1 INDICATIONS AND USAGE

1.1Non‑Hodgkin’s Lymphoma (NHL)

Rituxan® (rituximab) is indicated for the treatment of 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 Rituxan 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 CVP chemotherapy
• Previously untreated diffuse large B‑cell, CD20‑positive NHL in combination with CHOP or other anthracycline‑based chemotherapy regimens

1.2Chronic Lymphocytic Leukemia (CLL)

Rituxan® (rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.

1.3Rheumatoid Arthritis (RA)

Rituxan® (rituximab) 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.

1.4Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA)

Rituxan® (rituximab), in combination with glucocorticoids, is indicated for the treatment of adult patients with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA).

1.5Limitations of Use

Rituxan is not recommended for use in patients with severe, active infections.

2 DOSAGE AND ADMINISTRATION

2.1Administration

DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
Premedicate before each infusion [see Dosage and Administration (2.7)]. Administer only as an intravenous (IV) infusion [see Dosage and Administration (2.7)].

• First Infusion: Initiate infusion at a rate of 50mg/hr. In the absence of infusion toxicity, increase infusion rate by 50mg/hr increments every 30minutes, to a maximum of 400mg/hr.
• Subsequent Infusions: Initiate infusion at a rate of 100mg/hr. In the absence of infusion toxicity, increase rate by 100mg/hr increments at 30‑minute intervals, to a maximum of 400mg/hr.
• Interrupt the infusion or slow the infusion rate for infusion reactions [see Boxed Warning, Warnings and Precautions (5.1)]. Continue the infusion at one half the previous rate upon improvement of symptoms.

2.2Recommended Dose for Non‑Hodgkin’s Lymphoma (NHL)

The recommended dose is 375mg/m2 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 4or 8doses.
• Retreatment for Relapsed or Refractory, Low‑Grade or Follicular, CD20‑Positive, B‑Cell NHL
  Administer once weekly for 4doses.
• 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 Rituxan maintenance eight weeks following completion of Rituxan in combination with chemotherapy. Administer Rituxan 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 6–8cycles of CVP chemotherapy, administer once weekly for 4doses at 6‑month intervals to a maximum of 16doses.
• Diffuse Large B‑Cell NHL
  Administer on Day1 of each cycle of chemotherapy for up to 8infusions.

2.3Recommended Dose for Chronic Lymphocytic Leukemia (CLL)

The recommended dose is:

• 375mg/m2 the day prior to the initiation of FC chemotherapy, then 500mg/m2 on Day 1 of cycles 2-6 (every 28 days).

2.4Recommended Dose as a Component of Zeva lin®

• Infuse rituximab 250mg/m2 within 4hours prior to the administration of Indium‑111‑(In‑111‑) Zeva lin and within 4hours prior to the administration of Yttrium‑90‑ (Y‑90‑) Zeva lin.
• Administer Rituxan and In‑111‑Zeva lin 7–9days prior to Rituxan and Y‑90‑ Zeva lin.
• Refer to the Zeva lin package insert for full prescribing information regarding the Zeva lin therapeutic regimen.

2.5Recommended Dose for Rheumatoid Arthritis (RA)

• Administer Rituxan as two-1000mg intravenous infusions separated by 2weeks.
• Glucocorticoids administered as methylprednisolone 100mg intravenous or its equivalent 30minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions.
• Subsequent courses should be administered every 24weeks or based on clinical eva luation, but not sooner than every 16weeks.
• Rituxan is given in combination with methotrexate.

2.6Recommended Dose for Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA)

• Administer Rituxan as a 375 mg/m2 intravenous infusion once weekly for 4 weeks.
• Glucocorticoids administered as methylprednisolone 1000 mg intravenously per day for 1 to 3 days followed by oral prednisone 1 mg/kg/day (not to exceed 80 mg/day and tapered per clinical need) are recommended to treat severe vasculitis symptoms. This regimen should begin within 14 days prior to or with the initiation of Rituxan and may continue during and after the 4 week course of Rituximab treatment.
• Safety and efficacy of treatment with subsequent courses of Rituxan have not been established [see Warnings and Precautions (5.14)].

2.7Recommended Concomitant Medications

Premedicate before each infusion with acetaminophen and an antihistamine.

For RA patients, methylprednisolone 100mg intravenously or its equivalent is recommended 30minutes prior to each infusion.

For WG and MPA patients, glucocorticoids are given in combination with Rituxan [see Dosage and Administration (2.6)].

Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12months following treatment as appropriate.

PCP prophylaxis is also recommended for patients with WG and MPA during treatment and for at least 6 months following the last Rituxan infusion

2.8Preparation for Administration

Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use vial if particulates or discoloration is present. Withdraw the necessary amount of Rituxan and dilute to a final concentration of 1to4mg/mL in an infusion bag containing either 0.9%Sodium Chloride, USP, or 5%Dextrose in Water, 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.

3 DOSAGE FORMS AND STRENGTHS

100mg/10mL single‑use vial

500mg/50mL single‑use vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1Infusion Reactions

Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan‑induced infusion 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 patients, methylprednisolone 100mg intravenously or its equivalent is recommended 30minutes prior to each infusion. Institute medical management (e.g. glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion 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 (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions (5.7), Adverse Reactions (6.1).]

5.2Tumor Lysis Syndrome (TLS)

Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, some fatal, can occur within 12–24hours after the first infusion of Rituxan in patients with NHL. A high number of circulating malignant cells (≥25,000/mm3) 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 Boxed Warning, Warnings and Precautions (5.8).]

5.3Severe 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 varied from 1–13weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions (6, 6.1).]

5.4Progressive 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 12months of their last infusion of Rituxan.

Consider the diagnosis of PML in any patient presenting with new‑onset neurologic manifestations. eva luation 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. [See Boxed Warning, Adverse Reactions (6).]

5.5Hepatitis B Virus (HBV) Reactivation

Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients treated with Rituxan. The median time to the diagnosis of hepatitis among patients with hematologic malignancies was approximately 4months after the initiation of Rituxan and approximately onemonth after the last dose.

Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions (6.5).]

5.6Infections

Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and up to one year following the completion of Rituxan-based therapy. New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitisB and C. Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. [See Adverse Reactions (6, 6.1).]

5.7Cardiovascular

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).]

5.8Renal

Severe, including fatal, renal toxicity can occur after Rituxan 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 Rituxan is not an approved treatment regimen. Monitor closely for signs of renal failure and discontinue Rituxan in patients with a rising serum creatinine or oliguria. [See Warnings and Precautions (5.2).]

5.9Bowel Obstruction and Perforation

Abdominal pain, bowel obstruction and perforation, in some cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6(range 1–77)days in patients with NHL. Perform a thorough diagnostic eva luation and institute appropriate treatment for complaints of abdominal pain. [See Adverse Reactions (6).]

5.10 Immunization

The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended.

For RA patients, physicians should follow current immunization guidelines and administer non‑live vaccines at least 4weeks prior to a course of Rituxan.

The effect of Rituxan on immune responses was assessed in a randomized, controlled study in patients with RA treated with Rituxan 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 6of 12serotypes was lower in patients treated with Rituxan plus MTX as compared to patients treated with MTX alone (19% vs. 61%). A lower proportion of patients in the Rituxan 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 Rituxan plus MTX compared to patients on MTX alone (39% vs. 42%). The proportion of patients maintaining a positive Candida skin test (to eva luate delayed type hypersensitivity) was also similar (77% of patients on Rituxan plus MTX vs. 70% of patients on MTX alone).

Most patients in the Rituxan‑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.

5.11 Laboratory Monitoring

In patients with lymphoid malignancies, during treatment with Rituxan monotherapy, obtain complete blood counts (CBC) and platelet counts prior to each Rituxan course. During treatment with Rituxan and chemotherapy, obtain CBC 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, WG or MPA, obtain CBC and platelet counts at two to four month intervals during Rituxan therapy. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period.

5.12 Concomitant Use with Biologic Agents and DMARDS other than Methotrexate in RA, WG and MPA

Limited data are available on the safety of the use of biologic agents or 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 WG or MPA patients exhibiting peripheral B-cell depletion following treatment with Rituxan.

5.13 Use in RA Patients Who Have Not Had Prior Inadequate Response to Tumor Necrosis Factor (TNF) Antagonists

While the efficacy of Rituxan 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 Rituxan in patients with RA who have not had prior inadequate response to one or more TNF antagonists is not recommended [see Clinical Studies (14.5)].

5.14 Retreatment in Patients with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA)

Limited data are available on the safety and efficacy of subsequent courses of Rituxan in patients with WG and MPA. The safety and efficacy of retreatment with Rituxan have not been established [see Dosage and Administration (2.6), Adverse Reactions (6.3), and Clinical Studies (14.6)].

6 ADVERSE REACTIONS

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

• Infusion reactions [see Warnings and Precautions (5.1)]
• Tumor lysis syndrome [see Warnings and Precautions (5.2)]
• Mucocutaneous reactions [see Warnings and Precautions (5.3)]
• Progressive multifocal leukoencephalopathy [see Warnings and Precautions (5.4)]
• Hepatitis B reactivation with fulminant hepatitis [see Warnings and Precautions (5.5)]
• Infections [see Warnings and Precautions (5.6)]
• Cardiac arrhythmias[see Warnings and Precautions (5.7)]
• Renal toxicity[see Warnings and Precautions (5.8)]
• Bowel obstruction and perforation [see Warnings and Precautions (5.9)]

The most common adverse reactions of Rituxan (incidence ≥25%) observed in clinical trials of patients with NHL were infusion reactions, fever, lymphopenia, chills, infection, and asthenia.

The most common adverse reactions of Rituxan (incidence≥25%) observed in clinical trials of patients with CLL were infusion reactions and neutropenia.

6.1Clinical Trials Experience in Lymphoid Malignancies

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 practice.

The data described below reflect exposure to Rituxan in 2783patients, 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=1926). The population included 1180patients with low grade or follicular lymphoma, 927patients with DLBCL, and 676patients with CLL. Most NHL patients received Rituxan as an infusion of 375mg/m2 per infusion, given as a single agent weekly for up to 8doses, in combination with chemotherapy for up to 8doses, or following chemotherapy for up to 16doses. CLL patients received Rituxan 375mg/m2 as an initial infusion followed by 500mg/m2 for up to 5doses, in combination with fludarabine and cyclophosphamide. Seventy-one percent of CLL patients received 6cycles and 90% received at least 3cycles of Rituxan-based therapy.

Infusion Reactions

In the majority of patients with NHL, infusion 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 reactions typically occurred within 30to 120minutes 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 reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions (5.1).]

Infections

Serious infections (NCI CTCAE Grade3 or4), 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 (5.4), (5.5), (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.

Cytopenias and hypogammaglobulinemia

In patients with NHL receiving rituximab monotherapy, NCI‑CTC Grade3 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 14days (range, 1–588days) and of neutropenia was 13days (range, 2–116days). 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.

Relapsed or Refractory, Low-Grade NHL

Adverse reactions in Table1 occurred in 356patients with relapsed or refractory, low‑grade or follicular, CD20‑positive, B‑cell NHL treated in single‑arm studies of Rituxan administered as a single agent [see Clinical Studies (14.1)]. Most patients received Rituxan 375mg/m2 weekly for 4doses.