Rituximab

Abdominal pain, bowel obstruction, and perforation have been reported (rarely fatal), with an average onset of symptoms of ~6 days (range: 1 to 77 days); evaluate abdominal pain or repeated vomiting.

Discontinue infusion for 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.

Rituximab is associated with lymphopenia, leukopenia, neutropenia, thrombocytopenia, and anemia; the duration of cytopenias may be prolonged and may extend months beyond treatment. Monitor blood counts.

Hepatitis B virus (HBV) reactivation may occur with rituximab and in some cases may result in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection prior to treatment initiation, and monitor patients during and after treatment with rituximab. Discontinue rituximab and concomitant medications in the event of HBV reactivation. Screening should include hepatitis B surface antigen (HBsAg) and hepatitis B core antibody (anti-HBc); monitor patients for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months after treatment. If viral hepatitis develops, 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 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. - American Society of Clinical

Use is not recommended in patients with severe active infection. 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. 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.

Serious (including 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 to 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 anaphylactoid events. Closely monitor patients with a history of prior cardiopulmonary reactions or with preexisting 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). Medications for the treatment of hypersensitivity reactions (eg, bronchodilators, epinephrine, corticosteroids, oxygen) should be available for immediate use; treatment is symptomatic. If infusion reaction occurs, temporarily or permanently discontinue infusion (depending on the severity of the reaction and required interventions). After symptoms resolve, infusion may be resumed with at least a 50% infusion rate reduction.

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 reexposure following mucocutaneous reactions has not been evaluated.

Progressive multifocal leukoencephalopathy (PML) due to JC virus infection has been reported with rituximab; 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.

May cause fatal renal toxicity in patients with NHL. 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 leading to acute renal failure requiring dialysis (some fatal) may occur within 12 to 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, aggressive 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, and administer supportive care as indicated. Concurrent drug therapy issues:

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

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. Rheumatoid arthritis patients should be brought up to date with nonlive immunizations (following current guidelines) at least 4 weeks before initiating therapy; response to some immunizations may be lower in some patients receiving rituximab. Special populations:

Use with caution in the elderly. There is a higher risk of cardiac (supraventricular arrhythmia) and pulmonary adverse events (pneumonia, pneumonitis) and the incidence of serious infections and/or grade 3 or 4 adverse reactions are higher in elderly patients.

There are limited data on the safety of other biologics or disease-modifying antirheumatic drugs (DMARDs) other than methotrexate in patients with rheumatoid arthritis with B-cell depletion following rituximab treatment. Monitor patients closely for infection if biologic agents or DMARDS are used concomitantly. The use of rituximab is not recommended in RA patients who have not had prior inadequate response to one or more TNF antagonists. Dosage form specific issues:

Rituximab is for IV administration only. Do not substitute rituximab and hyaluronidase (SubQ) for rituximab (IV). Use caution during product selection, preparation, and administration.

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.