DailyMed Label: Riabni

DailyMed Label: Riabni

2024

DailyMed Prescription

Riabni

rituximab-arrx

Amgen Inc

NDC: 55513-224

NDC: 55513-224

NDC: 55513-326

NDC: 55513-326

Rituximab-arrx is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab-arrx has an approximate molecular weight of 145 kD. Rituximab-arrx is produced in a mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium. RIABNI (rituximab-arrx) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to slightly yellow solution for intravenous infusion. RIABNI is supplied at a concentration of 10 mg/mL in either 100 mg/10 mL or 500 mg/50 mL single-dose vials. Each mL of solution contains 10 mg rituximab-arrx, polysorbate 80 (0.7 mg), sodium chloride (9 mg), sodium citrate dihydrate (7.35 mg), and Water for Injection, USP. Hydrochloric acid is used to adjust the buffer solution pH. The pH is 6.5.

RIABNI 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. 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 patients in combination with glucocorticoids ( 1.3 ). RIABNI 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. RIABNI, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL. RIABNI, 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. RIABNI, in combination with glucocorticoids, is indicated for the treatment of adult patients with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).

Administer only as an intravenous infusion ( 2.1 ). Do not administer as an intravenous push or bolus ( 2.1 ). RIABNI should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur ( 2.1 ). The dose for adult B-cell NHL is 375 mg/m 2 ( 2.2 ). The dose for CLL is 375 mg/m 2 in the first cycle and 500 mg/m 2 in cycles 2–6, in combination with FC, administered every 28 days ( 2.3 ). The dose as a component of Zevalin ® (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m 2 ( 2.4 ). The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion ( 2.5 ). The induction dose for adult patients with active GPA and MPA in combination with glucocorticoids is 375 mg/m 2 once weekly for 4 weeks. The follow up dose for adult patients with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation ( 2.6 ). Administer only as an intravenous infusion [see Dosage and Administration (2.7) ] . Do not administer as an intravenous push or bolus. RIABNI should only be administered by a healthcare professional with appropriate medical support to manage severe infusion-related reactions that can be fatal if they occur [see Warnings and Precautions (5.1) ]. Premedicate before each infusion [see Dosage and Administration (2.7) ] . Prior to First Infusion Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RIABNI [see Warnings and Precautions (5.3) ] . Obtain complete blood counts (CBC) including platelets prior to the first dose. During RIABNI Therapy In patients with lymphoid malignancies during treatment with RIABNI monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RIABNI course. During treatment with RIABNI and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias [see Adverse Reactions (6.1) ]. In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at two to four month intervals during RIABNI therapy. Continue to monitor for cytopenias after final dose and until resolution. First Infusion : Standard Infusion : Initiate infusion at a rate of 50 mg/hour. In the absence of infusion toxicity, increase infusion rate by 50 mg/hour increments every 30 minutes, to a maximum of 400 mg/hour. Subsequent Infusions: Standard Infusion: Initiate infusion at a rate of 100 mg/hour. In the absence of infusion toxicity, increase rate by 100 mg/hour increments at 30-minute intervals, to a maximum of 400 mg/hour. For Previously Untreated Follicular NHL and DLBCL Adult Patients: If patients did not experience a Grade 3 or 4 infusion-related adverse event during Cycle 1, a 90-minute infusion can be administered in Cycle 2 with a glucocorticoid-containing chemotherapy regimen. Initiate at a rate of 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes. If the 90-minute infusion is tolerated in Cycle 2, the same rate can be used when administering the remainder of the treatment regimen (through Cycle 6 or 8). Patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count greater than or equal to 5,000/mm 3 before Cycle 2 should not be administered the 90-minute infusion [see Clinical Studies (14.4) ] . Interrupt the infusion or slow the infusion rate for infusion-related reactions [see Boxed Warning , Warnings and Precautions (5.1) ]. Continue the infusion at one-half the previous rate upon improvement of symptoms. The recommended dose is 375 mg/m 2 as an intravenous infusion according to the following schedules: Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 or 8 doses. Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL Administer once weekly for 4 doses. Previously Untreated, Follicular, CD20-Positive, B-Cell NHL Administer on Day 1 of each cycle of chemotherapy, for up to 8 doses. In patients with complete or partial response, initiate RIABNI maintenance eight weeks following completion of a rituximab product in combination with chemotherapy. Administer RIABNI as a single-agent every 8 weeks for 12 doses. Non-progressing, Low-Grade, CD20-Positive, B-Cell NHL, after first-line CVP chemotherapy Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses. Diffuse Large B-Cell NHL Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions. The recommended dose is 375 mg/m 2 the day prior to the initiation of FC chemotherapy, then 500 mg/m 2 on Day 1 of cycles 2–6 (every 28 days). When used as part of the Zevalin therapeutic regimen, infuse 250 mg/m 2 in accordance with the Zevalin package insert. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen. Administer RIABNI as two-1,000 mg intravenous infusions separated by 2 weeks. Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion-related reactions. Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. RIABNI is given in combination with methotrexate. Induction Treatment of Adult Patients with Active GPA/MPA Administer RIABNI as a 375 mg/m 2 intravenous infusion once weekly for 4 weeks for patients with active GPA or MPA. Glucocorticoids administered as methylprednisolone 1,000 mg intravenously per day for 1 to 3 days followed by oral prednisone as per clinical practice. This regimen should begin within 14 days prior to or with the initiation of RIABNI and may continue during and after the 4 week induction course of RIABNI treatment. Follow up Treatment of Adult Patients with GPA/MPA who have Achieved Disease Control with Induction Treatment Administer RIABNI as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion every 6 months thereafter based on clinical evaluation. If induction treatment of active disease was with a rituximab product, initiate follow up treatment with RIABNI within 24 weeks after the last induction infusion with a rituximab product or based on clinical evaluation, but no sooner than 16 weeks after the last induction infusion with a rituximab product. If induction treatment of active disease was with other standard of care immunosuppressants, initiate RIABNI follow up treatment within the 4 week period that follows achievement of disease control. Premedicate with acetaminophen and an antihistamine before each infusion of RIABNI. For adult patients administered RIABNI according to the 90-minute infusion rate, the glucocorticoid component of their chemotherapy regimen should be administered prior to infusion [see Clinical Studies (14.4) ] . For RA, GPA, and MPA patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. Provide prophylaxis treatment for Pneumocystis jirovecii 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) ] . PCP prophylaxis is also recommended for patients with GPA and MPA during treatment and for at least 6 months following the last RIABNI infusion. Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. RIABNI should be a clear to slightly opalescent, colorless to slightly yellow liquid. Do not use vial if particulates or discoloration is present. Administration Use a sterile needle and syringe to prepare RIABNI. Withdraw the necessary amount of RIABNI and dilute to a final concentration of 1 mg/mL to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride Injection, USP, or 5% Dextrose Injection, USP. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial. Storage If not used immediately, store diluted RIABNI solutions as shown in Table 1. Table 1. Diluted RIABNI Solution Storage Conditions Diluent Used to Prepare Solution for Infusion Diluted RIABNI Solution Storage Conditions 0.9% Sodium Chloride Injection, USP Store RIABNI solution diluted in 0.9% Sodium Chloride Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 7 days after preparation and protect from light. 5% Dextrose Injection, USP Store RIABNI solution diluted in 5% Dextrose Injection, USP refrigerated at 2°C to 8°C (36°F to 46°F) for up to 24 hours after preparation. No incompatibilities between RIABNI and polyvinylchloride or polyethylene bags have been observed.

Injection: 100 mg/10 mL (10 mg/mL) and 500 mg/50 mL (10 mg/mL) as a clear to slightly opalescent, colorless to slightly yellow solution 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 RIABNI 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 RIABNI treatment is 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 ). Rituximab products can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituximab product-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 patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. 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 RIABNI. 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) ] . Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with rituximab products. 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 rituximab exposure. Discontinue RIABNI in patients who experience a severe mucocutaneous reaction. The safety of re-administration of rituximab products to patients with severe mucocutaneous reactions has not been determined. Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including rituximab products. 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 RIABNI. 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 RIABNI 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 RIABNI therapy. HBV reactivation has been reported up to 24 months following completion of rituximab therapy. In patients who develop reactivation of HBV while on RIABNI, immediately discontinue RIABNI and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming RIABNI treatment in patients who develop HBV reactivation. Resumption of RIABNI treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV. JC virus infection resulting in PML and death can occur in rituximab product-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received rituximab 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 rituximab. 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 RIABNI and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12–24 hours after the first infusion of rituximab products 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) ] . Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-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 RIABNI for serious infections and institute appropriate anti-infective therapy [see Adverse Reactions (6.1 , 6.3) ] . RIABNI is not recommended for use in patients with severe, active infections. Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving rituximab products. Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of RIABNI for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina [see Adverse Reactions (6.1) ] . Severe, including fatal, renal toxicity can occur after rituximab product administration in patients with NHL. Renal toxicity has occurred in patients who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RIABNI is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue RIABNI in patients with a rising serum creatinine or oliguria [see Warnings and Precautions (5.5) ] . Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving rituximab products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur. The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment. For patients treated with RIABNI, physicians should review the patient's vaccination status and patients should, if possible, be brought up-to-date with all immunizations in agreement with current immunization guidelines prior to initiating RIABNI and administer non-live vaccines at least 4 weeks prior to a course of RIABNI. The effect of rituximab on immune responses was assessed in a randomized, controlled study in patients with RA treated with rituximab and methotrexate (MTX) compared to patients treated with MTX alone. A response to pneumococcal vaccination (a T-cell independent antigen) as measured by an increase in antibody titers to at least 6 of 12 serotypes was lower in patients treated with rituximab plus MTX as compared to patients treated with MTX alone (19% vs. 61%). A lower proportion of patients in the rituximab plus MTX group developed detectable levels of anti-keyhole limpet hemocyanin antibodies (a novel protein antigen) after vaccination compared to patients on MTX alone (47% vs. 93%). A positive response to tetanus toxoid vaccine (a T-cell dependent antigen with existing immunity) was similar in patients treated with rituximab plus MTX compared to patients on MTX alone (39% vs. 42%). The proportion of patients maintaining a positive Candida skin test (to evaluate delayed type hypersensitivity) was also similar (77% of patients on rituximab plus MTX vs. 70% of patients on MTX alone). Most patients in the rituximab-treated group had B-cell counts below the lower limit of normal at the time of immunization. The clinical implications of these findings are not known. Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed in utero . Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving RIABNI and for 12 months after the last dose [see Use in Specific Populations (8.1 , 8.3) ] . Limited data are available on the safety of the use of biologic agents or disease modifying antirheumatic drugs (DMARDs) other than methotrexate in RA patients exhibiting peripheral B-cell depletion following treatment with rituximab. Observe patients closely for signs of infection if biologic agents and/or DMARDs are used concomitantly. Use of concomitant immunosuppressants other than corticosteroids has not been studied in GPA or MPA patients exhibiting peripheral B-cell depletion following treatment with rituximab products. While the efficacy of rituximab was supported in four controlled trials in patients with RA with prior inadequate responses to non-biologic DMARDs, and in a controlled trial in MTX-naïve patients, a favorable risk-benefit relationship has not been established in these populations. The use of RIABNI in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended [see Clinical Studies (14.6) ] .

The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:

Formal drug interaction studies have not been performed with rituximab products. In patients with CLL, rituximab 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 rituximab to FC ( 8.5 ). Risk Summary Based on human data, rituximab products can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed 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 6 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. 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 RIABNI and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children. Rituximab products 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 RIABNI. Contraception Females Advise females of reproductive potential to use effective contraception during treatment with RIABNI and for 12 months after the last dose. A pediatric assessment for RIABNI demonstrates that RIABNI is safe and effective for pediatric patients in an indication for which Rituxan (rituximab) is approved. However, RIABNI is not approved for such indication due to marketing exclusivity for Rituxan (rituximab). The safety and effectiveness of rituximab products, including RIABNI, have not been established in pediatric patients less than 2 years of age for GPA and MPA. The safety and effectiveness of rituximab products, including RIABNI, have not been established in pediatric patients with CLL. Rheumatoid Arthritis The safety and effectiveness of rituximab products have not been established in pediatric patients with RA. Rituximab 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. Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, active-controlled trials, 927 patients received rituximab 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. Low-Grade or Follicular Non-Hodgkin's Lymphoma Patients with previously untreated follicular NHL evaluated in NHL Study 5 were randomized to rituximab as single-agent maintenance therapy (n = 505) or observation (n = 513) after achieving a response to rituximab in combination with chemotherapy. Of these, 123 (24%) patients in the rituximab arm were age 65 or older. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other clinical studies of rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. Chronic Lymphocytic Leukemia Among patients with CLL evaluated in two randomized active-controlled trials, 243 of 676 rituximab-treated patients (36%) were 65 years of age or older; of these, 100 rituximab-treated patients (15%) were 70 years of age or older. In exploratory analyses defined by age, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in CLL Study 1 or in CLL Study 2; there was also no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in CLL Study 2 [see Clinical Studies (14.5) ] . Patients 70 years or older received lower dose intensity of fludarabine and cyclophosphamide compared to younger patients, regardless of the addition of rituximab. In CLL Study 1, the dose intensity of rituximab was similar in older and younger patients, however in CLL Study 2 older patients received a lower dose intensity of rituximab. The incidence of Grade 3 and 4 adverse reactions was higher among patients receiving R-FC who were 70 years or older compared to younger patients for neutropenia [44% vs. 31% (CLL Study 1); 56% vs. 39% (CLL Study 2)], febrile neutropenia [16% vs. 6% (NHL Study 10 (NCT00719472)], anemia [5% vs. 2% (CLL Study 1); 21% vs. 10% (CLL Study 2)], thrombocytopenia [19% vs. 8% (CLL Study 2)], pancytopenia [7% vs. 2% (CLL Study 1); 7% vs. 2% (CLL Study 2)] and infections [30% vs. 14% (CLL Study 2)]. Rheumatoid Arthritis Among the 2,578 patients in global RA studies completed to date, 12% were 65–75 years old and 2% were 75 years old and older. The incidences of adverse reactions were similar between older and younger patients. The rates of serious adverse reactions, including serious infections, malignancies, and cardiovascular events were higher in older patients. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis Of the 99 rituximab-treated GPA and MPA patients in GPA/MPA Study 1, 36 (36%) were 65 years old and over, while 8 (8%) were 75 years and over. No overall differences in efficacy were observed between patients that were 65 years old and over and younger patients. The overall incidence and rate of all serious adverse events was higher in patients 65 years old and over. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. In GPA/MPA Study 2, 30 (26%) of the enrolled patients were at least 65 years old, of which 12 patients were exposed to non-U.S.-licensed rituximab and 18 were exposed to azathioprine. The clinical study did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects.

RIABNI (rituximab-arrx) injection is a sterile, clear to slightly opalescent, colorless to slightly yellow preservative free solution for intravenous use supplied as a carton containing one 100 mg/10 mL (10 mg/mL) single dose vial (NDC 55513-224-01) and a carton containing one 500 mg/50 mL (10 mg/mL) single dose vial (NDC 55513-326-01). Store RIABNI vials refrigerated at 2°C to 8°C (36°F to 46°F). Protect RIABNI vials from direct sunlight. Do not freeze or shake.

Rituximab-arrx is a monoclonal antibody. Rituximab products target the CD20 antigen expressed on the surface of pre-B and mature B-lymphocytes. Upon binding to CD20, rituximab products mediate 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. Non-Hodgkin's Lymphoma (NHL) In NHL patients, administration of rituximab resulted in depletion of circulating and tissue-based B cells. Among 166 patients in NHL Study 1 (NCT000168740), circulating CD19-positive B cells were depleted within the first three weeks with sustained depletion for up to 6 to 9 months post treatment in 83% of patients. B-cell recovery began at approximately 6 months and median B-cell levels returned to normal by 12 months following completion of treatment. There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following rituximab administration; 14% of patients had IgM and/or IgG serum levels below the normal range. Rheumatoid Arthritis In RA patients, treatment with rituximab induced depletion of peripheral B lymphocytes, with the majority of patients demonstrating near complete depletion (CD19 counts below the lower limit of quantification, 20 cells/µL) within 2 weeks after receiving the first dose of rituximab. The majority of patients showed peripheral B-cell depletion for at least 6 months. A small proportion of patients (~4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment. Total serum immunoglobulin levels, IgM, IgG, and IgA were reduced at 6 months with the greatest change observed in IgM. At Week 24 of the first course of rituximab treatment, small proportions of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). In the experience with rituximab in RA patients during repeated rituximab treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving rituximab, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with rituximab are unclear. Treatment with rituximab in patients with RA was associated with reduction of certain biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis In GPA and MPA patients in GPA/MPA Study 1, peripheral blood CD19 B-cells depleted to less than 10 cells/µL following the first two infusions of rituximab, and remained at that level in most (84%) patients through Month 6. By Month 12, the majority of patients (81%) showed signs of B-cell return with counts greater than 10 cells/µL. By Month 18, most patients (87%) had counts greater than 10 cells/µL. In GPA/MPA Study 2 where patients received non-U.S.-licensed rituximab as two 500 mg intravenous infusions separated by two weeks, followed by a 500 mg intravenous infusion at Month 6, 12, and 18, 70% (30 out of 43) of the rituximab-treated patients with CD19+ peripheral B cells evaluated post-baseline had undetectable CD19+ peripheral B cells at Month 24. At Month 24, all 37 patients with evaluable baseline CD19+ peripheral B cells and Month 24 measurements had lower CD19+ B cells relative to baseline. Non-Hodgkin's Lymphoma (NHL) Pharmacokinetics were characterized in 203 NHL patients receiving 375 mg/m 2 rituximab weekly by intravenous infusion for 4 doses. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment. The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m 2 in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone. Based on a population pharmacokinetic analysis of data from 298 NHL patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half-life was 22 days (range, 6.1 to 52 days). Patients with higher CD19-positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance. However, dose adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender had no effect on the pharmacokinetics of rituximab. Pharmacokinetics were characterized in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14 to 62 days). Rheumatoid Arthritis Following administration of 2 doses of rituximab in patients with RA, the mean (± S.D.; % CV) concentrations after the first infusion (C max first) and second infusion (C max second) were 157 (± 46; 29%) and 183 (± 55; 30%) mcg/mL, and 318 (± 86; 27%) and 381 (± 98; 26%) mcg/mL for the 2 × 500 mg and 2 × 1,000 mg doses, respectively. Based on a population pharmacokinetic analysis of data from 2,005 RA patients who received rituximab, the estimated clearance of rituximab was 0.335 L/day; volume of distribution was 3.1 L and mean terminal elimination half-life was 18.0 days (range, 5.17 to 77.5 days). Age, weight and gender had no effect on the pharmacokinetics of rituximab in RA patients. Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis The pharmacokinetic parameters in adult patients with GPA/MPA receiving 375 mg/m 2 intravenous rituximab or non-U.S.-licensed rituximab once weekly for four doses are summarized in Table 5. Table 5. Population PK in Adult Patients with GPA/MPA Parameter Statistic GPA/MPA Study 1 N Number of Patients 97 Terminal Half-life (days) Median (Range) 25 (11 to 52) AUC 0-180d (µg/mL*day) Median (Range) 10,302 (3,653 to 21,874) Clearance (L/day) Median (Range) 0.279 (0.113 to 0.653) Volume of Distribution (L) Median (Range) 3.12 (2.42 to 3.91) The population PK analysis in adults with GPA and MPA showed that male patients and patients with higher BSA or positive anti-rituximab antibody levels have higher clearance. However, further dose adjustment based on gender or anti-drug antibody status is not necessary. Specific Populations The clearance and volume of distribution of rituximab increased with increasing body surface area (BSA). No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of rituximab products. Drug Interaction Studies Formal drug interaction studies have not been performed with rituximab products.

No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of rituximab products or to determine potential effects on fertility in males or females.

The safety and effectiveness of rituximab in relapsed, refractory CD20+ NHL were demonstrated in 3 single-arm studies enrolling 296 patients. NHL Study 1 A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m 2 of rituximab given as an intravenous infusion weekly for 4 doses. Patients with tumor masses > 10 cm or with > 5,000 lymphocytes/µL in the peripheral blood were excluded from the study. Results are summarized in Table 6. The median time to onset of response was 50 days. Disease-related signs and symptoms (including B-symptoms) resolved in 64% (25/39) of those patients with such symptoms at study entry. NHL Study 2 In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m 2 of rituximab weekly for 8 doses. Results are summarized in Table 6. NHL Study 3 In a multicenter, single-arm study, 60 patients received 375 mg/m 2 of rituximab weekly for 4 doses. All patients had relapsed or refractory, low-grade or follicular, B-cell NHL and had achieved an objective clinical response to rituximab administered 3.8–35.6 months (median 14.5 months) prior to retreatment with rituximab. Of these 60 patients, 5 received more than one additional course of rituximab. Results are summarized in Table 6. Bulky Disease In pooled data from studies 1 and 3, 39 patients with bulky (single lesion > 10 cm in diameter) and relapsed or refractory, low-grade NHL received rituximab 375 mg/m 2 weekly for 4 doses. Results are summarized in Table 6. Table 6. Summary of Rituximab Efficacy Data in NHL by Schedule and Clinical Setting Study 1 Weekly × N = 166 Study 2 Weekly × 8 N = 37 Study 1 and Study 3 Bulky disease, Weekly × 4 N = 39 Six of these patients are included in the first column. Thus, data from 296 intent-to-treat patients are provided in this table. Study 3 Retreatment, Weekly × 4 N = 60 Overall Response Rate 48% 57% 36% 38% Complete Response Rate 6% 14% 3% 10% Median Duration of Response Kaplan-Meier projected with observed range. , "+" indicates an ongoing response. , Duration of response: interval from the onset of response to disease progression. 11.2 13.4 6.9 15.0 (Months) [Range] [1.9 to 42.1+] [2.5 to 36.5+] [2.8 to 25.0+] [3.0 to 25.1+] The safety and effectiveness of rituximab in previously untreated, low-grade or follicular, CD20+ NHL were demonstrated in 3 randomized, controlled trials enrolling 1,662 patients. NHL Study 4 A total of 322 patients with previously untreated follicular NHL were randomized (1:1) to receive up to eight 3-week cycles of CVP chemotherapy alone (CVP) or in combination with rituximab 375 mg/m 2 on Day 1 of each cycle (R-CVP) in an open-label, multicenter study. The main outcome measure of the study was progression-free survival (PFS) defined as the time from randomization to the first of progression, relapse, or death. Twenty-six percent of the study population was > 60 years of age, 99% had Stage III or IV disease, and 50% had an International Prognostic Index (IPI) score greater than or equal to 2. The results for PFS as determined by a blinded, independent assessment of progression are presented in Table 7. The point estimates may be influenced by the presence of informative censoring. The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment. Table 7. Efficacy Results in NHL Study 4 Study Arm R-CVP N = 162 CVP N = 160 Median PFS (years) p less than 0.0001, two-sided stratified log-rank test. 2.4 1.4 Hazard ratio (95% CI) Estimates of Cox regression stratified by center. 0.44 (0.29, 0.65) NHL Study 5 An open-label, multicenter, randomized (1:1) study was conducted in 1,018 patients with previously untreated follicular NHL who achieved a response (CR or PR) to rituximab in combination with chemotherapy. Patients were randomized to rituximab as single-agent maintenance therapy, 375 mg/m 2 every 8 weeks for up to 12 doses or to observation. Rituximab was initiated at 8 weeks following completion of chemotherapy. The main outcome measure of the study was progression-free survival (PFS), defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death, as determined by independent review. Of the randomized patients, 40% were greater than or equal to 60 years of age, 70% had Stage IV disease, 96% had ECOG performance status (PS) 0–1, and 42% had FLIPI scores of 3–5. Prior to randomization to maintenance therapy, patients had received R-CHOP (75%), R-CVP (22%), or R-FCM (3%); 71% had a complete or unconfirmed complete response and 28% had a partial response. PFS was longer in patients randomized to rituximab as single agent maintenance therapy (HR: 0.54, 95% CI: 0.42, 0.70; see Figure 1 ). The PFS results based on investigator assessment of progression were similar to those obtained by the independent review assessment. Figure 1. Kaplan-Meier Plot of IRC Assessed PFS in NHL Study 5 Figure 1 NHL Study 6 A total of 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of CVP chemotherapy were enrolled in an open-label, multicenter, randomized trial. Patients were randomized (1:1) to receive rituximab, 375 mg/m 2 intravenous infusion, once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome measure of the study was progression-free survival defined as the time from randomization to progression, relapse, or death. Thirty-seven percent of the study population was greater than 60 years of age, 99% had Stage III or IV disease, and 63% had an IPI score greater than or equal to 2. There was a reduction in the risk of progression, relapse, or death (hazard ratio estimate in the range of 0.36 to 0.49) for patients randomized to rituximab as compared to those who received no additional treatment. The safety and effectiveness of rituximab were evaluated in three randomized, active-controlled, open-label, multicenter studies with a collective enrollment of 1,854 patients. Patients with previously untreated diffuse large B-cell NHL received rituximab in combination with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or other anthracycline-based chemotherapy regimens. NHL Study 7 A total of 632 patients age greater than or equal to 60 years with DLBCL (including primary mediastinal B-cell lymphoma) were randomized in a 1:1 ratio to treatment with CHOP or R-CHOP. Patients received 6 or 8 cycles of CHOP, each cycle lasting 21 days. All patients in the R-CHOP arm received 4 doses of rituximab 375 mg/m 2 on Days –7 and –3 (prior to Cycle 1) and 48–72 hours prior to Cycles 3 and 5. Patients who received 8 cycles of CHOP also received rituximab prior to Cycle 7. The main outcome measure of the study was progression-free survival, defined as the time from randomization to the first of progression, relapse, or death. Responding patients underwent a second randomization to receive rituximab or no further therapy. Among all enrolled patients, 62% had centrally confirmed DLBCL histology, 73% had Stage III–IV disease, 56% had IPI scores greater than or equal to 2, 86% had ECOG performance status of < 2, 57% had elevated LDH levels, and 30% had two or more extranodal disease sites involved. Efficacy results are presented in Table 8. These results reflect a statistical approach which allows for an evaluation of rituximab administered in the induction setting that excludes any potential impact of rituximab given after the second randomization. Analysis of results after the second randomization in NHL Study 7 demonstrates that for patients randomized to R-CHOP, additional rituximab exposure beyond induction was not associated with further improvements in progression-free survival or overall survival. NHL Study 8 A total of 399 patients with DLBCL, age greater than or equal to 60 years, were randomized in a 1:1 ratio to receive CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received rituximab 375 mg/m 2 on Day 1 of each cycle. The main outcome measure of the study was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause. Among all enrolled patients, 80% had Stage III or IV disease, 60% of patients had an age-adjusted IPI greater than or equal to 2, 80% had ECOG performance status scores less than 2, 66% had elevated LDH levels, and 52% had extranodal involvement in at least two sites. Efficacy results are presented in Table 8. NHL Study 9 A total of 823 patients with DLBCL, aged 18–60 years, were randomized in a 1:1 ratio to receive an anthracycline-containing chemotherapy regimen alone or in combination with rituximab. The main outcome measure of the study was time to treatment failure, defined as time from randomization to the earliest of progressive disease, failure to achieve a complete response, relapse, or death. Among all enrolled patients, 28% had Stage III–IV disease, 100% had IPI scores of less than or equal to 1, 99% had ECOG performance status of less than 2, 29% had elevated LDH levels, 49% had bulky disease, and 34% had extranodal involvement. Efficacy results are presented in Table 8. Table 8. Efficacy Results in NHL Studies 7, 8, and 9 Study 7 (n = 632) Study 8 (n = 399) Study 9 (n = 823) R-CHOP CHOP R-CHOP CHOP R-Chemo Chemo Main outcome Progression-free survival (years) Event-free survival (years) Time to treatment failure (years) Median of main outcome measure 3.1 1.6 2.9 1.1 NE NE = Not reliably estimable. NE Hazard ratio R-CHOP vs. CHOP. 0.69 Significant at p < 0.05, 2-sided. 0.60 0.45 Overall survival at 2 years Kaplan-Meier estimates. 74% 63% 69% 58% 95% 86% Hazard ratio 0.72 0.68 0.40 In NHL Study 8, overall survival estimates at 5 years were 58% vs. 46% for R-CHOP and CHOP, respectively. In NHL Study 10, a total of 363 patients with previously untreated follicular NHL (n = 113) or DLBCL (n = 250) were evaluated in a prospective, open-label, multi-center, single-arm trial for the safety of 90-minute rituximab infusions. Patients with follicular NHL received rituximab 375 mg/m 2 plus CVP chemotherapy. Patients with DLBCL received rituximab 375 mg/m 2 plus CHOP chemotherapy. Patients with clinically significant cardiovascular disease were excluded from the study. Patients were eligible for a 90-minute infusion at Cycle 2 if they did not experience a Grade 3-4 infusion-related adverse event with Cycle 1 and had a circulating lymphocyte count less than or equal to 5,000/mm 3 before Cycle 2. All patients were pre-medicated with acetaminophen and an antihistamine and received the glucocorticoid component of their chemotherapy prior to rituximab infusion. The main outcome measure was the development of Grade 3-4 infusion-related reactions on the day of, or day after, the 90-minute infusion at Cycle 2 [see Adverse Reactions (6.1) ] . Eligible patients received their Cycle 2 rituximab infusion over 90 minutes as follows: 20% of the total dose given in the first 30 minutes and the remaining 80% of the total dose given over the next 60 minutes [see Dosage and Administration (2.1) ] . Patients who tolerated the 90-minute rituximab infusion at Cycle 2 continued to receive subsequent rituximab infusions at the 90-minute infusion rate for the remainder of the treatment regimen (through Cycle 6 or Cycle 8). The incidence of Grade 3-4 infusion-related reactions at Cycle 2 was 1.1% (95% CI [0.3%, 2.8%]) among all patients, 3.5% (95% CI [1.0%, 8.8%]) for those patients treated with R-CVP, and 0.0% (95% CI [0.0%, 1.5%]) for those patients treated with R-CHOP. For Cycles 2-8, the incidence of Grade 3-4 infusion-related reactions was 2.8% (95% CI [1.3%, 5.0%]). No acute fatal infusion-related reactions were observed. The safety and effectiveness of rituximab were evaluated in two randomized (1:1) multicenter open-label studies comparing FC alone or in combination with rituximab for up to 6 cycles in patients with previously untreated CLL [CLL Study 1 (n = 817)] or previously treated CLL [CLL Study 2 (n = 552)]. Patients received fludarabine 25 mg/m 2 /day and cyclophosphamide 250 mg/m 2 /day on days 1, 2 and 3 of each cycle, with or without rituximab. In both studies, seventy-one percent of CLL patients received 6 cycles and 90% received at least 3 cycles of rituximab-based therapy. In CLL Study 1, 30% of patients were 65 years or older, 31% were Binet stage C, 45% had B symptoms, more than 99% had ECOG performance status (PS) 0–1, 74% were male, and 100% were White. In CLL Study 2, 44% of patients were 65 years or older, 28% had B symptoms, 82% received a prior alkylating drug, 18% received prior fludarabine, 100% had ECOG PS 0–1, 67% were male and 98% were White. The main outcome measure in both studies was progression-free survival (PFS), defined as the time from randomization to progression, relapse, or death, as determined by investigators (CLL Study 1) or an independent review committee (CLL Study 2). The investigator assessed results in CLL Study 2 were supportive of those obtained by the independent review committee. Efficacy results are presented in Table 9. Table 9. Efficacy Results in CLL Studies 1 and 2 Study 1 As defined in 1996 National Cancer Institute Working Group guidelines. (Previously untreated) Study 2 (Previously treated) R-FC N = 408 FC N = 409 R-FC N = 276 FC N = 276 Median PFS (months) 39.8 31.5 26.7 21.7 Hazard ratio (95% CI) 0.56 (0.43, 0.71) 0.76 (0.6, 0.96) P value (Log-Rank test) less than 0.01 0.02 Response rate (95% CI) 86% (82, 89) 73% (68, 77) 54% (48, 60) 45% (37, 51) Across both studies, 243 of 676 rituximab-treated patients (36%) were 65 years of age or older and 100 rituximab-treated patients (15%) were 70 years of age or older. The results of exploratory subset analyses in elderly patients are presented in Table 10. Table 10. Efficacy Results in CLL Studies 1 and 2 in Subgroups Defined by Age From exploratory analyses. Study 1 Study 2 Age subgroup Number of Patients Hazard Ratio for PFS (95% CI) Number of Patients Hazard Ratio for PFS (95% CI) Age less than 65 yrs 572 0.52 (0.39, 0.70) 313 0.61 (0.45, 0.84) Age greater than or equal to 65 yrs 245 0.62 (0.39, 0.99) 233 0.99 (0.70, 1.40) Age less than 70 yrs 736 0.51 (0.39, 0.67) 438 0.67 (0.51, 0.87) Age greater than or equal to 70 yrs 81 1.17 (0.51, 2.66) 108 1.22 (0.73, 2.04) Reducing the Signs and Symptoms: Initial and Re-Treatment Courses The efficacy and safety of rituximab were evaluated in two randomized, double-blind, placebo-controlled studies of adult patients with moderately to severely active RA who had a prior inadequate response to at least one TNF inhibitor. Patients were 18 years of age or older, diagnosed with active RA according to American College of Rheumatology (ACR) criteria, and had at least 8 swollen and 8 tender joints. In RA Study 1 (NCT00468546), patients were randomized to receive either rituximab 2×1,000 mg+MTX or placebo +MTX for 24 weeks. Further courses of rituximab 2×1,000 mg+MTX were administered in an open label extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of rituximab. In addition to the intravenous premedication, glucocorticoids were administered orally on a tapering schedule from baseline through Day 14. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24 of the placebo-controlled period are shown in Table 11. In RA Study 2 (NCT00266227), all patients received the first course of rituximab 2 × 1,000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either rituximab 2 × 1,000 mg + MTX or placebo + MTX, the majority between Weeks 24–28. The proportions of patients achieving ACR 20, 50, and 70 responses at Week 24, before the re-treatment course, and at Week 48, after retreatment, are shown in Table 11. Table 11. ACR Responses in RA Study 1 and RA Study 2 (Percent of Patients) (Modified Intent-to-Treat Population) Inadequate Response to TNF Antagonists Study 1 24 Week Placebo-Controlled (Week 24) Study 2 Placebo-Controlled Retreatment (Week 24 and Week 48)   Response Placebo + MTX n = 201 Rituximab + MTX n = 298 Treatment Difference (Rituximab – Placebo) For RA Study 1, weighted difference stratified by region (US, rest of the world) and Rheumatoid Factor (RF) status (positive greater than 20 IU/mL, negative < 20 IU/mL) at baseline; For RA Study 2, weighted difference stratified by RF status at baseline and greater than or equal to 20% improvement from baseline in both SJC and TJC at Week 24 (Yes/No). (95% CI) Response Placebo + MTX Retreatment n = 157 Rituximab + MTX Retreatment n = 318 Treatment Difference (Rituximab – Placebo) In RA Study 2, all patients received a first course of rituximab 2 × 1,000 mg. Patients who experienced ongoing disease activity were randomized to receive a second course of either rituximab 2 × 1,000 mg + MTX or placebo + MTX at or after Week 24. , Since all patients received a first course of rituximab, no comparison between placebo + MTX and rituximab + MTX is made at Week 24. , (95% CI) ACR20 ACR20 Week 24 18% 51% 33% (26%, 41%) Week 24 48% 45% NA Week 48 45% 54% 11% (2%, 20%) ACR50 ACR50 Week 24 5% 27% 21% (15%, 27%) Week 24 27% 21% NA Week 48 26% 29% 4% (-4%, 13%) ACR70 ACR70 Week 24 1% 12% 11% (7%, 15%) Week 24 11% 8% NA Week 48 13% 14% 1% (-5%, 8%) Improvement was also noted for all components of ACR response following treatment with rituximab, as shown in Table 12. Table 12. Components of ACR Response at Week 24 in RA Study 1 (Modified Intent-to-Treat Population) Inadequate Response to TNF Antagonists Parameter (median) Placebo + MTX (n = 201) Rituximab + MTX (n = 298) Baseline Wk 24 Baseline Wk 24 Tender Joint Count 31.0 27.0 33.0 13.0 Swollen Joint Count 20.0 19.0 21.0 9.5 Physician Global Assessment Visual Analogue Scale: 0 = best, 100 = worst. 71.0 69.0 71.0 36.0 Patient Global Assessment 73.0 68.0 71.0 41.0 Pain 68.0 68.0 67.0 38.5 Disability Index (HAQ) Disability Index of the Health Assessment Questionnaire: 0 = best, 3 = worst. 2.0 1.9 1.9 1.5 CRP (mg/dL) 2.4 2.5 2.6 0.9 The time course of ACR 20 response for RA Study 1 is shown in Figure 2. Although both treatment groups received a brief course of intravenous and oral glucocorticoids, resulting in similar benefits at Week 4, higher ACR 20 responses were observed for the rituximab group by Week 8. A similar proportion of patients achieved these responses through Week 24 after a single course of treatment (2 infusions) with rituximab. Similar patterns were demonstrated for ACR 50 and 70 responses. Figure 2. Percent of Patients Achieving ACR 20 Response by Visit The same patients may not have responded at each time point. RA Study 1 (Inadequate Response to TNF Antagonists) Figure 2 Radiographic Response In RA Study 1, structural joint damage was assessed radiographically and expressed as changes in Genant-modified Total Sharp Score (TSS) and its components, the erosion score (ES) and the joint space narrowing (JSN) score. Rituximab + MTX slowed the progression of structural damage compared to placebo + MTX after 1 year as shown in Table 13. Table 13. Mean Radiographic Change from Baseline to 104 Weeks in RA Study 1 Inadequate Response to TNF Antagonists Parameter Rituximab 2 × 1,000 mg + MTX Patients received up to 2 years of treatment with rituximab + MTX. Placebo + MTX Patients receiving placebo + MTX. Patients receiving placebo + MTX could have received retreatment with rituximab + MTX from Week 16 onward. Treatment Difference (Placebo – Rituximab) 95% CI Change during First Year   TSS 0.66 1.77 1.11 (0.47, 1.75)   ES 0.44 1.19 0.75 (0.32, 1.19)   JSN Score 0.22 0.58 0.36 (0.10, 0.62) Change during Second Year Based on radiographic scoring following 104 weeks of observation.   TSS 0.48 1.04 — —   ES 0.28 0.62 — —   JSN Score 0.20 0.42 — — In RA Study 1 and its open-label extension, 70% of patients initially randomized to rituximab + MTX and 72% of patients initially randomized to placebo + MTX were evaluated radiographically at Year 2. As shown in Table 13, progression of structural damage in rituximab + MTX patients was further reduced in the second year of treatment. Following 2 years of treatment with rituximab + MTX, 57% of patients had no progression of structural damage. During the first year, 60% of rituximab + MTX treated patients had no progression, defined as a change in TSS of zero or less compared to baseline, compared to 46% of placebo + MTX treated patients. In their second year of treatment with rituximab + MTX, more patients had no progression than in the first year (68% vs. 60%), and 87% of the rituximab + MTX treated patients who had no progression in the first year also had no progression in the second year. Lesser Efficacy of 500 Vs. 1,000 mg Treatment Courses for Radiographic Outcomes RA Study 3 (NCT00299104) is a randomized, double-blind, placebo-controlled study which evaluated the effect of placebo + MTX compared to rituximab 2 × 500 mg + MTX and rituximab 2 × 1,000 mg + MTX treatment courses in MTX-naïve RA patients with moderately to severely active disease. Patients received a first course of two infusions of rituximab or placebo on Days 1 and 15. MTX was initiated at 7.5 mg/week and escalated up to 20 mg/week by Week 8 in all three treatment arms. After a minimum of 24 weeks, patients with ongoing disease activity were eligible to receive re-treatment with additional courses of their assigned treatment. After one year of treatment, the proportion of patients achieving ACR 20/50/70 responses were similar in both rituximab dose groups and were higher than in the placebo group. However, with respect to radiographic scores, only the rituximab 1,000 mg treatment group demonstrated a statistically significant reduction in TSS: a change of 0.36 units compared to 1.08 units for the placebo group, a 67% reduction. Physical Function Response RA Study 4 (NCT00299130) is a randomized, double-blind, placebo-controlled study in adult RA patients with moderately to severely active disease with inadequate response to MTX. Patients were randomized to receive an initial course of rituximab 500 mg, rituximab 1,000 mg, or placebo in addition to background MTX. Physical function was assessed at Weeks 24 and 48 using the Health Assessment Questionnaire Disability Index (HAQ-DI). From baseline to Week 24, a greater proportion of rituximab-treated patients had an improvement in HAQ-DI of at least 0.22 (a minimal clinically important difference) and a greater mean HAQ-DI improvement compared to placebo, as shown in Table 14. HAQ-DI results for the rituximab 500 mg treatment group were similar to the rituximab 1,000 mg treatment group; however radiographic responses were not assessed Dosing Precaution in the Radiographic Responses section above). These improvements were maintained at 48 weeks. Table 14. Improvement from Baseline in Health Assessment Questionnaire Disability Index (HAQ-DI) at Week 24 in RA Study 4 Placebo + MTX n = 172 Rituximab 2 × 1,000 mg + MTX n = 170 Treatment Difference (Rituximab – Placebo) Adjusted difference stratified by region (US, rest of the world) and rheumatoid factor (RF) status (positive greater than or equal to 20 IU/mL, negative less than 20 IU/mL) at baseline. (95% CI) Mean Improvement from Baseline 0.19 0.42 0.23 (0.11, 0.34) Percent of patients with "Improved" score (Change from Baseline greater than or equal to MCID) Minimal Clinically Important Difference: MCID for HAQ = 0.22. 48% 58% 11% (0%, 21%) Induction Treatment of Adult Patients with Active Disease (GPA/MPA Study 1) A total of 197 patients with active, severe GPA and MPA (two forms of ANCA Associated Vasculitides) were treated in a randomized, double-blind, active-controlled multicenter, non-inferiority study, conducted in two phases – a 6 month remission induction phase and a 12 month remission maintenance phase. Patients were 15 years of age or older, diagnosed with GPA (75% of patients) or MPA (24% of patients) according to the Chapel Hill Consensus conference criteria (1% of the patients had unknown vasculitis type). All patients had active disease, with a Birmingham Vasculitis Activity Score for Granulomatosis with Polyangiitis (BVAS/GPA) greater than or equal to 3, and their disease was severe, with at least one major item on the BVAS/GPA. Ninety-six (49%) of patients had new disease and 101 (51%) of patients had relapsing disease. Patients in both arms received 1,000 mg of pulse intravenous methylprednisolone per day for 1 to 3 days within 14 days prior to initial infusion. Patients were randomized in a 1:1 ratio to receive either rituximab 375 mg/m 2 once weekly for 4 weeks or oral cyclophosphamide 2 mg/kg daily for 3 to 6 months in the remission induction phase. Patients were pre-medicated with antihistamine and acetaminophen prior to rituximab infusion. Following intravenous corticosteroid administration, all patients received oral prednisone (1 mg/kg/day, not exceeding 80 mg/day) with pre-specified tapering. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The rituximab group did not receive additional therapy to maintain remission. The main outcome measure for both GPA and MPA patients was achievement of complete remission at 6 months defined as a BVAS/GPA of 0, and off glucocorticoid therapy. The pre-specified non-inferiority margin was a treatment difference of 20%. As shown in Table 15, the study demonstrated non-inferiority of rituximab to cyclophosphamide for complete remission at 6 months. Table 15. Percentage of Patients with GPA/ MPA Who Achieved Complete Remission at 6 Months (Intent-to-Treat Population) Rituximab (n = 99) Cyclophosphamide (n = 98) Treatment Difference (Rituximab – Cyclophosphamide) Rate 95.1% CI The 95.1% confidence level reflects an additional 0.001 alpha to account for an interim efficacy analysis. 64% (54%, 73%) 53% (43%, 63%) 11% (-3%, 24%) Non-inferiority was demonstrated because the lower bound was higher than the prespecified non-inferiority margin (-3% greater than -20%). Complete Remission (CR) at 12 and 18 months In the rituximab group, 44% of patients achieved CR at 6 and 12 months, and 38% of patients achieved CR at 6, 12, and 18 months. In patients treated with cyclophosphamide (followed by azathioprine for maintenance of CR), 38% of patients achieved CR at 6 and 12 months, and 31% of patients achieved CR at 6, 12, and 18 months. Retreatment of Flares with Rituximab Based upon investigator judgment, 15 patients received a second course of rituximab therapy for treatment of relapse of disease activity which occurred between 8 and 17 months after the induction treatment course of rituximab. Follow up Treatment of Adult Patients with GPA/MPA who have achieved disease control with other Immunosuppressant (GPA/MPA Study 2) A total of 115 patients (86 with GPA, 24 with MPA, and 5 with renal-limited ANCA-associated vasculitis) in disease remission were randomized to receive azathioprine (58 patients) or non-U.S.-licensed rituximab (57 patients) in this open-label, prospective, multi-center, randomized, active-controlled study. Eligible patients were 21 years and older and had either newly diagnosed (80%) or relapsing disease (20%). A majority of the patients were ANCA-positive. Remission of active disease was achieved using a combination of glucocorticoids and cyclophosphamide. Within a maximum of 1 month after the last cyclophosphamide dose, eligible patients (based on BVAS of 0), were randomized in a 1:1 ratio to receive either non-U.S.-licensed rituximab or azathioprine. The non-U.S.-licensed rituximab was administered as two 500 mg intravenous infusions separated by two weeks (on Day 1 and Day 15) followed by a 500 mg intravenous infusion every 6 months for 18 months. Azathioprine was administered orally at a dose of 2 mg/kg/day for 12 months, then 1.5 mg/kg/day for 6 months, and finally 1 mg/kg/day for 4 months; treatment was discontinued after 22 months. Prednisone treatment was tapered and then kept at a low dose (approximately 5 mg per day) for at least 18 months after randomization. Prednisone dose tapering and the decision to stop prednisone treatment after month 18 were left at the investigator's discretion. Planned follow-up was until month 28 (10 or 6 months, respectively, after the last non-U.S.-licensed rituximab infusion or azathioprine dose). The primary endpoint was the occurrence of major relapse (defined by the reappearance of clinical and/or laboratory signs of vasculitis activity that could lead to organ failure or damage, or could be life threatening) through month 28. By month 28, major relapse occurred in 3 patients (5%) in the non-U.S.-licensed rituximab group and 17 patients (29%) in the azathioprine group. The observed cumulative incidence rate of first major relapse during the 28 months was lower in patients on non-U.S.-licensed rituximab relative to azathioprine (Figure 3). Figure 3. Cumulative Incidence Over Time of First Major Relapse in Patients with GPA/MPA Patients were censored at the last follow-up dates if they had no event. Figure 3

100 mg/10 mL AMGEN ® RIABNI ® (rituximab-arrx) Injection NDC 55513-224-01 Single-dose Vial Discard unused portion. 100 mg/10 mL (10 mg/mL) For Intravenous Infusion After Dilution Store refrigerated at 2°C to 8°C (36°F to 46°F). Protect from direct sunlight. Do not freeze or shake. Sterile Solution - No Preservative ATTENTION: Enclosed Medication Guide is required for each patient. Contains 1 Single-dose Vial. Rx Only PRINCIPAL DISPLAY PANEL - 100 mg/10 mL Vial Label