

Formal drug interaction studies have not been performed with RITUXAN. In patients with CLL, RITUXAN did not alter systemic exposure to fludarabine or cyclophosphamide. In clinical trials of patients with RA, concomitant administration of methotrexate or cyclophosphamide did not alter the pharmacokinetics of rituximab. Renal toxicity when used in combination with cisplatin ( 5.8 ).

Lactation: Advise not to breastfeed ( 8.2 ). Geriatric Use: In CLL patients older than 70 years of age, exploratory analyses suggest no benefit with the addition of RITUXAN to FC ( 8.5 ).

8.1 Pregnancy Risk Summary Based on human data, RITUXAN can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to RITUXAN in-utero ( see Clinical Considerations ). In animal reproduction studies, intravenous administration of rituximab to pregnant cynomolgus monkeys during the period of organogenesis caused lymphoid B-cell depletion in the newborn offspring at doses resulting in 80% of the exposure (based on AUC) of those achieved following a dose of 2 grams in humans. Advise pregnant women of the risk to a fetus. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated populations is unknown. 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 Reactions Observe newborns and infants for signs of infection and manage accordingly. Data Human data Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Animal Data 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 a dose of 2 grams in humans. Rituximab crosses the monkey placenta. Exposed offspring did not exhibit any teratogenic effects but did have decreased lymphoid tissue B cells. A subsequent pre-and postnatal reproductive toxicity study in cynomolgus monkeys was completed to assess developmental effects including the recovery of B cells and immune function in infants exposed to rituximab in utero. Animals were treated with a loading dose of 0, 15, or 75 mg/kg every day for 3 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 B 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 6 months postpartum.

8.2 Lactation There are limited data on the presence of rituximab in human milk and the effect on the breastfed child, and there are no data on the effect on milk production. 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 and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.

8.3 Females and Males of Reproductive Potential RITUXAN can cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating RITUXAN. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with RITUXAN and for 12 months after the last dose.

8.4 Pediatric Use Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) RITUXAN is indicated for the treatment of GPA and MPA in pediatric patients 2 years of age and older with GPA and MPA. RITUXAN is not indicated in pediatric patients less than 2 years of age with GPA or MPA. The use of RITUXAN for the treatment of pediatric patients with GPA and MPA 6 years of age and older is supported by evidence from adequate and well-controlled studies of RITUXAN in adults with GPA and MPA; a trial in pediatric patients 6 years of age and older with active GPA and MPA; and population pharmacokinetic (PK) analyses showing similar drug exposure levels in adults and pediatric patients 6 years to 17 years of age. The use of RITUXAN for the treatment of pediatric patients with GPA and MPA ages 2 to less than 6 years of age is supported by PK modeling in patients 2 years of age and older and safety data from pediatric patients less than 6 years of age treated with rituximab. The pediatric trial was a multicenter, open-label, single arm study (GPA/MPA Study 4) to evaluate the safety, PK and exploratory efficacy of RITUXAN or non-U.S.-licensed rituximab in 25 pediatric patients (6 patients 6 years to less than 12 years of age and 19 patients 12 years to 17 years of age) with active GPA and MPA over a 6-month remission induction phase and minimum 12-month follow-up phase, up to 54 months [see Adverse Reactions (6.1) , Clinical Pharmacology (12.3) , and Clinical Studies (14.7) ]. Mature B-Cell NHL/B-AL The safety and effectiveness of RITUXAN in combination with chemotherapy for the treatment of previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL have been established in pediatric patients aged 6 months and older. Use of RITUXAN for this indication is supported by evidence from an adequate and well-controlled study in pediatric patients aged 1 year and older on the basis that the course of advanced disease is expected to be similar between pediatric patients aged 6 months to less than 1 year to that of pediatric patients aged 1 year and older to allow extrapolation of data to younger pediatric patients and use pharmacokinetic modeling [see Clinical Pharmacology (12.3) , Clinical Studies (14.2) ] . Patients younger than 3 years had a higher incidence of infections compared to patients 3 years and older [see Adverse Reactions (6.1) ] . The safety and effectiveness of RITUXAN in combination with chemotherapy for previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL have not been established in pediatric patients less than 6 months of age. The safety and effectiveness of RITUXAN have not been established in pediatric patients with CLL. Rheumatoid Arthritis and Pemphigus Vulgaris The safety and effectiveness of RITUXAN have not been established in pediatric patients with PV or RA. RITUXAN was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion in the developing juvenile immune system.

8.5 Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received RITUXAN in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or greater. No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions, mostly supraventricular arrhythmias, occurred more frequently among elderly patients. Serious pulmonary adverse reactions were also more common among the elderly, including pneumonia and pneumonitis. […]

Rituximab is a 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). B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or proinflammatory cytokine production.