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RiTUXimab

Pronunciation

Pronunciation

(ri TUK si mab)

Index Terms

  • Anti-CD20 Monoclonal Antibody
  • C2B8 Monoclonal Antibody
  • IDEC-C2B8
  • Rituximab, inj

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Rituxan: 10 mg/mL (10 mL, 50 mL) [contains polysorbate 80]

Brand Names: U.S.

  • Rituxan

Pharmacologic Category

  • Antineoplastic Agent, Anti-CD20
  • Antineoplastic Agent, Monoclonal Antibody
  • Antirheumatic Miscellaneous
  • Immunosuppressant Agent
  • Monoclonal Antibody

Pharmacology

Rituximab is a monoclonal antibody directed against the CD20 antigen on B-lymphocytes. CD20 regulates cell cycle initiation; and, possibly, functions as a calcium channel. Rituximab binds to the antigen on the cell surface, activating complement-dependent B-cell cytotoxicity; and to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity. B-cells are believed to play a role in the development and progression of rheumatoid arthritis. Signs and symptoms of RA are reduced by targeting B-cells and the progression of structural damage is delayed.

Absorption

IV: Immediate and results in a rapid and sustained depletion of circulating and tissue-based B cells

Distribution

RA: 3.1 L; GPA/MPA: 4.5 L

Excretion

Uncertain; may undergo phagocytosis and catabolism in the reticuloendothelial system (RES)

Duration of Action

Detectable in serum 3-6 months after completion of treatment; B-cell recovery begins ~6 months following completion of treatment; median B-cell levels return to normal by 12 months following completion of treatment

Half-Life Elimination

CLL: Median terminal half-life: 32 days (range: 14-62 days)

NHL: Median terminal half-life: 22 days (range: 6-52 days)

RA: Mean terminal half-life: 18 days (range: 5-78 days)

GPA/MPA: 23 days (range: 9-49 days)

Use: Labeled Indications

Treatment of CD20-positive non-Hodgkin lymphomas (NHL):

Relapsed or refractory, low-grade or follicular B-cell NHL (as a single agent)

Follicular B-cell NHL, previously untreated (in combination with first-line chemotherapy, and as single-agent maintenance therapy if response to first-line rituximab with chemotherapy)

Nonprogressing, low-grade B-cell NHL (as a single agent after first-line CVP treatment)

Diffuse large B-cell NHL, previously untreated (in combination with CHOP chemotherapy [or other anthracycline-based regimen])

Treatment of CD20-positive chronic lymphocytic leukemia (CLL) (in combination with fludarabine and cyclophosphamide)

Treatment of moderately- to severely-active rheumatoid arthritis (in combination with methotrexate) in adult patients with inadequate response to one or more TNF antagonists

Treatment of granulomatosis with polyangiitis (GPA; Wegener’s granulomatosis) (in combination with glucocorticoids)

Treatment of microscopic polyangiitis (MPA) (in combination with glucocorticoids)

Use: Unlabeled

Treatment of Burkitt's lymphoma, central nervous system lymphoma, Hodgkin's lymphoma (lymphocyte predominant); mucosal associated lymphoid tissue (MALT) lymphoma (gastric and nongastric), splenic marginal zone lymphoma; Waldenström macroglobulinemia (WM); post-transplant lymphoproliferative disorder (PTLD); autoimmune hemolytic anemia (AIHA) in children; chronic immune thrombocytopenia (ITP); refractory pemphigus vulgaris; treatment of steroid-refractory chronic graft-versus-host disease (GVHD); refractory lupus nephritis; relapsed/refractory thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS), resistant idiopathic membranous nephropathy (IMN), refractory nephrotic syndrome (children)

Contraindications

There are no contraindications listed in the FDA-approved manufacturer’s labeling.

Canadian labeling (not in U.S. labeling): Type 1 hypersensitivity or anaphylactic reaction to murine proteins, Chinese Hamster Ovary (CHO) cell proteins, or any component of the formulation; patients who have or have had progressive multifocal leukoencephalopathy (PML)

Dosing: Adult

Note: Details concerning dosing in combination regimens should also be consulted. Pretreatment with acetaminophen and an antihistamine is recommended for all indications. For oncology uses, antihyperuricemic therapy and aggressive hydration are recommended for patients at risk for tumor lysis syndrome (high tumor burden or lymphocytes >25,000/mm3). In patients with CLL, Pneumocystis jirovecii pneumonia (PCP) and antiherpetic viral prophylaxis is recommended during treatment (and for up to 12 months following treatment). In patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), PCP prophylaxis is recommended during and for 6 months after rituximab treatment. For patients with RA, premedication with methylprednisolone 100 mg IV (or equivalent) is recommended 30 minutes prior to each dose.

Chronic lymphocytic leukemia (CLL): IV infusion: 375 mg/m2 on the day prior to fludarabine/cyclophosphamide in cycle 1, then 500 mg/m2 on day 1 (every 28 days) of cycles 2 to 6

Granulomatosis with polyangiitis (GPA; Wegener's granulomatosis): IV infusion: 375 mg/m2 once weekly for 4 doses (in combination with methylprednisolone IV for 1 to 3 days followed by daily prednisone)

Non-Hodgkin lymphoma (NHL; relapsed/refractory, low-grade or follicular CD20-positive, B-cell): IV infusion: 375 mg/m2 once weekly for 4 or 8 doses

Re-treatment following disease progression: 375 mg/m2 once weekly for 4 doses

NHL (diffuse large B-cell): IV infusion: 375 mg/m2 given on day 1 of each chemotherapy cycle for up to 8 doses

NHL (follicular, CD20-positive, B-cell, previously untreated): IV infusion: 375 mg/m2 given on day 1 of each chemotherapy cycle for up to 8 doses

Maintenance therapy (as a single agent, in patients with partial or complete response to rituximab plus chemotherapy; begin 8 weeks after completion of combination chemotherapy): IV infusion: 375 mg/m2 every 8 weeks for 12 doses

NHL (nonprogressing, low-grade, CD20-positive, B-cell, after 6 to 8 cycles of first line CVP are completed): IV infusion: 375 mg/m2 once weekly for 4 doses every 6 months for a maximum of 16 doses

NHL: Combination therapy with ibritumomab: IV infusion: 250 mg/m2 IV day 1; repeat in 7 to 9 days with ibritumomab (also see Ibritumomab monograph)

Canadian labeling: NHL, low grade or follicular: IV infusion:

Initial: 375 mg/m2 once weekly for 4 doses (as a single agent) or 375 mg/m2 on day 1 of each 21-day cycle for 8 cycles (in combination with CVP chemotherapy)

Maintenance (responding to induction therapy): 375 mg/m2 every 3 months until disease progression or up to a maximum of 2 years

Rheumatoid arthritis: IV infusion: 1,000 mg on days 1 and 15 in combination with methotrexate; subsequent courses may be administered every 24 weeks (based on clinical evaluation), if necessary may be repeated no sooner than every 16 weeks

Microscopic polyangiitis (MPA): IV infusion: 375 mg/m2 once weekly for 4 doses (in combination with methylprednisolone IV for 1 to 3 days followed by daily prednisone)

Antibody-mediated rejection in cardiac transplantation, treatment (off-label use): 375 mg/m2 once weekly for 1 to 4 doses (AHA [Colvin 2015]; ISHLT [Costanzo 2010]) or 1,000 mg on days 7 and 21 or on days 7 and 22 (AHA [Colvin 2015])

Chronic graft-versus-host disease (GVHD), refractory (off-label use): IV infusion: 375 mg/m2 once weekly for 4 doses (Cutler 2006)

Idiopathic thrombocytopenic purpura (ITP; off-label use): IV infusion: 375 mg/m2 once weekly for 4 doses (Arnold 2007; Godeau 2008)

Hodgkin lymphoma (off-label use): IV infusion: 375 mg/m2 once weekly for 4 weeks (Ekstrand 2003; Schulz 2008)

Idiopathic membranous nephropathy (IMN), resistant (off-label use): IV infusion: 375 mg/m2 once weekly for 4 doses with re-treatment at 6 months (Fervenza 2010) or 1,000 mg on days 1 and 15 (Fervenza 2008) or 375 mg/m2 single doses titrated to B cell response (Cravedi 2007)

Lupus nephritis, refractory (off-label use): IV infusion: 375 mg/m2 once weekly for 4 doses (Melander 2009) or 500 to 1000 mg on days 1 and 15 (Vigna-Perez 2006)

Pemphigus vulgaris, refractory (off-label use): IV infusion: 375 mg/m2 once weekly of weeks 1, 2, and 3 of a 4-week cycle, repeat for 1 additional cycle, then 1 dose per month for 4 months (total of 10 doses in 6 months) (Ahmed 2006)

Post-transplant lymphoproliferative disorder (off-label use): IV infusion: 375 mg/m2 once weekly for 4 doses (Choquet 2006)

Thrombotic thrombocytopenic purpura (TTP), relapsed/refractory (off-label use): IV infusion: 375 mg/m2 once weekly for 4 doses (Scully 2007; Scully 2011)

Waldenström's macroglobulinemia (off-label use): IV infusion: 375 mg/m2 once weekly for 4 weeks (Dimopoulos 2002)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Pretreatment with acetaminophen and an antihistamine is recommended.

Autoimmune hemolytic anemia (AIHA; off-label use): IV infusion: 375 mg/m2 once weekly for 2-4 doses (Zecca, 2003)

Chronic immune thrombocytopenia (ITP; off-label use): IV infusion: 375 mg/m2 once weekly for 4 doses (Parodi, 2009; Wang, 2005)

Nephrotic syndrome, severe, refractory (off-label use): IV infusion: 375 mg/m2 once weekly for 1-4 doses has been used in small case series, case reports, and retrospective analyses, including reports of successful remission induction of severe or refractory nephrotic syndromes that are poorly responsive to standard therapies (Dello Strologo, 2009; Fujinaga, 2010; Guigonis, 2008; Prytula, 2010)

Dosing: Renal Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

No dosage adjustment provided in manufacturer’s labeling (has not been studied).

Reconstitution

Withdraw necessary amount of rituximab and dilute to a final concentration of 1-4 mg/mL with 0.9% sodium chloride or 5% dextrose in water. Gently invert the bag to mix the solution. Do not shake.

Administration

Note: Some pediatric protocols utilize an alternate rituximab administration rate. Refer to specific protocol for administration rate guidelines.

Do not administer IV push or bolus. If a reaction occurs, slow or stop the infusion. If the reaction abates, restart infusion at 50% of the previous rate. Discontinue infusion in the event of serious or life-threatening cardiac arrhythmias.

IV: Initial infusion: Start rate of 50 mg/hour; if there is no reaction, increase the rate by 50 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.

Subsequent infusions:

Standard infusion rate: If patient tolerated initial infusion, start at 100 mg/hour; if there is no reaction, increase the rate by 100 mg/hour increments every 30 minutes, to a maximum rate of 400 mg/hour.

Accelerated infusion rate (90 minutes): For patients with previously untreated follicular NHL and diffuse large B-cell NHL who are receiving a corticosteroid as part of their combination chemotherapy regimen, have a circulating lymphocyte count <5000/mm3, or have no significant cardiovascular disease. After tolerance has been established (no grade 3 or 4 infusion-related event) at the recommended infusion rate in cycle 1, a rapid infusion rate may be used beginning with cycle 2. The daily corticosteroid, acetaminophen, and diphenhydramine are administered prior to treatment, then the rituximab dose is administered over 90 minutes, with 20% of the dose administered over the first 30 minutes and the remaining 80% is given over 60 minutes (Sehn, 2007). If the 90-minute infusion in cycle 2 is tolerated, the same rate may be used for the remainder of the treatment regimen (through cycles 6 or 8).

Compatibility

Stable in NS, D5W

Storage

Store intact vials refrigerated at 2°C to 8°C (36°F to 46°F); do not freeze. Do not shake. Protect vials from direct sunlight. Solutions for infusion are stable at 2°C to 8°C (36°F to 46°F) for 24 hours and at room temperature for an additional 24 hours.

Drug Interactions

Abatacept: RiTUXimab may enhance the adverse/toxic effect of Abatacept. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Certolizumab Pegol: RiTUXimab may enhance the immunosuppressive effect of Certolizumab Pegol. Avoid combination

CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Avoid combination

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: RiTUXimab may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Note: Patients treated with rituximab for rheumatoid arthritis (RA) may experience fewer adverse reactions.

>10%:

Cardiovascular: Peripheral edema (8% to 16%), hypertension (6% to 12%)

Central nervous system: Fever (5% to 53%), fatigue (13% to 39%), chills (3% to 33%), headache (17% to 19%), insomnia (≤14%), pain (12%)

Dermatologic: Rash (10% to 17%; grades 3/4: 1%), pruritus (5% to 17%), angioedema (11%; grades 3/4: 1%)

Gastrointestinal: Nausea (8% to 23%), diarrhea (10% to 17%), abdominal pain (2% to 14%), weight gain (11%)

Hematologic: Cytopenias (grades 3/4: ≤48%; may be prolonged), lymphopenia (48%; grades 3/4: 40%; median duration: 14 days), anemia (8% to 35%; grades 3/4: 3%), leukopenia (NHL: 14%; grades 3/4: 4%; CLL: grades 3/4: 23%; GPA/MPA: 10%), neutropenia (NHL: 14%; grades 3/4: 4% to 6%; median duration: 13 days; CLL: grades 3/4: 30% to 49%), neutropenic fever (CLL: grades 3/4: 9% to 15%), thrombocytopenia (12%; grades 3/4: 2% to 11%)

Hepatic: ALT increased (≤13%)

Neuromuscular & skeletal: Neuropathy (≤30%), weakness (2% to 26%), muscle spasm (≤17%), arthralgia (6% to 13%)

Respiratory: Cough (13%), rhinitis (3% to 12%), epistaxis (≤11%)

Miscellaneous: Infusion-related reactions (lymphoma: First dose 77%; decreases with subsequent infusions; may include angioedema, bronchospasm, chills, dizziness, fever, headache, hyper-/hypotension, myalgia, nausea, pruritus, rash, rigors, urticaria, and vomiting; reactions reported are lower [first infusion: 32%] in RA; CLL: 59%; grades 3/4: 7% to 9%; GPA/MPA: 12%); infection (19% to 62%; grades 3/4: 4%; bacterial: 19%; viral 10%; fungal: 1%), human antichimeric antibody (HACA) positive (1% to 23%), night sweats (15%)

1% to 10%:

Cardiovascular: Hypotension (10%; grades 3/4: 2%), flushing (5%)

Central nervous system: Dizziness (10%), anxiety (2% to 5%), migraine (RA: 2%)

Dermatologic: Urticaria (2% to 8%)

Endocrine & metabolic: Hyperglycemia (9%)

Gastrointestinal: Vomiting (10%), dyspepsia (RA: 3%)

Neuromuscular & skeletal: Back pain (10%), myalgia (10%), paresthesia (2%)

Respiratory: Dyspnea (≤10%), throat irritation (2% to 9%), bronchospasm (8%), dyspnea (7%), upper respiratory tract infection (RA: 7%), sinusitis (6%)

Miscellaneous: LDH increased (7%)

Postmarketing and/or case reports: Acute renal failure, anaphylactoid reaction/anaphylaxis, angina, aplastic anemia, ARDS, arrhythmia, bowel obstruction/perforation, bronchiolitis obliterans, cardiac failure, cardiogenic shock, encephalomyelitis, fatal infusion-related reactions, fulminant hepatitis, gastrointestinal perforation, hemolytic anemia, hepatic failure, hepatitis, hepatitis B reactivation, hyperviscosity syndrome (in Waldenström’s macroglobulinemia), hypogammaglobulinemia (prolonged), hypoxia, interstitial pneumonitis, laryngeal edema, lichenoid dermatitis, lupus-like syndrome, marrow hypoplasia, MI, mucositis, mucocutaneous reaction, neutropenia (late-onset occurring >40 days after last dose), optic neuritis, pancytopenia (prolonged), paraneoplastic pemphigus (uncommon), pleuritis, pneumonia, pneumonitis, polyarticular arthritis, polymyositis, posterior reversible encephalopathy syndrome (PRES), progressive multifocal leukoencephalopathy (PML), pure red cell aplasia, renal toxicity, reversible posterior leukoencephalopathy syndrome (RPLS), serum sickness, Stevens-Johnson syndrome, supraventricular arrhythmia, systemic vasculitis, toxic epidermal necrolysis, tuberculosis reactivation, tumor lysis syndrome, uveitis, vasculitis with rash, ventricular fibrillation, ventricular tachycardia, vesiculobullous dermatitis, viral reactivation (includes JC virus, cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C), wheezing

ALERT: U.S. Boxed Warning

Fatal infusion reactions:

Rituximab administration can result in serious, including fatal, infusion reactions. Deaths within 24 hours of rituximab infusion have been reported. Approximately 80% of fatal infusion reactions occurred in association with the first infusion.

Carefully monitor patients during infusions. Discontinue rituximab infusion for severe reactions and administer medical treatment for grade 3 or 4 infusion reactions.

Severe mucocutaneous reactions:

Severe, including fatal, mucocutaneous reactions can occur in patients receiving rituximab treatment.

Hepatitis B virus reactivation:

Hepatitis B virus (HBV) reactivation can occur in patients treated with rituximab, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before treatment initiation, and monitor patients during and after treatment with rituximab. Discontinue rituximab and concomitant medications in the event of HBV reactivation.

Progressive multifocal leukoencephalopathy:

JC virus infection resulting in progressive multifocal leukoencephalopathy (PML) and death can occur in patients treated with rituximab.

Warnings/Precautions

Concerns related to adverse effects:

• Bowel obstruction/perforation: Abdominal pain, bowel obstruction, and perforation have been reported (rarely fatal), with an average onset of symptoms of ~6 days (range: 1-77 days); complaints of abdominal pain or repeated vomiting should be evaluated, especially if early in the treatment course.

• Hepatitis B virus reactivation: [U.S. Boxed Warning]: Hepatitis B virus (HBV) reactivation may occur with use and may result in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection by measuring hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc) prior to therapy initiation; monitor patients for clinical and laboratory signs of hepatitis or HBV during and for several months after treatment. Discontinue rituximab (and concomitant medications) if viral hepatitis develops and initiate appropriate antiviral therapy. Reactivation has occurred in patients who are HBsAg positive as well as in those who are HBsAg negative but are anti-HBc positive; HBV reactivation has also been observed in patients who had previously resolved HBV infection. HBV reactivation has been reported up to 24 months after therapy discontinuation. Use cautiously in patients who show evidence of prior HBV infection (eg, HBsAg positive [regardless of antibody status] or HBsAG negative but anti-HBc positive); consult with appropriate clinicians regarding monitoring and consideration of antiviral therapy before and/or during rituximab treatment. The safety of resuming rituximab treatment following HBV reactivation is not known; discuss reinitiation of therapy in patients with resolved HBV reactivation with physicians experienced in HBV management.

• Infections: Use is not recommended if severe active infection is present; serious and potentially fatal bacterial, fungal, and either new or reactivated viral infections may occur during treatment and after completing rituximab. Infections have been observed in patients with prolonged hypogammaglobulinemia, defined as hypogammaglobulinemia >11 months after rituximab exposure; monitor immunoglobulin levels as necessary. Associated new or reactivated viral infections have included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis B and C. Discontinue rituximab (and concomitant chemotherapy) in patients who develop viral hepatitis and initiate antiviral therapy. Discontinue rituximab in patients who develop other serious infections and initiate appropriate anti-infective treatment.

• Infusion reactions: [U.S. Boxed Warning]: Severe (occasionally fatal) infusion-related reactions have been reported, usually with the first infusion; fatalities have been reported within 24 hours of infusion; monitor closely during infusion; discontinue for severe reactions and provide medical intervention for grades 3 or 4 infusion reactions. Reactions usually occur within 30-120 minutes and may include hypotension, angioedema, bronchospasm, hypoxia, urticaria, and in more severe cases pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, and/or anaphylaxis. Risk factors associated with fatal outcomes include chronic lymphocytic leukemia, female gender, mantle cell lymphoma, or pulmonary infiltrates. Closely monitor patients with a history of prior cardiopulmonary reactions or with pre-existing cardiac or pulmonary conditions and patients with high numbers of circulating malignant cells (>25,000/mm3). Prior to infusion, premedicate patients with acetaminophen and an antihistamine (and methylprednisolone for patients with RA). Discontinue infusion for severe reactions and serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after the infusion in patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. Medications for the treatment of hypersensitivity reactions (eg, bronchodilators, epinephrine, antihistamines, corticosteroids) should be available for immediate use; treatment is symptomatic. Mild-to-moderate infusion-related reactions (eg, chills, fever, rigors) occur frequently and are typically managed through slowing or interrupting the infusion. Infusion may be resumed at a 50% infusion rate reduction upon resolution of symptoms. Due to the potential for hypotension, consider withholding antihypertensives 12 hours prior to treatment.

• Mucocutaneous reactions: [U.S. Boxed Warning]: Severe and sometimes fatal mucocutaneous reactions (lichenoid dermatitis, paraneoplastic pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis and vesiculobullous dermatitis) have been reported; onset has been variable but has occurred as early as the first day of exposure. Discontinue in patients experiencing severe mucocutaneous skin reactions; the safety of re-exposure following mucocutaneous reactions has not been evaluated.

• Progressive multifocal leukoencephalopathy: [U.S. Boxed Warning]: Progressive multifocal leukoencephalopathy (PML) due to JC virus infection has been reported with rituximab use; may be fatal. Cases were reported in patients with hematologic malignancies receiving rituximab either with combination chemotherapy, or with hematopoietic stem cell transplant. Cases were also reported in patients receiving rituximab for autoimmune diseases who had received concurrent or prior immunosuppressant therapy. Onset may be delayed, although most cases were diagnosed within 12 months of the last rituximab dose. A retrospective analysis of patients (n=57) diagnosed with PML following rituximab therapy, found a median of 16 months (following rituximab initiation), 5.5 months (following last rituximab dose), and 6 rituximab doses preceded PML diagnosis. Clinical findings included confusion/disorientation, motor weakness/hemiparesis, altered vision/speech, and poor motor coordination with symptoms progressing over weeks to months (Carson, 2009). Promptly evaluate any patient presenting with neurological changes; consider neurology consultation, brain MRI and lumbar puncture for suspected PML. Discontinue rituximab in patients who develop PML; consider reduction/discontinuation of concurrent chemotherapy or immunosuppressants.

• Renal toxicity: May cause fatal renal toxicity in patients with hematologic malignancies. Patients who received combination therapy with cisplatin and rituximab for NHL experienced renal toxicity during clinical trials; this combination is not an approved treatment regimen. Renal toxicity also occurred due to tumor lysis syndrome. Monitor for signs of renal failure; discontinue rituximab with increasing serum creatinine or oliguria.

• Tumor lysis syndrome: Tumor lysis syndrome leading to acute renal failure requiring dialysis (some fatal) may occur 12-24 hours following the first dose when used as a single agent in the treatment of NHL. Hyperkalemia, hypocalcemia, hyperuricemia, and/or hyperphosphatemia may occur. Administer prophylaxis (antihyperuricemic therapy, hydration) in patients at high risk (high numbers of circulating malignant cells ≥25,000/mm3 or high tumor burden). Correct electrolyte abnormalities; monitor renal function and hydration status.

Disease-related concerns:

• Cardiovascular disease: Use with caution in patients with pre-existing cardiovascular disease or prior cardiopulmonary events. Discontinue with serious cardiac arrhythmia.

• Respiratory disease: Use with caution in patients with pre-existing pulmonary disease, or prior cardiopulmonary events.

Concurrent drug therapy issues:

• Biologic agents: Safety and efficacy of rituximab in combination with biologic agents have not been established.

• Disease-modifying antirheumatic drugs: Safety and efficacy of rituximab in combination with disease-modifying antirheumatic drugs (DMARDs) other than methotrexate have not been established.

• Immunizations: Live vaccines should not be given concurrently with rituximab; there is no data available concerning secondary transmission of live vaccines with or following rituximab treatment. RA patients should be brought up to date with nonlive immunizations (following current guidelines) at least 4 weeks before initiating therapy; evaluate risks of therapy delay versus benefit (of nonlive vaccines) for NHL patients.

Special populations:

• Elderly: Use with caution in the elderly; higher risk of cardiac (supraventricular arrhythmia) and pulmonary adverse events (pneumonia, pneumonitis).

• Granulomatosis with polyangiitis (GPA; Wegener’s granulomatosis)/microscopic polyangiitis (MPA): The safety of concomitant immunosuppressants other than corticosteroids has not been evaluated in patients with GPA or MPA after rituximab-induced B-cell depletion. There are only limited data on subsequent courses of rituximab for GPA or MPA; safety and efficacy of re-treatment have not been established.

• Rheumatoid arthritis (RA) patients: Monitor RA patients closely during and after each infusion; increased risk of cardiovascular events. Safety and efficacy of re-treatment for RA have not been established. Rituximab is not recommended for use in RA patients who have not had prior inadequate response to TNF antagonists.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Monitoring Parameters

CBC with differential and platelets (obtain at weekly to monthly intervals and more frequently in patients with cytopenias, or at 2-4 month intervals in rheumatoid arthritis patients, GPA and MPA), peripheral CD20+ cells; HAMA/HACA titers (high levels may increase the risk of allergic reactions); renal function, fluid balance; vital signs; monitor for infusion reactions, cardiac monitoring during and after infusion in rheumatoid arthritis patients and in patients with pre-existing cardiac disease or if arrhythmias develop during or after subsequent infusions.

Screen all patients for HBV infection prior to therapy initiation (eg, HBsAG and anti-HBc measurements). In addition, carriers and patients with evidence of current infection or recovery from prior hepatitis B infection should be monitored closely for clinical and laboratory signs of HBV reactivation and/or infection during therapy and for up to 2 years following completion of treatment. High-risk patients should be screened for hepatitis C (per NCCN NHL guidelines v.2.2013).

Complaints of abdominal pain, especially early in the course of treatment, should prompt a thorough diagnostic evaluation and appropriate treatment. Signs or symptoms of progressive multifocal leukoencephalopathy (focal neurologic deficits, which may present as hemiparesis, visual field deficits, cognitive impairment, aphasia, ataxia, and/or cranial nerve deficits). If PML is suspected, obtain brain MRI scan and lumbar puncture.

Pregnancy Risk Factor

C

Pregnancy Considerations

Animal reproduction studies have demonstrated adverse effects including decreased (reversible) B-cells and immunosuppression. Rituximab crosses the placenta and can be detected in the newborn. In one infant born at 41 weeks gestation, in utero exposure occurred from week 16-37; rituximab concentrations were higher in the neonate at birth (32,095 ng/mL) than the mother (9750 ng/mL) and still measurable at 18 weeks of age (700 ng/mL infant; 500 ng/mL mother) (Friedrichs, 2006).

B-cell lymphocytopenia lasting <6 months may occur in exposed infants. Limited information is available following maternal use of rituximab for the treatment of lymphomas and hematologic disorders (Ton, 2011). Retrospective case reports of inadvertent pregnancy during rituximab treatment collected by the manufacturer (often combined with concomitant teratogenic therapies) describe premature births and infant hematologic abnormalities and infections; no specific pattern of birth defects has been observed (limited data) (Chakravarty, 2010). Use is not recommended to treat non-life-threatening maternal conditions (eg, rheumatoid arthritis) during pregnancy (Makol, 2011; Østensen, 2008) and other agents are preferred for treating lupus nephritis in pregnant women (Hahn, 2012).

Effective contraception should be used during and for 12 months following treatment. Healthcare providers are encouraged to enroll women with rheumatoid arthritis exposed to rituximab during pregnancy in the MotherToBabyAutoImmune Diseases Study by contacting the Organization of Teratology Information Specialists (OTIS) (877-311-8972).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience abdominal pain, diarrhea, rhinorrhea, muscle spasms, back pain, insomnia, or night sweats. Have patient report immediately to prescriber signs of infection, signs of progressive multifocal leukoencephalopathy (confusion, depression, trouble with memory, behavioral changes, change in strength on one side, trouble speaking, change in balance, vision changes), signs of Stevens-Johnson syndrome/toxic epidermal necrolysis (red, swollen, blistered, or peeling skin [with or without fever]; red or irritated eyes; or sores in mouth, throat, nose, or eyes), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, weight gain), signs of bowel problems (black, tarry, or bloody stools; fever; mucus in stools; vomiting; vomiting blood; severe abdominal pain; constipation; diarrhea), angina, tachycardia, arrhythmia, severe dizziness, passing out, loss of strength and energy, severe headache, severe nausea, vomiting, bruising, bleeding, shortness of breath, excessive weight gain, swelling of arms or legs, severe muscle pain, severe joint pain, burning or numbness feeling, or signs of tumor lysis syndrome (fast heartbeat or abnormal heartbeat; any passing out; trouble passing urine; muscle weakness or cramps; nausea, vomiting, diarrhea or lack of appetite; or feeling sluggish) (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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