Rituxan

— THERAPEUTIC CATEGORIES —
  • Arthritis/rheumatic disorders
  • Leukemias, lymphomas, and other hematologic cancers
  • Miscellaneous dermatological conditions
  • Miscellaneous immune disorders
PAGE CONTENTS
  • Jump to Section
  • Generic Name & Formulations
  • Indications
  • Dosage and Administration
  • Contraindications
  • Boxed Warnings
  • Warnings/Precautions
  • Pharmacokinetics
  • Interactions
  • Adverse Reactions
  • Clinical Trials
  • Note
  • Patient Counseling

    • Rituxan Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Rituximab 10mg/mL; soln for IV infusion after dilution; preservative-free.

    Pharmacological Class

    CD20-directed cytolytic monoclonal antibody.

    How Supplied

    Single-dose vial (10mL)—1, 10; Single-dose vial (50mL)—1

    How Supplied

    Rituxan (rituximab) injection is a sterile, preservative-free, clear, colorless solution for intravenous infusion supplied as follows: 

    • One 100 mg/10 mL (10 mg/mL) single-dose vial

    • Ten 100 mg/10 mL (10 mg/mL) single-dose vials

    • One 500 mg/50 mL (10 mg/mL) single-dose vial

     

    Storage

    • Store Rituxan vials refrigerated at 2°C to 8°C (36°F to 46°F). Rituxan vials should be protected from direct sunlight. Do not freeze or shake. 

    • Diluted Rituxan solutions for infusion may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for 24 hours. 

    • Diluted Rituxan solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since Rituxan solutions do not contain a preservative, diluted solutions should be stored refrigerated (2C to 8C).

    Manufacturer

    Genentech and Biogen

    Rituxan Indications

    Indications

    In combination with methotrexate (MTX): for the treatment of moderately to severely active rheumatoid arthritis in patients who have had an inadequate response to one or more TNF antagonist therapies.

    Rituxan Dosage and Administration

    Prior to Treatment Evaluations

    Prior to First Infusion

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

    • Obtain CBCs including platelets prior to the first dose.

    Adult

    Give by IV infusion. Give glucocorticoids 30mins prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase by 50mg/hr increments every 30mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase by 100mg/hr increments every 30mins. Both: max 400mg/hr if infusion reactions do not occur. In combination with MTX: two 1000mg separated by 2 weeks. Subsequent courses should be given every 24 weeks or based on response, but not sooner than every 16 weeks.

    Children

    Not established.

    Rituxan Contraindications

    Not Applicable

    Rituxan Boxed Warnings

    Boxed Warning

    Fatal infusion-related reactions. Severe mucocutaneous reactions. Hepatitis B virus (HBV) reactivation. Progressive multifocal leukoencephalopathy.

    Boxed Warning

    Fatal Infusion-Related Reactions

    • May result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of infusion have occurred. There have been approximately 80% of fatal reactions occurring in association with the first infusion. Monitor closely.

    • Discontinue if severe reactions occur and provide medical treatment for Grade 3 or 4 reactions.

    Severe Mucocutaneous Reactions

    • May results in severe, including fatal, mucocutaneous reactions.

    Hepatitis B Virus (HBV) Reactivation

    • HBV reactivation may occur, and in some cases result in fulminant hepatitis, hepatic failure, and death.

    • Screen all patients prior to initiation, and monitor during and after treatment.

    • Discontinue treatment and concomitant medications if HBV reactivation occurs.

    Progressive Multifocal Leukoencephalopathy (PML)

    • May be fatal.

    Rituxan Warnings/Precautions

    Warnings/Precautions

    Discontinue if severe infusion-related or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, cardiogenic shock, paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops. Tumor lysis syndrome (esp. with high tumor burden); monitor for renal toxicity, fluid balance, electrolyte abnormalities (correct if occurs). Discontinue if SCr rises or oliguria occurs. Severe, active infections: not recommended. Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiovascular or pulmonary disease; monitor during and after treatment. Monitor CBCs, platelet counts during treatment, then periodically. Update vaccination status prior to initiation. Elderly. Embryo-fetal toxicity. Advise females of reproductive potential to use effective contraception during and for 12 months after the last dose. Pregnancy: exclude status prior to initiation. Newborns/infants: monitor for infection. Nursing mothers: not recommended (during and for 6 months after the last dose).

    Warnings/Precautions

    Infusion-Related Reactions

    • Severe, including fatal, infusion-related reactions may occur. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes.

    • Premedicate with antihistamine and acetaminophen prior to dosing. Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed.

    • Temporarily or permanently discontinue Rituxan based on the severity of the infusion-related reaction and the required interventions. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved.

    • Monitor closely in 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).

    Severe Mucocutaneous Reactions

    • Mucocutaneous reactions, some with fatal outcomes, may occur. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction.

    • The onset of these reactions has been variable and includes reports with onset on the first day of Rituxan exposure. The safety of re-administration of Rituxan to patients with severe mucocutaneous reactions has not been determined.

    Hepatitis B Virus (HBV) Reactivation

    • HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur. 

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

    • Discontinue Rituxan immediately and any concomitant chemotherapy if HBV reactivation occurs, and institute appropriate treatment. There is insufficient data 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)

    • 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. 

    Tumor Lysis Syndrome

    • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of Rituxan products 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 IV 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.

    Infections

    • Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. 

    • Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. Rituxan is not recommended for use in patients with severe, active infections. 

    Cardiovascular Adverse Reactions 

    • Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving Rituxan. 

    • Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.

    Renal Toxicity

    • Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with NHL. Renal toxicity has occurred in patients who experience TLS and in patients with NHL administered with 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.

    Bowel 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. 

    • Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

    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 before or during treatment.

    • For patients treated with Rituxan, 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 Rituxan and administer non-live vaccines at least 4 weeks prior to initiating Rituxan.

    Embryo-Fetal Toxicity

    • Based on human data, Rituxan 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 Rituxan and for 12 months after the last dose.

    Concomitant Use with Other Biologic Agents and DMARDS other than Methotrexate in RA, GPA and MPA

    • 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 Rituxan.

    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 4 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 1 or more TNF antagonists is not recommended.

    Pregnancy Considerations

    Based on human data, Rituxan can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed in-utero. 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. 

    Clinical Considerations

    • Fetal/Neonatal Adverse Reactions: Observe newborns and infants for signs of infection and manage accordingly.  

     

    Nursing Mother Considerations

    There are limited data on the presence of Rituxan in human milk, and the effect on the breastfed child, and there are no data on the effect on milk production. 

    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.  

    Pediatric Considerations

    Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) 

    • Not indicated in pediatric patients less than 2 years of age with GPA or MPA.

    Mature B-Cell NHL/B-AL  

    • The safety and effectiveness of Rituxan in combination with chemotherapy for previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL have not been established in pediatric patients less than 6 months of age. 

    • The safety and effectiveness of Rituxan have not been established in pediatric patients with CLL. 

    Rheumatoid Arthritis and Pemphigus Vulgaris 

    • The safety and effectiveness of Rituxan have not been established in pediatric patients with PV or RA. 

    • Rituxan was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA).

    Geriatric Considerations

    Diffuse Large B-Cell NHL

    • No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions (mostly supraventricular arrhythmias) and serious pulmonary adverse reactions (eg, pneumonia, pneumonitis) occurred more frequently among elderly patients. 

    Low-Grade or Follicular Non-Hodgkin’s Lymphoma 

    • 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

    • 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.

    Rheumatoid Arthritis

    • 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

    • 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.  

    Pemphigus Vulgaris  

    • The clinical study did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating Rituxan.

    • Contraception (Females): Advise females of reproductive potential to use effective contraception during treatment with Rituxan and for 12 months after the last dose. 

    Rituxan Pharmacokinetics

    Metabolism

    Opsonization.

    Elimination

    Half-life: 18 days (range: 5.17–77.5 days).

    Rituxan Interactions

    Interactions

    Concomitant live virus vaccines: not recommended. RA: give non-live vaccines at least 4 weeks prior to Rituxan. Concomitant biologics/DMARDs; monitor for infection. Concomitant immunosuppressants other than corticosteroids have not been studied. Renal toxicity with concomitant cisplatin.

    Rituxan Adverse Reactions

    Adverse Reactions

    Infusion-related reactions (may be fatal), fever, lymphopenia, chills, infections (may be serious), asthenia, neutropenia, upper RTI, nasopharyngitis, UTI, bronchitis, CV events, infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, depression; mucocutaneous reactions (may be fatal), PML, tumor lysis syndrome, renal toxicity, HBV reactivation with fulminant hepatitis, cardiac arrhythmias (discontinue if serious). Also with concomitant chemotherapy: bowel obstruction and perforation; evaluate if abdominal pain or persistent vomiting occur. Pediatric B-NHL/B-AL with chemotherapy: febrile neutropenia, stomatitis, enteritis, sepsis, increased ALT, hypokalemia.

    Rituxan Clinical Trials

    Clinical Trials

    Rheumatoid Arthritis (RA) 

    • The efficacy and safety of Rituxan were evaluated in 2 randomized, double-blind, placebo-controlled studies (RA Study 1 [NCT00468546] and RA Study 2 [NCT00266227]) in adults with moderately to severely active RA who had a prior inadequate response to at least 1 TNF inhibitor, and had at least 8 swollen and 8 tender joints. 
    • In RA Study 1, patients were randomly assigned to receive either Rituxan 2 × 1000mg + MTX or placebo + MTX for 24 weeks. Further courses of Rituxan 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 Rituxan.
    • In RA Study 2, all patients received the first course of Rituxan 2 × 1,000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either Rituxan 2 × 1,000 mg + MTX or placebo + MTX, the majority between Weeks 24-28.

    Results from RA Study 1 showed the following American College of Rheumatology (ACR) responses for Rituxan + MTX vs placebo + MTX at week 24, respectively:

    • ACR20 response: 51% vs 18% (treatment difference, 33%; 95% CI, 26-41)
    • ACR50 response: 27% vs 5% (treatment difference, 21%; 95% CI, 15-27)
    • ACR70 response: 12% vs 1% (treatment difference, 11%; 95% CI 7-15)
    • Rituxan + MTX also slowed the progression of structural damage after 1 year vs placebo + MTX, and further reduced for Rituxan + MTX in the second year.

    Results from RA Study 2 showed the following ACR responses for Rituxan + MTX vs placebo + MTX, respectively:

    • ACR20 response: 45% vs 48% at week 24 (treatment difference, NA); 54% vs 45% at week 48 (treatment difference, 11%; 95% CI, 2-20)

    • ACR50 response: 21% vs 27% at week 24 (treatment difference, NA); 29% vs 26% at week 48 (treatment difference, 4%; 95% CI, -4, 13)

    • ACR70 response: 8% vs 11% (treatment difference, NA); 14% vs 13% at week 48 (treatment difference, 1%; 95% CI, -5, 8)

    Rituxan Note

    Not Applicable

    Rituxan Patient Counseling

    Patient Counseling

    Inform patients about the signs and symptoms of infusion-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of infusion-related reactions.

    Advise patients to contact their healthcare provider immediately for signs and symptoms of severe mucocutaneous reactions, bowel obstruction and perforation, hepatitis, PML including new or changes in neurological symptoms, tumor lysis syndrome.

    Advise patients of the increased risk of infections during and after treatment. 

    Advise patients of the risk of cardiovascular adverse reactions and to contact their healthcare provider immediately to report chest pain and irregular heartbeats. 

    Advise patients of the risk of renal toxicity.

    Advise pregnant women of the potential risk to the fetus. 

    Advise females of reproductive potential to use effective contraception during and for 12 months after the last dose of Rituxan. Advise women not to breastfeed during and for 6 months after the last dose of Rituxan.

    Rituxan Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Rituximab 10mg/mL; soln for IV infusion after dilution; preservative-free.

    Pharmacological Class

    CD20-directed cytolytic monoclonal antibody.

    How Supplied

    Single-dose vial (10mL)—1, 10; Single-dose vial (50mL)—1

    How Supplied

    Rituxan (rituximab) injection is a sterile, preservative-free, clear, colorless solution for intravenous infusion supplied as follows: 

    • One 100 mg/10 mL (10 mg/mL) single-dose vial

    • Ten 100 mg/10 mL (10 mg/mL) single-dose vials

    • One 500 mg/50 mL (10 mg/mL) single-dose vial

     

    Storage

    • Store Rituxan vials refrigerated at 2°C to 8°C (36°F to 46°F). Rituxan vials should be protected from direct sunlight. Do not freeze or shake. 

    • Diluted Rituxan solutions for infusion may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for 24 hours. 

    • Diluted Rituxan solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since Rituxan solutions do not contain a preservative, diluted solutions should be stored refrigerated (2C to 8C).

    Manufacturer

    Genentech and Biogen

    Rituxan Indications

    Indications

    In adults with: relapsed or refractory, low-grade or follicular, CD20(+), B-cell non-Hodgkin's lymphoma (NHL) as a single agent; previously untreated follicular, CD20(+), B-cell NHL in combination with first line chemotherapy and, in patients achieving a complete or partial response to rituximab in combination with chemotherapy, as single-agent maintenance therapy; non-progressing (including stable disease), low-grade, CD20(+), B-cell NHL as a single agent after first-line CVP chemotherapy; previously untreated diffuse large B-cell, CD20(+) NHL (DLBCL) in combination with CHOP or other anthracycline-based chemotherapy regimens. In pediatric patients with previously untreated, advanced stage, CD20(+) DLBCL, Burkitt lymphoma (BL), Burkitt-like lymphoma (BLL), or mature B-cell acute leukemia (B-AL) in combination with chemotherapy. In adults with CD20(+) chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide.

    Rituxan Dosage and Administration

    Prior to Treatment Evaluations

    Prior to First Infusion

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

    • Obtain CBCs including platelets prior to the first dose.

    Adult

    Give by IV infusion. Premedicate with an antihistamine and acetaminophen prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase by 50mg/hr increments every 30mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase by 100mg/hr increments every 30mins. Both: max 400mg/hr if infusion reactions do not occur. Previously untreated follicular NHL and DLBCL patients: if no Grade 3 or 4 infusion related adverse events during Cycle 1, a 90-minute infusion may be given in Cycle 2 with a glucocorticoid-containing chemotherapy regimen (see full labeling). NHL: 375mg/m2 once weekly for 4 or 8 doses. Retreatment therapy: 375mg/m2 once weekly for 4 doses. Previously untreated, follicular, CD20(+), B-cell NHL: 375mg/m2 on Day 1 of each cycle of chemotherapy for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance 8 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(+), B-cell NHL after CVP chemotherapy: 375mg/m2 once weekly for 4 doses every 6 months for up to 16 doses. Diffuse large B-cell NHL: 375mg/m2 on Day 1 of each chemotherapy cycle for up to 8 infusions. CLL: 375mg/m2 the day prior to FC chemotherapy, then 500mg/m2 on Day 1 of Cycles 2–6 (every 28 days). Give PCP and antiherpetic viral prophylaxis during and up to 12 months after CLL therapy. As a component of Zevalin regimen: see full labeling.

    Adult

    Give by IV infusion. Premedicate with an antihistamine and acetaminophen prior to each infusion. 

    First infusion: 

    • Initially at a rate of 50mg/hr; may increase by 50mg/hr increments every 30mins. Max 400mg/hr if infusion reactions do not occur.

    Subsequent infusions: 

    • Initially at a rate of 100mg/hr; may increase by 100mg/hr increments every 30mins. Max 400mg/hr if infusion reactions do not occur.

    • For previously untreated follicular NHL and DLBCL patients: 

      • If no Grade 3 or 4 infusion related adverse events during Cycle 1, a 90-minute infusion may be given 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 for the remainder of the regimen (through Cycle 6 or 8).

      • Do not administer the 90-minute infusion in patients who have clinically significant cardiovascular disease or who have a circulating lymphocyte count greater than or equal to 5,000/mm3 before Cycle 2.

    Non-Hodgkin’s Lymphoma (NHL)

    • Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL: 375mg/m2 as an IV infusion once weekly for 4 or 8 doses.

    • Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL: 375mg/m2 once weekly for 4 doses.

    • Previously Untreated, Follicular, CD20-Positive, B-Cell NHL: 375mg/m2 on Day 1 of each cycle of chemotherapy for up to 8 doses. In patients with complete or partial response, initiate Rituxan maintenance 8 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 6-8 cycles of CVP chemotherapy, 375mg/m2 once weekly for 4 doses every 6 months for a maximum of 16 doses. 

    • Diffuse Large B-cell NHL: 375mg/m2 on Day 1 of each chemotherapy cycle for up to 8 infusions. 

    Chronic Lymphocytic Leukemia (CLL)  

    • 375mg/m2 the day prior to FC chemotherapy, then 500mg/m2 on Day 1 of Cycles 2–6 (every 28 days). Give PCP and antiherpetic viral prophylaxis during and up to 12 months after CLL therapy. 

    As a component of Zevalin regimen for the treatment of NHL

    • Infuse 250 mg/m2 in accordance with the Zevalin package insert. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.

    Children

    <6mos (mature B-cell NHL/B-AL): not established. Give by IV infusion. Premedicate with an antihistamine and acetaminophen 30–60mins prior to each infusion. First infusion: initially at a rate of 0.5mg/kg/hr (max 50mg/hr); may increase by 0.5mg/kg/hr increments every 30mins. Subsequent infusions: initially at a rate of 1mg/kg/hr (max 50mg/hr); may increase by 1mg/kg/hr increments every 30mins. Both: max 400mg/hr if infusion reactions do not occur. ≥6mos (mature B-cell NHL/B-AL): 375mg/m2 in combination with systemic Lymphome Malin B (LMB) chemotherapy (see full labeling). Give a total of 6 Rituxan infusions: 2 doses during each induction courses (COPDAM1 and COPDAM2), and 1 dose during each consolidation courses (CYM and CYVE).

    Children

    <6mos (mature B-cell NHL/B-AL): not established. Give by IV infusion. Premedicate with an H1 antihistamine (eg, diphenhydramine or equivalent) and acetaminophen 30–60mins prior to each infusion. 

    First infusion: 

    • Initially at a rate of 0.5mg/kg/hr (max 50mg/hr); may increase by 0.5mg/kg/hr increments every 30mins. Max 400mg/hr if infusion reactions do not occur.

    Subsequent infusions: 

    • Initially at a rate of 1mg/kg/hr (max 50mg/hr); may increase by 1mg/kg/hr increments every 30mins. Max 400mg/hr if infusion reactions do not occur. 

    For patients aged 6 months and older with previously untreated mature B-cell NHL/B-AL: 

    • 375mg/m2 in combination with systemic Lymphome Malin B (LMB) chemotherapy. Give a total of 6 Rituxan infusions: 2 doses during each induction courses (COPDAM1 and COPDAM2), and 1 dose during each consolidation courses (CYM and CYVE).

    • Posology of Rituxan Administration for Pediatric Mature B-cell NHL/B-AL:

      • Prephase (COP) - No Rituxan given on day of treatment.

      • Induction courses 1 and 2 (COPDAM1 and COPDAM2) - 2 doses at 48 hour intervals are given at Day -2 and Day 1 of each course. 

      • Consolidation courses 1 and 2 (CYM/CYVE) - 1 dose during each consolidation course.

    Rituxan Contraindications

    Not Applicable

    Rituxan Boxed Warnings

    Boxed Warning

    Fatal infusion-related reactions. Severe mucocutaneous reactions. Hepatitis B virus (HBV) reactivation. Progressive multifocal leukoencephalopathy.

    Rituxan Warnings/Precautions

    Warnings/Precautions

    Discontinue if severe infusion-related or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, cardiogenic shock, paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops. Tumor lysis syndrome (esp. with high tumor burden); monitor for renal toxicity, fluid balance, electrolyte abnormalities (correct if occurs). Discontinue if SCr rises or oliguria occurs. Severe, active infections: not recommended. Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiovascular or pulmonary disease; monitor during and after treatment. Monitor CBCs, platelet counts during treatment, then periodically. Update vaccination status prior to initiation. Elderly. Embryo-fetal toxicity. Advise females of reproductive potential to use effective contraception during and for 12 months after the last dose. Pregnancy: exclude status prior to initiation. Newborns/infants: monitor for infection. Nursing mothers: not recommended (during and for 6 months after the last dose).

    Warnings/Precautions

    Infusion-Related Reactions

    • Severe, including fatal, infusion-related reactions may occur. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes.

    • Premedicate with antihistamine and acetaminophen prior to dosing. Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed.

    • Temporarily or permanently discontinue Rituxan based on the severity of the infusion-related reaction and the required interventions. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved.

    • Monitor closely in 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).

    Severe Mucocutaneous Reactions

    • Mucocutaneous reactions, some with fatal outcomes, may occur. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction.

    • The onset of these reactions has been variable and includes reports with onset on the first day of Rituxan exposure. The safety of re-administration of Rituxan to patients with severe mucocutaneous reactions has not been determined.

    Hepatitis B Virus (HBV) Reactivation

    • HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur. 

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

    • Discontinue Rituxan immediately and any concomitant chemotherapy if HBV reactivation occurs, and institute appropriate treatment. There is insufficient data 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)

    • 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. 

    Tumor Lysis Syndrome

    • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of Rituxan products 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 IV 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.

    Infections

    • Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. 

    • Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. Rituxan is not recommended for use in patients with severe, active infections. 

    Cardiovascular Adverse Reactions 

    • Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving Rituxan. 

    • Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.

    Renal Toxicity

    • Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with NHL. Renal toxicity has occurred in patients who experience TLS and in patients with NHL administered with 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.

    Bowel 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. 

    • Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

    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 before or during treatment.

    • For patients treated with Rituxan, 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 Rituxan and administer non-live vaccines at least 4 weeks prior to initiating Rituxan.

    Embryo-Fetal Toxicity

    • Based on human data, Rituxan 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 Rituxan and for 12 months after the last dose.

    Concomitant Use with Other Biologic Agents and DMARDS other than Methotrexate in RA, GPA and MPA

    • 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 Rituxan.

    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 4 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 1 or more TNF antagonists is not recommended.

    Pregnancy Considerations

    Based on human data, Rituxan can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed in-utero. 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. 

    Clinical Considerations

    • Fetal/Neonatal Adverse Reactions: Observe newborns and infants for signs of infection and manage accordingly.  

     

    Nursing Mother Considerations

    There are limited data on the presence of Rituxan in human milk, and the effect on the breastfed child, and there are no data on the effect on milk production. 

    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.  

    Pediatric Considerations

    Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) 

    • Not indicated in pediatric patients less than 2 years of age with GPA or MPA.

    Mature B-Cell NHL/B-AL  

    • The safety and effectiveness of Rituxan in combination with chemotherapy for previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL have not been established in pediatric patients less than 6 months of age. 

    • The safety and effectiveness of Rituxan have not been established in pediatric patients with CLL. 

    Rheumatoid Arthritis and Pemphigus Vulgaris 

    • The safety and effectiveness of Rituxan have not been established in pediatric patients with PV or RA. 

    • Rituxan was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA).

    Geriatric Considerations

    Diffuse Large B-Cell NHL

    • No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions (mostly supraventricular arrhythmias) and serious pulmonary adverse reactions (eg, pneumonia, pneumonitis) occurred more frequently among elderly patients. 

    Low-Grade or Follicular Non-Hodgkin’s Lymphoma 

    • 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

    • 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.

    Rheumatoid Arthritis

    • 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

    • 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.  

    Pemphigus Vulgaris  

    • The clinical study did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating Rituxan.

    • Contraception (Females): Advise females of reproductive potential to use effective contraception during treatment with Rituxan and for 12 months after the last dose. 

    Rituxan Pharmacokinetics

    Metabolism

    Opsonization.

    Elimination

    Half-life: NHL: 22 days (range: 6.1–52 days); CLL: 32 days (range: 14–62 days).

    Rituxan Interactions

    Interactions

    Concomitant live virus vaccines: not recommended. RA: give non-live vaccines at least 4 weeks prior to Rituxan. Concomitant biologics/DMARDs; monitor for infection. Concomitant immunosuppressants other than corticosteroids have not been studied. Renal toxicity with concomitant cisplatin.

    Rituxan Adverse Reactions

    Adverse Reactions

    Infusion-related reactions (may be fatal), fever, lymphopenia, chills, infections (may be serious), asthenia, neutropenia, upper RTI, nasopharyngitis, UTI, bronchitis, CV events, infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, depression; mucocutaneous reactions (may be fatal), PML, tumor lysis syndrome, renal toxicity, HBV reactivation with fulminant hepatitis, cardiac arrhythmias (discontinue if serious). Also with concomitant chemotherapy: bowel obstruction and perforation; evaluate if abdominal pain or persistent vomiting occur. Pediatric B-NHL/B-AL with chemotherapy: febrile neutropenia, stomatitis, enteritis, sepsis, increased ALT, hypokalemia.

    Rituxan Clinical Trials

    Clinical Trials

    Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL

    NHL Study 1

    • The safety and efficacy of Rituxan was evaluated in a multicenter, open-label, single-arm study in 166 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m2 of Rituxan given as an intravenous infusion weekly for 4 doses.

    • 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.

    • The overall response rate (ORR) was 48%, of which 6% achieved complete response (CR). The median duration of response (DOR) was 11.2 months (range, 1.9 to 42.1+).

    NHL Study 2

    • The safety and efficacy of Rituxan was evaluated in a multicenter, single-arm study in 37 patients with relapsed or refractory, low-grade NHL who received 375 mg/m2 of Rituxan weekly for 8 doses. 

    • The ORR was 57%, of which 14% achieved CR. The median DOR was 13.4 months (range, 2.5 to 36.5+).

    NHL Study 3

    • The safety and efficacy of Rituxan was evaluated in a multicenter, single-arm study in 60 patients with relapsed or refractory, low-grade or follicular, B-cell NHL who received 375 mg/m2 of Rituxan weekly for 4 doses. 

    • All patients had achieved an objective clinical response to rituximab administered 3.8-35.6 months (median 14.5 months) prior to retreatment with rituximab.

    • The ORR was 38%, of which 10% achieved CR. The median DOR was 15.0 months (range, 3.0 to 25.1+).

    Bulky Disease 

    • In pooled data from NHL studies 1 and 3, there were 39 patients with bulky (single lesion >10 cm in diameter) and relapsed or refractory, low-grade NHL who received Rituxan 375 mg/m2 weekly for 4 doses. 

    • The ORR was 36%, of which 3% achieved CR. The median DOR was 6.9 months (range, 2.8 to 25.0+).

     

    Previously Untreated, Low-Grade or Follicular, CD20-Positive, B-Cell NHL 

    NHL Study 4

    • The safety and efficacy of Rituxan was evaluated in an open-label, multicenter study in 322 patients with previously untreated follicular NHL.

    • Patients were randomly assigned 1:1 to receive up to eight 3-week cycles of CVP (cyclophosphamide, vincristine, prednisone) chemotherapy alone or in combination with Rituxan 375mg/m2 on Day 1 of each cycle (R-CVP). The main outcome measure was progression-free survival (PFS), defined as the time from randomization to the first of progression, relapse, or death.

    • The median PFS was 2.4 years for the R-CVP arm vs 1.4 years for the CVP arm (hazard ratio [HR], 0.44; 95% CI, 0.29-0.65; P <.0001). 

    NHL Study 5

    • The safety and efficacy of Rituxan was evaluated in an open-label, multicenter study in 1018 patients with previously untreated follicular NHL who achieved a response (complete or partial response) to Rituxan in combination with chemotherapy.

    • Patients were randomly assigned 1:1 to receive either Rituxan as single-agent maintenance therapy, 375mg/m2 every 8 weeks for up to 12 doses or to observation. Rituxan was initiated at 8 weeks following completion of chemotherapy. The main outcome measure was PFS, defined as the time from randomization in the maintenance/observation phase to progression, relapse, or death.

    • PFS was longer in patients who received Rituxan as single agent maintenance therapy (HR, 0.54; 95% CI, 0.42-0.70). 

    NHL Study 6

    • The safety and efficacy of Rituxan was evaluated in an open-label, multicenter study in 322 patients with previously untreated low-grade, B-cell NHL who did not progress after 6 or 8 cycles of CVP chemotherapy.

    • Patients were randomly assigned 1:1 to receive either Rituxan 375mg/m2 IV infusion once weekly for 4 doses every 6 months for up to 16 doses or no further therapeutic intervention. The main outcome was PFS, defined as the time from randomization to progression, relapse, or death.

    • 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 who received Rituxan compared with those who received no additional treatment. 

    NHL Study 11

    • The safety and efficacy of Rituxan in combination with chemotherapy was evaluated in an open-label, multicenter, randomized Inter-B-NHL Ritux 2010 trial in patients 6 months of age and older with previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL.

    • Patients were randomly assigned 1:1 to receive  Lymphome Malin B (LMB) chemotherapy (corticosteroids, vincristine, cyclophosphamide, high-dose methotrexate, cytarabine, doxorubicin, etoposide and triple drug [methotrexate/cytarabine/ corticosteroid] intrathecal therapy) alone (n=164) or in combination with Rituxan or non-U.S. licensed rituximab (n=164). 

    • The primary endpoint was event-free survival (EFS), where an event was defined as occurrence of progressive disease, relapse, second malignancy, death from any cause, or nonresponse as evidenced by detection of viable cells in residue after the second CYVE course, whichever occurs first.

    • Interim analysis showed that after a median follow-up of 3.1 years, there were 28 events in the LMB chemotherapy arm and 10 events in the Rituxan plus LMB arm (adjusted Cox hazard ratio 0.32; 90% CI, 0.17-0.58; P =.0012). As of data cutoff date on December 31, 2017, there were 20 deaths reported in the LMB arm and 8 deaths in the rituximab plus LMB arm, with an estimated overall survival (OS) hazard ratio of 0.36 (95% CI, 0.16-0.81). The OS result is considered descriptive because a formal statistical test was not conducted for OS.

     

    Diffuse Large B-Cell NHL (DLBCL)

    NHL Study 7

    • The safety and efficacy of Rituxan was evaluated in a randomized, active-controlled, open-label, multicenter study in 632 patients with previously untreated DLBCL, including primary mediastinal B-cell lymphoma.

    • Patients were randomly assigned 1:1 to receive either cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or Rituxan in combination with CHOP (R-CHOP). The main outcome was PFS, defined as the time from randomization to the first of progression, relapse, or death. 

    • The median PFS was 3.1 years for the R-CHOP arm vs 1.6 years for the CHOP arm (HR, 0.69; 2-sided P <.05). The overall survival (OS) estimates at 2 years were 74% for the R-CHOP arm vs 63% for the CHOP arm (HR, 0.72; 2-sided P <.05).

    • Responding patients underwent a second randomization to receive rituximab or no further therapy. Results showed that there were no further improvements in PFS or overall survival among responding patients who received R-CHOP and additional Rituxan exposure beyond induction. 

    NHL Study 8

    • The safety and efficacy of Rituxan was evaluated in a randomized, active-controlled, open-label, multicenter study in 399 patients with previously untreated DLBCL.

    • Patients were randomly assigned 1:1 to receive either CHOP or R-CHOP. All patients received up to eight 3-week cycles of CHOP induction; patients in the R-CHOP arm received Rituxan 375 mg/m2 on Day 1 of each cycle. The main outcome measure was event-free survival, defined as the time from randomization to relapse, progression, change in therapy, or death from any cause.

    • The median event-free survival was 2.9 years for the R-CHOP arm vs 1.1 years for the CHOP arm (HR, 0.60; 2-sided P <.05). The OS estimates at 2 years were 69% for the R-CHOP arm vs 58% for the CHOP arm (HR, 0.68; 2-sided P <.05). The OS estimates at 5 years were 58% for the R-CHOP arm vs 46% for the CHOP arm.

    NHL Study 9

    • The safety and efficacy of Rituxan was evaluated in a randomized, active-controlled, open-label, multicenter study in 823 patients with previously untreated DLBCL.

    • Patients were randomly assigned 1:1 to receive either an anthracycline-containing chemotherapy regimen alone or in combination with Rituxan. The main outcome measure 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.

    • The median time to treatment failure was not reliably estimable for both arms (HR, 0.45; 2-sided P <.05). The OS estimates at 2 years were 95% for the R-chemotherapy arm vs 86% for the chemotherapy arm (HR, 0.40; 2-sided P <.05).

     

    Chronic Lymphocytic Leukemia (CLL)

    The safety and efficacy of Rituxan were evaluated in two randomized (1:1) multicenter open-label studies comparing fludarabine and cyclophosphamide (FC) alone or in combination with Rituxan (R-FC) 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 25mg/m2/day and cyclophosphamide 250mg/m2/day on days 1, 2, and 3 of each cycle, with or without Rituxan. In both studies, 71% of CLL patients received 6 cycles and 90% received at least 3 cycles of Rituxan-based therapy. The main outcome measure for both studies was 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). 

    Results for CLL Study 1

    • The median PFS was 39.8 months for the R-FC arm vs 31.5 months for the FC arm (HR, 0.56; 95% CI, 0.43-0.71; P <.01). The response rate was 86% (95% CI, 82-89) for the R-FC arm vs 73% (95% CI, 68-77) for the FC arm.

    Results for CLL Study 2

    • The median PFS was 26.7 months for the R-FC arm vs 21.7 months for the FC arm (HR, 0.76; 95% CI, 0.60-0.96; P =.02). The response rate was 54% (95% CI, 48-60) for the R-FC arm vs 45% (95% CI, 37-51) for the FC arm.

    Exploratory subset analyses in CLL Studies 1 and 2 in elderly patients:

    CLL Study 1

    • 572 patients aged <65yrs (HR for PFS, 0.52; 95% CI, 0.39-0.70)

    • 245 patients aged ≥65yrs (HR for PFS, 0.62; 95% CI, 0.39-0.99)

    • 736 patients aged <70yrs (HR for PFS, 0.51; 95% CI, 0.39-0.67)

    • 81 patients aged ≥70yrs (HR for PFS, 1.17; 95% CI, 0.51-2.66)

    CLL Study 2

    • 313 patients aged <65yrs (HR for PFS, 0.61; 95% CI, 0.45-0.84)

    • 233 patients aged ≥65yrs (HR for PFS, 0.99; 95% CI, 0.70-1.40)

    • 438 patients aged <70yrs (HR for PFS, 0.67; 95% CI, 0.51-0.87)

    • 108 patients aged ≥70yrs (HR for PFS, 1.22; 95% CI, 0.73-2.04)

    Rituxan Note

    Notes

    Testing considerations: FCGR3A genotype testing

    Rituxan Patient Counseling

    Patient Counseling

    Inform patients about the signs and symptoms of infusion-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of infusion-related reactions.

    Advise patients to contact their healthcare provider immediately for signs and symptoms of severe mucocutaneous reactions, bowel obstruction and perforation, hepatitis, PML including new or changes in neurological symptoms, tumor lysis syndrome.

    Advise patients of the increased risk of infections during and after treatment. 

    Advise patients of the risk of cardiovascular adverse reactions and to contact their healthcare provider immediately to report chest pain and irregular heartbeats. 

    Advise patients of the risk of renal toxicity.

    Advise pregnant women of the potential risk to the fetus. 

    Advise females of reproductive potential to use effective contraception during and for 12 months after the last dose of Rituxan. Advise women not to breastfeed during and for 6 months after the last dose of Rituxan.

    Rituxan Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Rituximab 10mg/mL; soln for IV infusion after dilution; preservative-free.

    Pharmacological Class

    CD20-directed cytolytic monoclonal antibody.

    How Supplied

    Single-dose vial (10mL)—1, 10; Single-dose vial (50mL)—1

    How Supplied

    Rituxan (rituximab) injection is a sterile, preservative-free, clear, colorless solution for intravenous infusion supplied as follows: 

    • One 100 mg/10 mL (10 mg/mL) single-dose vial

    • Ten 100 mg/10 mL (10 mg/mL) single-dose vials

    • One 500 mg/50 mL (10 mg/mL) single-dose vial

     

    Storage

    • Store Rituxan vials refrigerated at 2°C to 8°C (36°F to 46°F). Rituxan vials should be protected from direct sunlight. Do not freeze or shake. 

    • Diluted Rituxan solutions for infusion may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for 24 hours. 

    • Diluted Rituxan solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since Rituxan solutions do not contain a preservative, diluted solutions should be stored refrigerated (2C to 8C).

    Manufacturer

    Genentech and Biogen

    Rituxan Indications

    Indications

    Moderate to severe pemphigus vulgaris (PV).

    Rituxan Dosage and Administration

    Prior to Treatment Evaluations

    Prior to First Infusion

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

    • Obtain CBCs including platelets prior to the first dose.

    Adult

    Give by IV infusion. Give glucocorticoids 30mins prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase by 50mg/hr increments every 30mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase by 100mg/hr increments every 30mins. Both: max 400mg/hr if infusion reactions do not occur. In combination with glucocorticoid taper: two 1000mg separated by 2 weeks. Maintenance: 500mg at Month 12 and every 6 months thereafter, or based on clinical response. Relapse: 1000mg; may resume or increase glucocorticoid dose based on response. Subsequent infusions should be given no sooner than 16 weeks after the previous infusion. Consider PCP prophylaxis during and after treatment.

    Children

    Not established.

    Rituxan Contraindications

    Not Applicable

    Rituxan Boxed Warnings

    Boxed Warning

    Fatal infusion-related reactions. Severe mucocutaneous reactions. Hepatitis B virus (HBV) reactivation. Progressive multifocal leukoencephalopathy.

    Boxed Warning

    Fatal Infusion-Related Reactions

    • May result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of infusion have occurred. There have been approximately 80% of fatal reactions occurring in association with the first infusion. Monitor closely.

    • Discontinue if severe reactions occur and provide medical treatment for Grade 3 or 4 reactions.

    Severe Mucocutaneous Reactions

    • May results in severe, including fatal, mucocutaneous reactions.

    Hepatitis B Virus (HBV) Reactivation

    • HBV reactivation may occur, and in some cases result in fulminant hepatitis, hepatic failure, and death.

    • Screen all patients prior to initiation, and monitor during and after treatment.

    • Discontinue treatment and concomitant medications if HBV reactivation occurs.

    Progressive Multifocal Leukoencephalopathy (PML)

    • May be fatal.

    Rituxan Warnings/Precautions

    Warnings/Precautions

    Discontinue if severe infusion-related or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, cardiogenic shock, paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops. Tumor lysis syndrome (esp. with high tumor burden); monitor for renal toxicity, fluid balance, electrolyte abnormalities (correct if occurs). Discontinue if SCr rises or oliguria occurs. Severe, active infections: not recommended. Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiovascular or pulmonary disease; monitor during and after treatment. Monitor CBCs, platelet counts during treatment, then periodically. Update vaccination status prior to initiation. Elderly. Embryo-fetal toxicity. Advise females of reproductive potential to use effective contraception during and for 12 months after the last dose. Pregnancy: exclude status prior to initiation. Newborns/infants: monitor for infection. Nursing mothers: not recommended (during and for 6 months after the last dose).

    Warnings/Precautions

    Infusion-Related Reactions

    • Severe, including fatal, infusion-related reactions may occur. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes.

    • Premedicate with antihistamine and acetaminophen prior to dosing. Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed.

    • Temporarily or permanently discontinue Rituxan based on the severity of the infusion-related reaction and the required interventions. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved.

    • Monitor closely in 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).

    Severe Mucocutaneous Reactions

    • Mucocutaneous reactions, some with fatal outcomes, may occur. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction.

    • The onset of these reactions has been variable and includes reports with onset on the first day of Rituxan exposure. The safety of re-administration of Rituxan to patients with severe mucocutaneous reactions has not been determined.

    Hepatitis B Virus (HBV) Reactivation

    • HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur. 

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

    • Discontinue Rituxan immediately and any concomitant chemotherapy if HBV reactivation occurs, and institute appropriate treatment. There is insufficient data 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)

    • 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. 

    Tumor Lysis Syndrome

    • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of Rituxan products 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 IV 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.

    Infections

    • Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. 

    • Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. Rituxan is not recommended for use in patients with severe, active infections. 

    Cardiovascular Adverse Reactions 

    • Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving Rituxan. 

    • Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.

    Renal Toxicity

    • Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with NHL. Renal toxicity has occurred in patients who experience TLS and in patients with NHL administered with 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.

    Bowel 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. 

    • Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

    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 before or during treatment.

    • For patients treated with Rituxan, 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 Rituxan and administer non-live vaccines at least 4 weeks prior to initiating Rituxan.

    Embryo-Fetal Toxicity

    • Based on human data, Rituxan 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 Rituxan and for 12 months after the last dose.

    Concomitant Use with Other Biologic Agents and DMARDS other than Methotrexate in RA, GPA and MPA

    • 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 Rituxan.

    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 4 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 1 or more TNF antagonists is not recommended.

    Pregnancy Considerations

    Based on human data, Rituxan can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed in-utero. 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. 

    Clinical Considerations

    • Fetal/Neonatal Adverse Reactions: Observe newborns and infants for signs of infection and manage accordingly.  

     

    Nursing Mother Considerations

    There are limited data on the presence of Rituxan in human milk, and the effect on the breastfed child, and there are no data on the effect on milk production. 

    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.  

    Pediatric Considerations

    Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) 

    • Not indicated in pediatric patients less than 2 years of age with GPA or MPA.

    Mature B-Cell NHL/B-AL  

    • The safety and effectiveness of Rituxan in combination with chemotherapy for previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL have not been established in pediatric patients less than 6 months of age. 

    • The safety and effectiveness of Rituxan have not been established in pediatric patients with CLL. 

    Rheumatoid Arthritis and Pemphigus Vulgaris 

    • The safety and effectiveness of Rituxan have not been established in pediatric patients with PV or RA. 

    • Rituxan was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA).

    Geriatric Considerations

    Diffuse Large B-Cell NHL

    • No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions (mostly supraventricular arrhythmias) and serious pulmonary adverse reactions (eg, pneumonia, pneumonitis) occurred more frequently among elderly patients. 

    Low-Grade or Follicular Non-Hodgkin’s Lymphoma 

    • 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

    • 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.

    Rheumatoid Arthritis

    • 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

    • 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.  

    Pemphigus Vulgaris  

    • The clinical study did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating Rituxan.

    • Contraception (Females): Advise females of reproductive potential to use effective contraception during treatment with Rituxan and for 12 months after the last dose. 

    Rituxan Pharmacokinetics

    Metabolism

    Opsonization.

    Elimination

    Half-life: 21.1 days (range: 9.3–36.2 days).

    Rituxan Interactions

    Interactions

    Concomitant live virus vaccines: not recommended. RA: give non-live vaccines at least 4 weeks prior to Rituxan. Concomitant biologics/DMARDs; monitor for infection. Concomitant immunosuppressants other than corticosteroids have not been studied. Renal toxicity with concomitant cisplatin.

    Rituxan Adverse Reactions

    Adverse Reactions

    Infusion-related reactions (may be fatal), fever, lymphopenia, chills, infections (may be serious), asthenia, neutropenia, upper RTI, nasopharyngitis, UTI, bronchitis, CV events, infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, depression; mucocutaneous reactions (may be fatal), PML, tumor lysis syndrome, renal toxicity, HBV reactivation with fulminant hepatitis, cardiac arrhythmias (discontinue if serious). Also with concomitant chemotherapy: bowel obstruction and perforation; evaluate if abdominal pain or persistent vomiting occur. Pediatric B-NHL/B-AL with chemotherapy: febrile neutropenia, stomatitis, enteritis, sepsis, increased ALT, hypokalemia.

    Rituxan Clinical Trials

    Clinical Trials

    Pemphigus Vulgaris (PV) 

    PV Study 1 (NCT00784589) 

    • The randomized, open-label, controlled, multicenter study compared non-US-licensed rituximab in combination with short-term prednisone to prednisone monotherapy as first-line treatment in 90 newly diagnosed adult patients with moderate to severe pemphigus (74 Pemphigus Vulgaris [PV] and 16 Pemphigus Foliaceus [PF]).

    • The primary endpoint for the study was complete remission (complete epithelialization and absence of new and/or established lesions) at Month 24 without the use of prednisone therapy for 2 months or more (CRoff for greater than or equal to 2 months).

    • Results showed that 90% of PV patients treated with the Rituxan plus short-term prednisone regimen had complete remission off-therapy (without the use of steroids for ≥2 months) at month 24  (primary endpoint) compared with 28% of those treated with prednisone alone.  

    PV Study 2 (NCT02383589)  

    • The randomized, double-blind, double-dummy, active-comparator, multicenter study compared the efficacy and safety of Rituxan to mycophenolate mofetil (MMF) in 135 patients with moderate to severe PV who were receiving 60-120 mg/day oral prednisone or equivalent.

    • The primary efficacy endpoint for this study was the proportion of subjects achieving sustained complete remission defined as achieving healing of lesions with no new active lesions (i.e., PDAI activity score of 0) while on 0 mg/day prednisone or equivalent, and maintaining this response for at least 16 consecutive weeks, during the 52-week treatment period. Secondary endpoints included cumulative oral corticosteroid dose and the total number of disease flares.

    • Among 125 patients who were analyzed for efficacy, 40.3% (n=25/62) of patients had sustained complete remission off-therapy for 16 weeks or more at week 52 compared with 9.5% (n=6/63) of those treated with mycophenolate mofetil.

    • The total number of disease flares was lower in patients treated with Rituxan compared to MMF (6 vs. 44).

    Rituxan Note

    Not Applicable

    Rituxan Patient Counseling

    Patient Counseling

    Inform patients about the signs and symptoms of infusion-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of infusion-related reactions.

    Advise patients to contact their healthcare provider immediately for signs and symptoms of severe mucocutaneous reactions, bowel obstruction and perforation, hepatitis, PML including new or changes in neurological symptoms, tumor lysis syndrome.

    Advise patients of the increased risk of infections during and after treatment. 

    Advise patients of the risk of cardiovascular adverse reactions and to contact their healthcare provider immediately to report chest pain and irregular heartbeats. 

    Advise patients of the risk of renal toxicity.

    Advise pregnant women of the potential risk to the fetus. 

    Advise females of reproductive potential to use effective contraception during and for 12 months after the last dose of Rituxan. Advise women not to breastfeed during and for 6 months after the last dose of Rituxan.

    Rituxan Generic Name & Formulations

    Legal Class

    Rx

    General Description

    Rituximab 10mg/mL; soln for IV infusion after dilution; preservative-free.

    Pharmacological Class

    CD20-directed cytolytic monoclonal antibody.

    How Supplied

    Single-dose vial (10mL)—1, 10; Single-dose vial (50mL)—1

    How Supplied

    Rituxan (rituximab) injection is a sterile, preservative-free, clear, colorless solution for intravenous infusion supplied as follows: 

    • One 100 mg/10 mL (10 mg/mL) single-dose vial

    • Ten 100 mg/10 mL (10 mg/mL) single-dose vials

    • One 500 mg/50 mL (10 mg/mL) single-dose vial

    Storage

    • Store Rituxan vials refrigerated at 2°C to 8°C (36°F to 46°F). Rituxan vials should be protected from direct sunlight. Do not freeze or shake. 

    • Diluted Rituxan solutions for infusion may be stored refrigerated at 2°C to 8°C (36°F to 46°F) for 24 hours. 

    • Diluted Rituxan solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since Rituxan solutions do not contain a preservative, diluted solutions should be stored refrigerated (2C to 8C).

    Manufacturer

    Genentech and Biogen

    Rituxan Indications

    Indications

    Granulomatosis with polyangiitis (GPA) (Wegener's granulomatosis) and microscopic polyangiitis (MPA), in combination with glucocorticoids.

    Rituxan Dosage and Administration

    Prior to Treatment Evaluations

    Prior to First Infusion

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

    • Obtain CBCs including platelets prior to the first dose.

    Adult

    Give by IV infusion. Premedicate with an antihistamine and acetaminophen prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase by 50mg/hr increments every 30mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase by 100mg/hr increments every 30mins. Both: max 400mg/hr if infusion reactions do not occur. Induction: 375mg/m2 once weekly for 4 weeks. Begin glucocorticoids within 14 days prior to or with initiation of Rituxan and continue during and after the 4 week course (see full labeling). Follow-up treatment (in patients who achieved disease control with induction therapy): initiate within 24 weeks after last rituximab product induction dose or as clinically indicated, but no sooner than 16 weeks after last induction infusion; or within the 4 week period after disease controlled with other immunosuppressants. 500mg once, followed by second 500mg 2 weeks later, then 500mg every 6 months thereafter as clinically indicated. Give glucocorticoids 30mins before each infusion (see full labeling). PCP prophylaxis recommended during and for at least 6 months following last infusion.

    Children

    <2yrs: not established. Give by IV infusion. Premedicate with an antihistamine and acetaminophen prior to each infusion. First infusion: initially at a rate of 50mg/hr; may increase by 50mg/hr increments every 30mins. Subsequent infusions: initially at a rate of 100mg/hr; may increase by 100mg/hr increments every 30mins. Both: max 400mg/hr if infusion reactions do not occur. ≥2yrs: Induction: 375mg/m2 once weekly for 4 weeks. Begin glucocorticoids within 3 days prior to initiation of Rituxan and continue during and per clinical practice (see full labeling). Follow-up treatment (in patients who achieved disease control with induction therapy): initiate within 24 weeks after last rituximab product induction dose or as clinically indicated, but no sooner than 16 weeks after last induction infusion; or within the 4 week period after disease controlled with other immunosuppressants. 250mg/m2 once, followed by second 250mg/m2 2 weeks later, then 250mg/m2 every 6 months thereafter as clinically indicated. Give glucocorticoids 30mins before each infusion (see full labeling). PCP prophylaxis recommended during and for at least 6 months following last infusion.

    Rituxan Contraindications

    Not Applicable

    Rituxan Boxed Warnings

    Boxed Warning

    Fatal infusion-related reactions. Severe mucocutaneous reactions. Hepatitis B virus (HBV) reactivation. Progressive multifocal leukoencephalopathy.

    Boxed Warning

    Fatal Infusion-Related Reactions

    • May result in serious, including fatal, infusion-related reactions. Deaths within 24 hours of infusion have occurred. There have been approximately 80% of fatal reactions occurring in association with the first infusion. Monitor closely.

    • Discontinue if severe reactions occur and provide medical treatment for Grade 3 or 4 reactions.

    Severe Mucocutaneous Reactions

    • May results in severe, including fatal, mucocutaneous reactions.

    Hepatitis B Virus (HBV) Reactivation

    • HBV reactivation may occur, and in some cases result in fulminant hepatitis, hepatic failure, and death.

    • Screen all patients prior to initiation, and monitor during and after treatment.

    • Discontinue treatment and concomitant medications if HBV reactivation occurs.

    Progressive Multifocal Leukoencephalopathy (PML)

    • May be fatal.

    Rituxan Warnings/Precautions

    Warnings/Precautions

    Discontinue if severe infusion-related or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, MI, ventricular fibrillation, cardiogenic shock, paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid or vesiculobullous dermatitis, toxic epidermal necrolysis). Increased risk of HBV reactivation. Test/treat HBV infection prior to initiating therapy. Monitor for signs of hepatitis or HBV reactivation during and for several months after therapy; discontinue if HBV reactivation occurs. Monitor for new-onset neurologic manifestations; discontinue if progressive multifocal leukoencephalopathy (PML) develops. Tumor lysis syndrome (esp. with high tumor burden); monitor for renal toxicity, fluid balance, electrolyte abnormalities (correct if occurs). Discontinue if SCr rises or oliguria occurs. Severe, active infections: not recommended. Discontinue and treat if serious infections (eg, bacterial, fungal, viral) occur. Pre-existing cardiovascular or pulmonary disease; monitor during and after treatment. Monitor CBCs, platelet counts during treatment, then periodically. Update vaccination status prior to initiation. Elderly. Embryo-fetal toxicity. Advise females of reproductive potential to use effective contraception during and for 12 months after the last dose. Pregnancy: exclude status prior to initiation. Newborns/infants: monitor for infection. Nursing mothers: not recommended (during and for 6 months after the last dose).

    Warnings/Precautions

    Infusion-Related Reactions

    • Severe, including fatal, infusion-related reactions may occur. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes.

    • Premedicate with antihistamine and acetaminophen prior to dosing. Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed.

    • Temporarily or permanently discontinue Rituxan based on the severity of the infusion-related reaction and the required interventions. Resume infusion at a minimum 50% reduction in rate after symptoms have resolved.

    • Monitor closely in 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).

    Severe Mucocutaneous Reactions

    • Mucocutaneous reactions, some with fatal outcomes, may occur. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction.

    • The onset of these reactions has been variable and includes reports with onset on the first day of Rituxan exposure. The safety of re-administration of Rituxan to patients with severe mucocutaneous reactions has not been determined.

    Hepatitis B Virus (HBV) Reactivation

    • HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur. 

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

    • Discontinue Rituxan immediately and any concomitant chemotherapy if HBV reactivation occurs, and institute appropriate treatment. There is insufficient data 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)

    • 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. 

    Tumor Lysis Syndrome

    • Acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia from tumor lysis, sometimes fatal, can occur within 12-24 hours after the first infusion of Rituxan products 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 IV 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.

    Infections

    • Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of rituximab product-based therapy. New or reactivated viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. 

    • Discontinue Rituxan for serious infections and institute appropriate anti-infective therapy. Rituxan is not recommended for use in patients with severe, active infections. 

    Cardiovascular Adverse Reactions 

    • Cardiac adverse reactions, including ventricular fibrillation, myocardial infarction, and cardiogenic shock may occur in patients receiving Rituxan. 

    • Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias, or who have a history of arrhythmia or angina.

    Renal Toxicity

    • Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with NHL. Renal toxicity has occurred in patients who experience TLS and in patients with NHL administered with 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.

    Bowel 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. 

    • Evaluate if symptoms of obstruction such as abdominal pain or repeated vomiting occur.

    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 before or during treatment.

    • For patients treated with Rituxan, 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 Rituxan and administer non-live vaccines at least 4 weeks prior to initiating Rituxan.

    Embryo-Fetal Toxicity

    • Based on human data, Rituxan 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 Rituxan and for 12 months after the last dose.

    Concomitant Use with Other Biologic Agents and DMARDS other than Methotrexate in RA, GPA and MPA

    • 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 Rituxan.

    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 4 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 1 or more TNF antagonists is not recommended.

    Pregnancy Considerations

    Based on human data, Rituxan can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed in-utero. 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. 

    Clinical Considerations

    • Fetal/Neonatal Adverse Reactions: Observe newborns and infants for signs of infection and manage accordingly.  

     

    Nursing Mother Considerations

    There are limited data on the presence of Rituxan in human milk, and the effect on the breastfed child, and there are no data on the effect on milk production. 

    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.  

    Pediatric Considerations

    Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) 

    • Not indicated in pediatric patients less than 2 years of age with GPA or MPA.

    Mature B-Cell NHL/B-AL  

    • The safety and effectiveness of Rituxan in combination with chemotherapy for previously untreated, advanced stage, CD20-positive DLBCL/BL/BLL/B-AL have not been established in pediatric patients less than 6 months of age. 

    • The safety and effectiveness of Rituxan have not been established in pediatric patients with CLL. 

    Rheumatoid Arthritis and Pemphigus Vulgaris 

    • The safety and effectiveness of Rituxan have not been established in pediatric patients with PV or RA. 

    • Rituxan was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA).

    Geriatric Considerations

    Diffuse Large B-Cell NHL

    • No overall differences in effectiveness were observed between these patients and younger patients. Cardiac adverse reactions (mostly supraventricular arrhythmias) and serious pulmonary adverse reactions (eg, pneumonia, pneumonitis) occurred more frequently among elderly patients. 

    Low-Grade or Follicular Non-Hodgkin’s Lymphoma 

    • 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

    • 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.

    Rheumatoid Arthritis

    • 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

    • 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.  

    Pemphigus Vulgaris  

    • The clinical study did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients.

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

    • Pregnancy Testing: Verify pregnancy status in females of reproductive potential prior to initiating Rituxan.

    • Contraception (Females): Advise females of reproductive potential to use effective contraception during treatment with Rituxan and for 12 months after the last dose. 

    Rituxan Pharmacokinetics

    Metabolism

    Opsonization.

    Elimination

    Half-life: 25 days (range: 11–52 days).

    Rituxan Interactions

    Interactions

    Concomitant live virus vaccines: not recommended. RA: give non-live vaccines at least 4 weeks prior to Rituxan. Concomitant biologics/DMARDs; monitor for infection. Concomitant immunosuppressants other than corticosteroids have not been studied. Renal toxicity with concomitant cisplatin.

    Rituxan Adverse Reactions

    Adverse Reactions

    Infusion-related reactions (may be fatal), fever, lymphopenia, chills, infections (may be serious), asthenia, neutropenia, upper RTI, nasopharyngitis, UTI, bronchitis, CV events, infections, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, depression; mucocutaneous reactions (may be fatal), PML, tumor lysis syndrome, renal toxicity, HBV reactivation with fulminant hepatitis, cardiac arrhythmias (discontinue if serious). Also with concomitant chemotherapy: bowel obstruction and perforation; evaluate if abdominal pain or persistent vomiting occur. Pediatric B-NHL/B-AL with chemotherapy: febrile neutropenia, stomatitis, enteritis, sepsis, increased ALT, hypokalemia.

    Rituxan Clinical Trials

    Clinical Trials

    Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) 

    GPA/MPA Study 1 (Induction Treatment of Adults with Active Disease)

    • The randomized, double-blind, active-controlled, multicenter, non-inferiority study evaluated Rituxan in 197 patients with active, severe GPA and MPA. The study was conducted in 2 phases - a 6 month remission induction phase and a 12 month remission maintenance phase.

    • Patients were randomly assigned 1:1 to receive either Rituxan 375mg/m2 once weekly for 4 weeks or oral cyclophosphamide 2mg/kg daily for 3 to 6 months in the remission induction phase. Once remission was achieved or at the end of the 6 month remission induction period, the cyclophosphamide group received azathioprine to maintain remission. The Rituxan arm 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.

    • Results showed that 64% (95% CI, 54-73) of patients treated with Rituxan achieved complete remission (CR) at 6 months vs 53% (95% CI, 43-63) of patients treated with cyclophosphamide (treatment difference, 11%; 95% CI, -3, 24).

    • In the Rituxan arm, 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. 

    Follow Up Treatment of Adults with Active Disease who achieved disease control with other immunosuppressant (GPA/MPA Study 2)

    • The open-label, prospective, multicenter, randomized, active-controlled study included 115 patients 21 years of age and older with GPA/MPA, who were randomly assigned 1:1 to receive azathioprine or non-US-licensed rituximab.

    • 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-US-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-US-licensed rituximab relative to azathioprine.

    Treatment of Pediatric Patients (GPA/MPA Study 4) 

    • The multicenter, open-label, single-arm, uncontrolled study consisted of an initial 6-month remission induction phase, and a minimum 12­ month follow-up phase up to a maximum of 54 months (4.5 years) in 25 pediatric patients 2 years to 17 years of age with GPA and MPA. Patients received a minimum of 3 doses of IV methylprednisolone (30 mg/kg/day, not exceeding 1 g/day) prior to the first Rituxan or non-US-licensed rituximab IV infusion.

    • The primary objectives of the study were to evaluate safety and PK parameters in pediatric GPA and MPA patients (2 years to 17 years of age). The efficacy objectives of the study were exploratory and principally assessed using the Pediatric Vasculitis Activity Score (PVAS). 

    • Results showed the following percentages of patients who achieved PVAS remission by Month 6, 12 and 18:

      • Month 6: 56% (95% CI, 34.9-75.6)

      • Month 12: 92% (95% CI, 74-99)

      • Month 18: 100% (95% CI, 86.3-100)

    Follow-Up Treatment After the 6-month Remission Induction Phase

    • Patients who did not achieve remission or who had progressive disease or flare that could not be controlled by glucocorticoids alone received additional treatment for GPA and MPA, that could include Rituxan or non-U.S.-licensed rituximab and/or other therapies, at the discretion of the investigator. Planned follow-up was until Month 18 (from Day 1). 

    • Of the 14 patients who received follow-up treatment between Month 6 and Month 18: 

      • 4 patients first achieved remission between Months 6 and 12 

      • 1 patient first achieved remission between Months 12 and 18

      • 9 patients achieved PVAS remission by Month 6 but required additional follow-up treatment after Month 6

    Rituxan Note

    Not Applicable

    Rituxan Patient Counseling

    Patient Counseling

    Inform patients about the signs and symptoms of infusion-related reactions. Advise patients to contact their healthcare provider immediately to report symptoms of infusion-related reactions.

    Advise patients to contact their healthcare provider immediately for signs and symptoms of severe mucocutaneous reactions, bowel obstruction and perforation, hepatitis, PML including new or changes in neurological symptoms, tumor lysis syndrome.

    Advise patients of the increased risk of infections during and after treatment. 

    Advise patients of the risk of cardiovascular adverse reactions and to contact their healthcare provider immediately to report chest pain and irregular heartbeats. 

    Advise patients of the risk of renal toxicity.

    Advise pregnant women of the potential risk to the fetus. 

    Advise females of reproductive potential to use effective contraception during and for 12 months after the last dose of Rituxan. Advise women not to breastfeed during and for 6 months after the last dose of Rituxan.

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