Rituxan

• Fatal infusion-related reactions within 24 hours of RITUXAN infusion; approximately 80% of fatal reactions occurred with first infusion. Monitor patients and discontinue RITUXAN infusion for severe reactions (

  5.1 Infusion-Related Reactions

  RITUXAN can cause severe, including fatal, infusion-related reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. RITUXAN-induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death.

  Premedicate patients with an antihistamine and acetaminophen prior to dosing. For RA, GPA and MPA, and PV patients, methylprednisolone 100 mg intravenously or its equivalent is recommended 30 minutes prior to each infusion. For pediatric patients with mature B-cell NHL/B-AL, administer prednisone as part of chemotherapy regimen prior to RITUXAN during induction and as needed for subsequent cycles

  [see Dosage and Administration (2.2and 2.8)]

  . Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed. Depending on the severity of the infusion-related reaction and the required interventions, temporarily or permanently discontinue RITUXAN. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with pre-existing cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (greater than or equal to 25,000/mm³)

  [see Warnings and Precautions (5.7), Adverse Reactions (6.1)]

  .

  ).
• Severe mucocutaneous reactions, some with fatal outcomes (

  5.2 Severe Mucocutaneous Reactions

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

  ).
• Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death (

  5.3 Hepatitis B Virus (HBV) Reactivation

  Hepatitis B virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure and death, can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies, including RITUXAN. Cases have been reported in patients who are hepatitis B surface antigen (HBsAg) positive and also in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation also has occurred in patients who appear to have resolved hepatitis B infection (i.e., HBsAg negative, anti-HBc positive and hepatitis B surface antibody [anti-HBs] positive).

  HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA levels or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, i.e., increase in transaminase levels. In severe cases increase in bilirubin levels, liver failure, and death can occur.

  Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RITUXAN. For patients who show evidence of prior hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and/or during RITUXAN treatment.

  Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following RITUXAN therapy. HBV reactivation has been reported up to 24 months following completion of RITUXAN therapy.

  In patients who develop reactivation of HBV while on RITUXAN, immediately discontinue RITUXAN and any concomitant chemotherapy, and institute appropriate treatment. Insufficient data exist regarding the safety of resuming RITUXAN treatment in patients who develop HBV reactivation. Resumption of RITUXAN treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV.

  ).
• Progressive multifocal leukoencephalopathy (PML) resulting in death (

  5.4 Progressive Multifocal Leukoencephalopathy (PML)

  JC virus infection resulting in PML and death can occur in RITUXAN-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received RITUXAN in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of RITUXAN.

  Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture.

  Discontinue RITUXAN and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML.

  ).

RITUXAN is a CD20-directed cytolytic antibody indicated for the treatment of:

• Adult patients with Non-Hodgkin's Lymphoma (NHL) (
  1.1 Non–Hodgkin's Lymphoma (NHL)

  RITUXAN is indicated for the treatment of adult patients with:

  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

  RITUXAN is indicated for the treatment of pediatric patients aged 6 months and older with:

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

  RITUXAN is indicated for the treatment of adult patients with:

  • Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent.
  • Previously untreated follicular, CD20-positive, B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to a rituximab product in combination with chemotherapy, as single-agent maintenance therapy.
  • Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL as a single agent after first-line cyclophosphamide, vincristine, and prednisone (CVP) chemotherapy.
  • Previously untreated diffuse large B-cell, CD20-positive NHL in combination with cyclophosphamide, doxorubicin, vincristine, prednisone (CHOP) or other anthracycline-based chemotherapy regimens.

  RITUXAN is indicated for the treatment of pediatric patients aged 6 months and older with:

  • Previously untreated, advanced stage, CD20-positive diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy.
  )
  • Previously untreated, advanced stage, CD20-positive, diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL) or mature B-cell acute leukemia (B-AL) in combination with chemotherapy.
• Adult patients with Chronic Lymphocytic Leukemia (CLL) (
  1.2 Chronic Lymphocytic Leukemia (CLL)

  RITUXAN, in combination with fludarabine and cyclophosphamide (FC), is indicated for the treatment of adult patients with previously untreated and previously treated CD20-positive CLL.
  ).
  • 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 Rheumatoid Arthritis (RA)

  RITUXAN, in combination with methotrexate, is indicated for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.
  ).
• Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA) in adult and pediatric patients 2 years of age and older in combination with glucocorticoids (
  1.4 Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

  RITUXAN, in combination with glucocorticoids, is indicated for the treatment of adult and pediatric patients 2 years of age and older with Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA).
  ).
• Moderate to severe Pemphigus Vulgaris (PV) in adult patients (
  1.5 Pemphigus Vulgaris (PV)

  RITUXAN is indicated for the treatment of adult patients with moderate to severe pemphigus vulgaris.
  ).

• Administer only as an intravenous infusion (
  2.1 Important Dosing Information

  Administer only as an Intravenous Infusion

  [see Dosage and Administration (2.8)]

  . Do not administer as an intravenous push or bolus.

  RITUXAN 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 (2.8)]

  .

  Prior to First Infusion:

  Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RITUXAN

  [see Warnings and Precautions (5.3)]

  . Obtain complete blood counts (CBC) including platelets prior to the first dose.

  During RITUXAN Therapy:

  In patients with lymphoid malignancies, during treatment with RITUXAN monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RITUXAN course. During treatment with RITUXAN 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 RITUXAN therapy. Continue to monitor for cytopenias after final dose and until resolution.

  • First Infusion

    :
    
    

    Standard Infusion:

    Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
    
    

    For Pediatric Patients with mature B-cell NHL/B-AL

    :
    
    Initiate infusion at a rate of 0.5 mg/kg/hr (maximum 50 mg/hr). In the absence of infusion toxicity, increase infusion rate by 0.5 mg/kg/hr every 30 minutes, to a maximum of 400 mg/hr.
  • Subsequent Infusions

    :

    Standard Infusion:

    Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.
    
    

    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/mm³before Cycle 2 should not be administered the 90-minute infusion

    [see Clinical Studies (14.4)]

    .
    
    

    For Pediatric Patients with mature B-cell NHL/B-AL:

    
    
    Initiate infusion rate of 1 mg/kg/hr (maximum 50 mg/hr). In the absence of infusion toxicity, increase rate by 1 mg/kg/hr every 30 minutes, to a maximum of 400 mg/hr.
  • 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.
  ).
• Do not administer as an intravenous push or bolus (
  2.1 Important Dosing Information

  Administer only as an Intravenous Infusion

  [see Dosage and Administration (2.8)]

  . Do not administer as an intravenous push or bolus.

  RITUXAN 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 (2.8)]

  .

  Prior to First Infusion:

  Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RITUXAN

  [see Warnings and Precautions (5.3)]

  . Obtain complete blood counts (CBC) including platelets prior to the first dose.

  During RITUXAN Therapy:

  In patients with lymphoid malignancies, during treatment with RITUXAN monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RITUXAN course. During treatment with RITUXAN 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 RITUXAN therapy. Continue to monitor for cytopenias after final dose and until resolution.

  • First Infusion

    :
    
    

    Standard Infusion:

    Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
    
    

    For Pediatric Patients with mature B-cell NHL/B-AL

    :
    
    Initiate infusion at a rate of 0.5 mg/kg/hr (maximum 50 mg/hr). In the absence of infusion toxicity, increase infusion rate by 0.5 mg/kg/hr every 30 minutes, to a maximum of 400 mg/hr.
  • Subsequent Infusions

    :

    Standard Infusion:

    Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.
    
    

    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/mm³before Cycle 2 should not be administered the 90-minute infusion

    [see Clinical Studies (14.4)]

    .
    
    

    For Pediatric Patients with mature B-cell NHL/B-AL:

    
    
    Initiate infusion rate of 1 mg/kg/hr (maximum 50 mg/hr). In the absence of infusion toxicity, increase rate by 1 mg/kg/hr every 30 minutes, to a maximum of 400 mg/hr.
  • 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.
  ).
• RITUXAN 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 Important Dosing Information

  Administer only as an Intravenous Infusion

  [see Dosage and Administration (2.8)]

  . Do not administer as an intravenous push or bolus.

  RITUXAN 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 (2.8)]

  .

  Prior to First Infusion:

  Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RITUXAN

  [see Warnings and Precautions (5.3)]

  . Obtain complete blood counts (CBC) including platelets prior to the first dose.

  During RITUXAN Therapy:

  In patients with lymphoid malignancies, during treatment with RITUXAN monotherapy, obtain complete blood counts (CBC) with differential and platelet counts prior to each RITUXAN course. During treatment with RITUXAN 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 RITUXAN therapy. Continue to monitor for cytopenias after final dose and until resolution.

  • First Infusion

    :
    
    

    Standard Infusion:

    Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr.
    
    

    For Pediatric Patients with mature B-cell NHL/B-AL

    :
    
    Initiate infusion at a rate of 0.5 mg/kg/hr (maximum 50 mg/hr). In the absence of infusion toxicity, increase infusion rate by 0.5 mg/kg/hr every 30 minutes, to a maximum of 400 mg/hr.
  • Subsequent Infusions

    :

    Standard Infusion:

    Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr.
    
    

    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/mm³before Cycle 2 should not be administered the 90-minute infusion

    [see Clinical Studies (14.4)]

    .
    
    

    For Pediatric Patients with mature B-cell NHL/B-AL:

    
    
    Initiate infusion rate of 1 mg/kg/hr (maximum 50 mg/hr). In the absence of infusion toxicity, increase rate by 1 mg/kg/hr every 30 minutes, to a maximum of 400 mg/hr.
  • 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 dose for adult and pediatric B-cell NHL is 375 mg/m² (
  2.2 Recommended Dose for Non-Hodgkin's Lymphoma (NHL)

  The recommended dose is 375 mg/m²as 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 RITUXAN maintenance eight weeks following completion of a rituximab product 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 6–8 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.
  • Pediatric patients aged 6 months and older with previously untreated mature B-cell NHL/B-AL

    
    
    RITUXAN is given in combination with systemic Lymphome Malin B (LMB) chemotherapy. In total, six infusions of RITUXAN are given, two doses during each of the induction courses, COPDAM1 and COPDAM2, and one dose during each of the two consolidation courses of CYM/CYVE (for details see Table 1).

  Table 1: Posology of RITUXAN Administration for Pediatric Mature B-cell NHL/B-AL

  Cycle	Day of treatment	Administration details
  COP = Cyclophosphamide, Oncovin (vincristine), Prednisone; COPDAM = Cyclophosphamide, Oncovin (vincristine), Prednisolone, Adriamycin (doxorubicin), Methotrexate; CYM = CYtarabine (Aracytine, Ara-C), Methotrexate; CYVE = CYtarabine (Aracytine, Ara-C), VEposide (VP16)
  Prephase (COP)	No RITUXAN given	-
  Induction courses 1 and 2 (COPDAM1 and COPDAM2)	Day -2 1stand 3rdRITUXAN infusions	During the 1stinduction course, prednisone is given as part of the chemotherapy course, and should be administered prior to RITUXAN.
  	Day 1 2ndand 4thRITUXAN infusions	RITUXAN will be given 48 hours after the first infusion of RITUXAN.
  Consolidation courses 1 and 2 (CYM/CYVE)	Day 1 5thand 6thRITUXAN infusions	-
  ).
• The dose for CLL is 375 mg/m² in the first cycle and 500 mg/m² in cycles 2–6, in combination with FC, administered every 28 days (
  2.3 Recommended Dose for Chronic Lymphocytic Leukemia (CLL)

  The recommended dose is 375 mg/m²the day prior to the initiation of FC chemotherapy, then 500 mg/m²on Day 1 of cycles 2–6 (every 28 days).
  ).
• The dose as a component of Zevalin^® (ibritumomab tiuxetan) Therapeutic Regimen is 250 mg/m² (
  2.4 Recommended Dose as a Component of Zevalin^®for treatment of NHL

  • When used as part of the Zevalin therapeutic regimen, infuse 250 mg/m²in accordance with the Zevalin package insert. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.
  ).
• 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 Recommended Dose for Rheumatoid Arthritis (RA)

  • Administer RITUXAN 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.
  • RITUXAN is given in combination with methotrexate.
  ).
• The induction dose for adult patients with active GPA and MPA in combination with glucocorticoids is 375 mg/m² 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 Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

  Induction Treatment of Adult Patients with Active GPA/MPA

  • Administer RITUXAN as a 375 mg/m²intravenous 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 RITUXAN and may continue during and after the 4 week induction course of RITUXAN treatment.

  Follow up Treatment of Adult Patients with GPA/MPA who have achieved disease control with induction treatment

  • Administer RITUXAN 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 RITUXAN 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 RITUXAN follow up treatment within the 4 week period that follows achievement of disease control.

  Induction treatment of Pediatric Patients with Active GPA/MPA

  • Administer RITUXAN as a 375 mg/m²intravenous infusion once weekly for 4 weeks.
  • Prior to the first RITUXAN infusion, administer intravenous methylprednisolone 30 mg/kg (not to exceed 1g/day) once daily for 3 days.
  • Following intravenous methylprednisolone administration, oral steroids should be continued per clinical practice.

  Follow up Treatment of Pediatric Patients with GPA/MPA who have achieved disease control with induction treatment

  • Administer RITUXAN as two 250 mg/m²intravenous infusions separated by two weeks, followed by a 250 mg/m²intravenous 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 RITUXAN 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 RITUXAN follow up treatment within the 4 week period following achievement of disease control.
  ).
• The induction dose for pediatric patients with GPA and MPA in combination with glucocorticoids is 375 mg/m² once weekly for 4 weeks. The follow up dose for pediatric patients with GPA and MPA who have achieved disease control with induction treatment, in combination with glucocorticoids is two 250 mg/m² intravenous infusions separated by two weeks, followed by a 250 mg/m² intravenous infusion every 6 months thereafter based on clinical evaluation (
  2.6 Recommended Dose for Granulomatosis with Polyangiitis (GPA) (Wegener's Granulomatosis) and Microscopic Polyangiitis (MPA)

  Induction Treatment of Adult Patients with Active GPA/MPA

  • Administer RITUXAN as a 375 mg/m²intravenous 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 RITUXAN and may continue during and after the 4 week induction course of RITUXAN treatment.

  Follow up Treatment of Adult Patients with GPA/MPA who have achieved disease control with induction treatment

  • Administer RITUXAN 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 RITUXAN 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 RITUXAN follow up treatment within the 4 week period that follows achievement of disease control.

  Induction treatment of Pediatric Patients with Active GPA/MPA

  • Administer RITUXAN as a 375 mg/m²intravenous infusion once weekly for 4 weeks.
  • Prior to the first RITUXAN infusion, administer intravenous methylprednisolone 30 mg/kg (not to exceed 1g/day) once daily for 3 days.
  • Following intravenous methylprednisolone administration, oral steroids should be continued per clinical practice.

  Follow up Treatment of Pediatric Patients with GPA/MPA who have achieved disease control with induction treatment

  • Administer RITUXAN as two 250 mg/m²intravenous infusions separated by two weeks, followed by a 250 mg/m²intravenous 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 RITUXAN 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 RITUXAN follow up treatment within the 4 week period following achievement of disease control.
  ).
• The dose for PV is two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids, then a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation. Dose upon relapse is a 1,000 mg intravenous infusion with considerations to resume or increase the glucocorticoid dose based on clinical evaluation. Subsequent infusions may be no sooner than 16 weeks after the previous infusion (
  2.7 Recommended Dose for Pemphigus Vulgaris (PV)

  • Administer RITUXAN as two-1,000 mg intravenous infusions separated by 2 weeks in combination with a tapering course of glucocorticoids.
  • Maintenance treatment
    
    
    Administer RITUXAN as a 500 mg intravenous infusion at Month 12 and every 6 months thereafter or based on clinical evaluation.
  • Treatment of relapse
    
    
    Administer RITUXAN as a 1,000 mg intravenous infusion on relapse, and consider resuming or increasing the glucocorticoid dose based on clinical evaluation.

  Subsequent infusions of RITUXAN may be administered no sooner than 16 weeks following the previous infusion.
  ). Methylprednisolone 100 mg intravenous or equivalent glucocorticoid is recommended 30 minutes prior to each infusion (
  2.8 Recommended Dose for Premedication and Prophylactic Medications

  Premedicate with acetaminophen and an antihistamine before each infusion of RITUXAN. For adult patients administered RITUXAN 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 pediatric patients with mature B-cell NHL/B-AL, premedication with acetaminophen and H1 antihistamine (diphenhydramine or equivalent) should be administered 30 to 60 minutes before the start of each RITUXAN intravenous infusion.

  For RA, GPA and MPA, and PV 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 RITUXAN infusion.

  PCP prophylaxis should be considered for patients with PV during and following RITUXAN treatment.
  ).

Injection: RITUXAN is a colorless, clear solution for intravenous infusion:

• 100 mg/10 mL (10 mg/mL) in a single-dose vial
• 500 mg/50 mL (10 mg/mL) in a single-dose vial

• Lactation: Advise not to breastfeed (
  8.2 Lactation

  There are limited data on the presence of rituximab in human milk and the effect on the breastfed child, and there are no data on the effect on milk production. Rituximab is detected in the milk of lactating cynomolgus monkeys, and maternal IgG is present in human breast milk. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with RITUXAN and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.
  ).
• Geriatric Use: In CLL patients older than 70 years of age, exploratory analyses suggest no benefit with the addition of RITUXAN to FC (
  8.5 Geriatric Use

  Diffuse Large B-Cell NHL

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

  Low-Grade or Follicular Non-Hodgkin's Lymphoma

  Patients with previously untreated follicular NHL evaluated in NHL Study 5 were randomized to RITUXAN as single-agent maintenance therapy (n=505) or observation (n=513) after achieving a response to RITUXAN in combination with chemotherapy. Of these, 123 (24%) patients in the RITUXAN 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 RITUXAN 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 RITUXAN-treated patients (36%) were 65 years of age or older; of these, 100 RITUXAN-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 RITUXAN 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 RITUXAN 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 RITUXAN. In CLL Study 1, the dose intensity of RITUXAN was similar in older and younger patients, however in CLL Study 2 older patients received a lower dose intensity of RITUXAN.

  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 2578 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 RITUXAN-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.

  Pemphigus Vulgaris

  Of the 46 patients treated with non-U.S.-licensed rituximab, 15 (33%) patients were 65 years of age and older. The clinical study did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.
  ).