Ruxience

— THERAPEUTIC DISORDERS TREATED —
  • Arthritis/rheumatic disorders
  • Leukemias, lymphomas, and other hematologic cancers
  • 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

    • Ruxience Generic Name & Formulations

    Legal Class

    Rx

    General Description

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

    Pharmacological Class

    CD20-directed cytolytic monoclonal antibody.

    How Supplied

    Single-dose vial (10mL, 50mL)—1

    How Supplied

    Ruxience (rituximab-pvvr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brownish-yellow solution for intravenous infusion supplied as follows: 

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

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

    Storage

    Store vials refrigerated at 2° C to 8° C (36° F to 46° F) in the original carton. Protect vials from direct sunlight. Do not freeze or shake.

    Diluted Ruxience solutions for infusion may be stored refrigerated at 2° C to 8° C (36° F to 46° F) for 24 hours. Complete administration within 8 hours from removal from refrigeration.

    Manufacturer

    Pfizer Inc.

    Generic Availability

    NO

    Ruxience 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.

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

    During Ruxience Therapy: 

    • In patients with lymphoid malignancies, during treatment with Ruxience monotherapy, obtain CBC with differential and platelet counts prior to each Ruxience course. During treatment with Ruxience and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias.

    • In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at 2 to 4 month intervals during Ruxience therapy. Continue to monitor for cytopenias after final dose and until resolution.

    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.

    Other Modifications

    Females and Males of Reproductive Potential 

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

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

    Ruxience Contraindications

    Not Applicable

    Ruxience 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, Severe Mucocutaneous Reactions, Hepatitis B Virus Reactivation And Progressive Multifocal Leukoencephalopathy

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

    • Severe mucocutaneous reactions, some with fatal outcomes.

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

    • Progressive multifocal leukoencephalopathy (PML) resulting in death.

    Ruxience Warnings/Precautions

    Warnings/Precautions

    Discontinue if severe infusion-related or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, bronchospasm, 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, history of cardiopulmonary adverse reactions, circulating malignant cells (≥25000/mm3); monitor closely. Monitor CBCs, platelet counts prior to and during treatment, then as indicated. 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 with rituximab products. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes.

    • Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed.

    • Temporarily or permanently discontinue Ruxience 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.

    Severe Mucocutaneous Reactions

    • Mucocutaneous reactions, some with fatal outcomes, may occur. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. The safety of re-administration of rituximab 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 and has been reported up to 24 months following completion of rituximab therapy. 

    • 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 Ruxience 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 Ruxience therapy.

    • Discontinue Ruxience immediately and any concomitant chemotherapy if HBV reactivation occurs, and institute appropriate treatment. There is insufficient data regarding the safety of resuming Ruxience treatment in patients who develop HBV reactivation. Resumption of Ruxience 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 Ruxience 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 rituximab 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 Ruxience for serious infections and institute appropriate anti-infective therapy. Ruxience 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 rituximab products. 

    • Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Ruxience 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 rituximab product 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 Ruxience is not an approved treatment regimen. 

    • Monitor closely for signs of renal failure and discontinue Ruxience 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 rituximab products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with NHL. 

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

    Immunization

    • The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.

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

    Embryo-Fetal Toxicity

    • Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed in-utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving Ruxience 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 rituximab products.

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

    • While the efficacy of rituximab 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 Ruxience in patients with RA who have not had prior inadequate response to 1 or more TNF antagonists is not recommended.

    Pregnancy Considerations

    Risk Summary

    • Based on human data, rituximab products 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. 

    • Verify pregnancy status in females of reproductive potential prior to initiating Ruxience. Advise females of reproductive potential to use effective contraception during treatment with Ruxience and for 12 months after the last dose. 

    Nursing Mother Considerations

    Risk Summary

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

    • Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with Ruxience and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.

    Pediatric Considerations

    Safety and effectiveness of rituximab products have not been established in pediatric patients with NHL, CLL or RA. 

    Rituximab was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion.

    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 rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. 

     Chronic Lymphocytic Leukemia

    In exploratory analyses defined by age, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in CLL Study 1 or in CLL Study 2; there was also no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in CLL Study 2.

     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. 

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

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

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

    Ruxience Pharmacokinetics

    Distribution

    Volume of distribution: 3.1 L (RA) and 3.12 L (GPA/MPA).

    Elimination

    Terminal half-life: 18 days (RA; range, 5.17 to 77.5 days); 22 days (NHL; range, 6.1 to 52 days); 25 days (GPA/MPA; range, 11 to 52 days); 32 days (CLL; range, 14 to 62 days).

    Ruxience Interactions

    Interactions

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

    Ruxience Adverse Reactions

    Adverse Reactions

    Infusion-related reactions (may be fatal), fever, lymphopenia, chills, infections (may be serious), asthenia, neutropenia, upper RTI, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, UTI, bronchitis; 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.

    Ruxience Clinical Trials

    Clinical Trials

    Rheumatoid Arthritis (RA) 

    The efficacy and safety of rituximab 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 rituximab 2 × 1000mg + MTX or placebo + MTX for 24 weeks. Further courses of rituximab 2 × 1,000 mg + MTX were administered in an openlabel extension study at a frequency determined by clinical evaluation, but no sooner than 16 weeks after the preceding course of rituximab.

    In RA Study 2, all patients received the first course of rituximab 2 × 1,000 mg + MTX. Patients who experienced ongoing disease activity were randomized to receive a second course of either rituximab 2 × 1,000 mg + MTX or placebo + MTX, the majority between Weeks 24-28.

    Results from RA Study 1 showed the following American College of Rheumatology (ACR) responses for rituximab + 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)

    • Rituximab + MTX also slowed the progression of structural damage after 1 year vs placebo + MTX, and further reduced for rituximab + MTX in the second year. 

    Results from RA Study 2 showed the following ACR responses for rituximab + 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)

    Ruxience Note

    Not Applicable

    Ruxience Patient Counseling

    Patient Counseling

    Infusion-Related Reactions 

    • 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.

    Severe Mucocutaneous Reactions 

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the mouth, blisters, peeling skin, rash, and pustules.

    Hepatitis B Virus Reactivation

    • Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening
      fatigue or yellow discoloration of skin or eyes.

    Progressive Multifocal Leukoencephalopathy (PML) 

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including
      new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or
      walking, decreased strength or weakness on one side of the body, or vision problems.

    Tumor Lysis Syndrome (TLS)

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis
      syndrome such as nausea, vomiting, diarrhea, and lethargy.

    Infections

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including
      fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or
      headache, dysuria, oral herpes simplex infection, and painful wounds with erythema and advise patients of the
      increased risk of infections during and after treatment with Ruxience.

    Cardiovascular Adverse Reactions 

    • Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial
      infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report
      chest pain and irregular heartbeats.

    Renal Toxicity

    • Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor
      kidney function.

    Bowel Obstruction and Perforation

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction
      and perforation, including severe abdominal pain or repeated vomiting.

    Embryo-Fetal Toxicity 

    • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their
      healthcare provider of a known or suspected pregnancy.
    • Advise females of reproductive potential to use effective contraception during treatment with Ruxience and
      for 12 months after the last dose.

    Lactation

    • Advise women not to breastfeed during treatment with Ruxience and for 6 months after the last dose.

    Cost Savings Program

    The Ruxience savings program is available here.

    Ruxience Generic Name & Formulations

    Legal Class

    Rx

    General Description

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

    Pharmacological Class

    CD20-directed cytolytic monoclonal antibody.

    How Supplied

    Single-dose vial (10mL, 50mL)—1

    How Supplied

    Ruxience (rituximab-pvvr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brownish-yellow solution for intravenous infusion supplied as follows: 

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

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

    Storage

    Store vials refrigerated at 2° C to 8° C (36° F to 46° F) in the original carton. Protect vials from direct sunlight. Do not freeze or shake.

    Diluted Ruxience solutions for infusion may be stored refrigerated at 2° C to 8° C (36° F to 46° F) for 24 hours. Complete administration within 8 hours from removal from refrigeration.

    Manufacturer

    Pfizer Inc.

    Generic Availability

    NO

    Ruxience Indications

    Indications

    Relapsed or refractory, low-grade or follicular, CD20(+), B-cell non-Hodgkin's lymphoma (NHL). 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. CD20(+) chronic lymphocytic leukemia (CLL) in combination with fludarabine and cyclophosphamide.

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

    During Ruxience Therapy: 

    • In patients with lymphoid malignancies, during treatment with Ruxience monotherapy, obtain CBC with differential and platelet counts prior to each Ruxience course. During treatment with Ruxience and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias.

    • In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at 2 to 4 month intervals during Ruxience therapy. Continue to monitor for cytopenias after final dose and until resolution.

    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 Ruxience maintenance 8 weeks following completion of Ruxience in combination with chemotherapy. Administer Ruxience 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.

    Children

    Not established.

    Other Modifications

    Females and Males of Reproductive Potential 

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

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

    Ruxience Contraindications

    Not Applicable

    Ruxience 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, Severe Mucocutaneous Reactions, Hepatitis B Virus Reactivation And Progressive Multifocal Leukoencephalopathy

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

    • Severe mucocutaneous reactions, some with fatal outcomes.

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

    • Progressive multifocal leukoencephalopathy (PML) resulting in death.

    Ruxience Warnings/Precautions

    Warnings/Precautions

    Discontinue if severe infusion-related or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, bronchospasm, 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, history of cardiopulmonary adverse reactions, circulating malignant cells (≥25000/mm3); monitor closely. Monitor CBCs, platelet counts prior to and during treatment, then as indicated. 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 with rituximab products. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes.

    • Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed.

    • Temporarily or permanently discontinue Ruxience 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.

    Severe Mucocutaneous Reactions

    • Mucocutaneous reactions, some with fatal outcomes, may occur. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. The safety of re-administration of rituximab 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 and has been reported up to 24 months following completion of rituximab therapy. 

    • 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 Ruxience 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 Ruxience therapy.

    • Discontinue Ruxience immediately and any concomitant chemotherapy if HBV reactivation occurs, and institute appropriate treatment. There is insufficient data regarding the safety of resuming Ruxience treatment in patients who develop HBV reactivation. Resumption of Ruxience 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 Ruxience 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 rituximab 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 Ruxience for serious infections and institute appropriate anti-infective therapy. Ruxience 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 rituximab products. 

    • Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Ruxience 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 rituximab product 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 Ruxience is not an approved treatment regimen. 

    • Monitor closely for signs of renal failure and discontinue Ruxience 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 rituximab products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with NHL. 

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

    Immunization

    • The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.

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

    Embryo-Fetal Toxicity

    • Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed in-utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving Ruxience 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 rituximab products.

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

    • While the efficacy of rituximab 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 Ruxience in patients with RA who have not had prior inadequate response to 1 or more TNF antagonists is not recommended.

    Pregnancy Considerations

    Risk Summary

    • Based on human data, rituximab products 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. 

    • Verify pregnancy status in females of reproductive potential prior to initiating Ruxience. Advise females of reproductive potential to use effective contraception during treatment with Ruxience and for 12 months after the last dose. 

    Nursing Mother Considerations

    Risk Summary

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

    • Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with Ruxience and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.

    Pediatric Considerations

    Safety and effectiveness of rituximab products have not been established in pediatric patients with NHL, CLL or RA. 

    Rituximab was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion.

    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 rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. 

     Chronic Lymphocytic Leukemia

    In exploratory analyses defined by age, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in CLL Study 1 or in CLL Study 2; there was also no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in CLL Study 2.

     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. 

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

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

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

    Ruxience Pharmacokinetics

    Distribution

    Volume of distribution: 3.1 L (RA) and 3.12 L (GPA/MPA).

    Elimination

    Terminal half-life: 18 days (RA; range, 5.17 to 77.5 days); 22 days (NHL; range, 6.1 to 52 days); 25 days (GPA/MPA; range, 11 to 52 days); 32 days (CLL; range, 14 to 62 days).

    Ruxience Interactions

    Interactions

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

    Ruxience Adverse Reactions

    Adverse Reactions

    Infusion-related reactions (may be fatal), fever, lymphopenia, chills, infections (may be serious), asthenia, neutropenia, upper RTI, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, UTI, bronchitis; 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.

    Ruxience Clinical Trials

    Clinical Trials

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

    NHL Study 1

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

    • Patients were randomly assigned 1:1 to receive either rituximab as single-agent maintenance therapy, 375mg/m2 every 8 weeks for up to 12 doses or to observation. Rituximab was initiated at 8 weeks following completion of chemotherapy. The main outcome measure 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 rituximab as single agent maintenance therapy (HR, 0.54; 95% CI, 0.42-0.70). 

    NHL Study 6

    • The safety and efficacy of rituximab 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 rituximab 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 rituximab compared with those who received no additional treatment. 

     

    Diffuse Large B-Cell NHL (DLBCL)

    NHL Study 7

    • The safety and efficacy of rituximab 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 rituximab 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 rituximab exposure beyond induction. 

    NHL Study 8

    • The safety and efficacy of rituximab 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 rituximab 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 rituximab 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 rituximab. 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 rituximab were evaluated in two randomized (1:1) multicenter open-label studies comparing fludarabine and cyclophosphamide (FC) alone or in combination with rituximab (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 rituximab. In both studies, 71% of CLL patients received 6 cycles and 90% received at least 3 cycles of rituximab-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)

    Ruxience Note

    Notes

    Testing considerations: FCGR3A genotype testing

    Ruxience Patient Counseling

    Patient Counseling

    Infusion-Related Reactions 

    • 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.

    Severe Mucocutaneous Reactions 

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the mouth, blisters, peeling skin, rash, and pustules.

    Hepatitis B Virus Reactivation

    • Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening
      fatigue or yellow discoloration of skin or eyes.

    Progressive Multifocal Leukoencephalopathy (PML) 

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including
      new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or
      walking, decreased strength or weakness on one side of the body, or vision problems.

    Tumor Lysis Syndrome (TLS)

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis
      syndrome such as nausea, vomiting, diarrhea, and lethargy.

    Infections

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including
      fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or
      headache, dysuria, oral herpes simplex infection, and painful wounds with erythema and advise patients of the
      increased risk of infections during and after treatment with Ruxience.

    Cardiovascular Adverse Reactions 

    • Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial
      infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report
      chest pain and irregular heartbeats.

    Renal Toxicity

    • Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor
      kidney function.

    Bowel Obstruction and Perforation

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction
      and perforation, including severe abdominal pain or repeated vomiting.

    Embryo-Fetal Toxicity 

    • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their
      healthcare provider of a known or suspected pregnancy.
    • Advise females of reproductive potential to use effective contraception during treatment with Ruxience and
      for 12 months after the last dose.

    Lactation

    • Advise women not to breastfeed during treatment with Ruxience and for 6 months after the last dose.

    Cost Savings Program

    The Ruxience savings program is available here.

    Ruxience Generic Name & Formulations

    Legal Class

    Rx

    General Description

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

    Pharmacological Class

    CD20-directed cytolytic monoclonal antibody.

    How Supplied

    Single-dose vial (10mL, 50mL)—1

    How Supplied

    Ruxience (rituximab-pvvr) injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale brownish-yellow solution for intravenous infusion supplied as follows: 

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

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

    Storage

    Store vials refrigerated at 2° C to 8° C (36° F to 46° F) in the original carton. Protect vials from direct sunlight. Do not freeze or shake.

    Diluted Ruxience solutions for infusion may be stored refrigerated at 2° C to 8° C (36° F to 46° F) for 24 hours. Complete administration within 8 hours from removal from refrigeration.

    Manufacturer

    Pfizer Inc.

    Generic Availability

    NO

    Ruxience Indications

    Indications

    For the treatment of granulomatosis with polyangiitis (Wegener's granulomatosis) and microscopic polyangiitis, in combination with glucocorticoids.

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

    During Ruxience Therapy: 

    • In patients with lymphoid malignancies, during treatment with Ruxience monotherapy, obtain CBC with differential and platelet counts prior to each Ruxience course. During treatment with Ruxience and chemotherapy, obtain CBC with differential and platelet counts at weekly to monthly intervals and more frequently in patients who develop cytopenias.

    • In patients with RA, GPA or MPA, obtain CBC with differential and platelet counts at 2 to 4 month intervals during Ruxience therapy. Continue to monitor for cytopenias after final dose and until resolution.

    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 Ruxience 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 Ruxience 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

    Not established.

    Other Modifications

    Females and Males of Reproductive Potential 

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

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

    Ruxience Contraindications

    Not Applicable

    Ruxience 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, Severe Mucocutaneous Reactions, Hepatitis B Virus Reactivation And Progressive Multifocal Leukoencephalopathy

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

    • Severe mucocutaneous reactions, some with fatal outcomes.

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

    • Progressive multifocal leukoencephalopathy (PML) resulting in death.

    Ruxience Warnings/Precautions

    Warnings/Precautions

    Discontinue if severe infusion-related or mucocutaneous reactions occur (eg, urticaria, hypotension, angioedema, hypoxia, bronchospasm, 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, history of cardiopulmonary adverse reactions, circulating malignant cells (≥25000/mm3); monitor closely. Monitor CBCs, platelet counts prior to and during treatment, then as indicated. 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 with rituximab products. Severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes.

    • Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion-related reactions as needed.

    • Temporarily or permanently discontinue Ruxience 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.

    Severe Mucocutaneous Reactions

    • Mucocutaneous reactions, some with fatal outcomes, may occur. The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure. The safety of re-administration of rituximab 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 and has been reported up to 24 months following completion of rituximab therapy. 

    • 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 Ruxience 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 Ruxience therapy.

    • Discontinue Ruxience immediately and any concomitant chemotherapy if HBV reactivation occurs, and institute appropriate treatment. There is insufficient data regarding the safety of resuming Ruxience treatment in patients who develop HBV reactivation. Resumption of Ruxience 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 Ruxience 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 rituximab 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 Ruxience for serious infections and institute appropriate anti-infective therapy. Ruxience 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 rituximab products. 

    • Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Ruxience 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 rituximab product 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 Ruxience is not an approved treatment regimen. 

    • Monitor closely for signs of renal failure and discontinue Ruxience 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 rituximab products in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1-77) days in patients with NHL. 

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

    Immunization

    • The safety of immunization with live viral vaccines following rituximab product therapy has not been studied and vaccination with live virus vaccines is not recommended before or during treatment.

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

    Embryo-Fetal Toxicity

    • Based on human data, rituximab products can cause fetal harm due to B-cell lymphocytopenia in infants exposed in-utero. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception while receiving Ruxience 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 rituximab products.

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

    • While the efficacy of rituximab 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 Ruxience in patients with RA who have not had prior inadequate response to 1 or more TNF antagonists is not recommended.

    Pregnancy Considerations

    Risk Summary

    • Based on human data, rituximab products 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. 

    • Verify pregnancy status in females of reproductive potential prior to initiating Ruxience. Advise females of reproductive potential to use effective contraception during treatment with Ruxience and for 12 months after the last dose. 

    Nursing Mother Considerations

    Risk Summary

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

    • Given that the clinical significance of this finding for children is not known, advise women not to breastfeed during treatment with Ruxience and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.

    Pediatric Considerations

    Safety and effectiveness of rituximab products have not been established in pediatric patients with NHL, CLL or RA. 

    Rituximab was not studied in pediatric patients with polyarticular juvenile idiopathic arthritis (PJIA) due to concerns regarding the potential for prolonged immunosuppression as a result of B-cell depletion.

    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 rituximab in low-grade or follicular, CD20-positive, B-cell NHL did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger subjects. 

     Chronic Lymphocytic Leukemia

    In exploratory analyses defined by age, there was no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 70 years of age or older in CLL Study 1 or in CLL Study 2; there was also no observed benefit from the addition of rituximab to fludarabine and cyclophosphamide among patients 65 years of age or older in CLL Study 2.

     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. 

    Other Considerations for Specific Populations

    Females and Males of Reproductive Potential 

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

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

    Ruxience Pharmacokinetics

    Distribution

    Volume of distribution: 3.1 L (RA) and 3.12 L (GPA/MPA).

    Elimination

    Terminal half-life: 18 days (RA; range, 5.17 to 77.5 days); 22 days (NHL; range, 6.1 to 52 days); 25 days (GPA/MPA; range, 11 to 52 days); 32 days (CLL; range, 14 to 62 days).

    Ruxience Interactions

    Interactions

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

    Ruxience Adverse Reactions

    Adverse Reactions

    Infusion-related reactions (may be fatal), fever, lymphopenia, chills, infections (may be serious), asthenia, neutropenia, upper RTI, nausea, diarrhea, headache, muscle spasms, anemia, peripheral edema, UTI, bronchitis; 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.

    Ruxience Clinical Trials

    Clinical Trials

    Granulomatosis with Polyangiitis (GPA) (Wegener’s Granulomatosis) and Microscopic Polyangiitis (MPA) Study 1 (Induction Treatment of Adults with Active Disease)

    • The randomized, double-blind, active-controlled, multicenter, non-inferiority study evaluated rituximab 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 rituximab 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 rituximab 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 rituximab 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 rituximab 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. 

    GPA/MPA Study 1 (Follow Up Treatment of Adults with Active Disease who achieved disease control with other immunosuppressant)

    • 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.

    Ruxience Note

    Not Applicable

    Ruxience Patient Counseling

    Patient Counseling

    Infusion-Related Reactions 

    • 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.

    Severe Mucocutaneous Reactions 

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of severe mucocutaneous reactions, including painful sores or ulcers on the mouth, blisters, peeling skin, rash, and pustules.

    Hepatitis B Virus Reactivation

    • Advise patients to contact their healthcare provider immediately for symptoms of hepatitis including worsening
      fatigue or yellow discoloration of skin or eyes.

    Progressive Multifocal Leukoencephalopathy (PML) 

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of PML, including
      new or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or
      walking, decreased strength or weakness on one side of the body, or vision problems.

    Tumor Lysis Syndrome (TLS)

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of tumor lysis
      syndrome such as nausea, vomiting, diarrhea, and lethargy.

    Infections

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of infections including
      fever, cold symptoms (e.g., rhinorrhea or laryngitis), flu symptoms (e.g., cough, fatigue, body aches), earache or
      headache, dysuria, oral herpes simplex infection, and painful wounds with erythema and advise patients of the
      increased risk of infections during and after treatment with Ruxience.

    Cardiovascular Adverse Reactions 

    • Advise patients of the risk of cardiovascular adverse reactions, including ventricular fibrillation, myocardial
      infarction, and cardiogenic shock. Advise patients to contact their healthcare provider immediately to report
      chest pain and irregular heartbeats.

    Renal Toxicity

    • Advise patients of the risk of renal toxicity. Inform patients of the need for healthcare providers to monitor
      kidney function.

    Bowel Obstruction and Perforation

    • Advise patients to contact their healthcare provider immediately for signs and symptoms of bowel obstruction
      and perforation, including severe abdominal pain or repeated vomiting.

    Embryo-Fetal Toxicity 

    • Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their
      healthcare provider of a known or suspected pregnancy.
    • Advise females of reproductive potential to use effective contraception during treatment with Ruxience and
      for 12 months after the last dose.

    Lactation

    • Advise women not to breastfeed during treatment with Ruxience and for 6 months after the last dose.

    Cost Savings Program

    The Ruxience savings program is available here.

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