No

Antineoplastic Agent, Miscellaneous

Non-Hodgkin's lymphoma: Treatment of patients with relapsed or refractory low-grade or follicular, CD20 positive, B-cell non-Hodgkin's lymphoma

C

Type I hypersensitivity or anaphylactic reactions to murine proteins or to any component of this product

Rituximab is associated with hypersensitivity reactions which may respond to adjustments in the infusion rate. Hypotension, bronchospasm, and angioedema have occurred as part of an infusion-related symptom complex. Interrupt rituximab infusion for severe reactions and resume at a 50% reduction in rate (eg, from 100 to 50 mg/hour) when symptoms have completely resolved. Treatment of these symptoms with diphenhydramine and acetaminophen is recommended; additional treatment with bronchodilators or I.V. saline may be indicated. In most cases, patients who have experienced nonlife-threatening reactions have been able to complete the full course of therapy. Medications for the treatment of hypersensitivity reactions (eg, epinephrine, antihistamines, corticosteroids) should be available for immediate use in the event of such a reaction during administration.

>10%:

Central nervous system: Headache, fever, chills

Gastrointestinal: Nausea

Hematologic: Leukopenia

Neuromuscular & skeletal: Asthenia

Miscellaneous: Angioedema

Immunologic: Rituximab-induced B-cell depletion occurred in 70% to 80% of patients and was associated with decreased serum immunoglobulins in a minority of patients. The incidence of infections does not appear to be increased. During the treatment period, 50 patients in the pivotal trial developed infectious events, including six grade 3 events (there were no grade 4 events. The six serious events were not associated with neutropenia).

Infusion-related: An infusion-related symptom complex consisting of fever and chills/rigors occurred in the majority of patients during the first rituximab infusion. Other frequent infusion-related symptoms included nausea, urticaria, fatigue, headache, pruritus, bronchospasm, dyspnea, sensation of tongue or throat swelling (angioedema), rhinitis, vomiting, hypotension, flushing, and pain at disease sites. These reactions generally occurred within 30 minutes to 2 hours of beginning the first infusion, and resolved with slowing or interruption of the infusion and with supportive care (I.V. saline, diphenhydramine, and acetaminophen). The incidence of infusion related events decreased from 80% during the first to ~40% with subsequent infusions. Mild to moderate hypotension requiring interruption of rituximab infusion, with or without the administration of I.V. saline, occurred in 10%. Isolated occurrences of severe reactions requiring epinephrine have been reported in patients receiving rituximab for other indicators. Angioedema was reported in 13% and was serious in one patient.

1% to 10%:

Cardiovascular: Hypotension

Central nervous system: Myalgia, dizziness

Dermatologic: Pruritus, rash, urticaria

Gastrointestinal: Vomiting, abdominal pain

Hematologic: Thrombocytopenia, neutropenia; during the treatment period (up to 30 days following the last dose), the following occurred: Severe thrombocytopenia, severe neutropenia, and severe anemia

Respiratory: Bronchospasm occurred in 8%; 25% of these patients were treated with bronchodilators; rhinitis

Miscellaneous: Throat irritation

<1%:

Four patients developed arrhythmias during rituximab infusion. One of the four discontinued treatment based on ventricular tachycardia and supraventricular tachycardias. The other three patients experienced trigeminy and irregular pulses and did not require discontinuation of therapy. Angina was reported during infusion and myocardial infarction occurred 4 days postinfusion in one subject with a history of myocardial infarction.

A single occurrence of transient aplastic anemia (pure red-cell aplasia) and two occurrences of hemolytic anemia were reported.

Note: Twenty-one patients have received more than one course of rituximab. The percentage of patients reporting any adverse event upon retreatment was similar to the percentage of patients reporting adverse events upon initial exposure. The following adverse events were reported more frequently in retreated patients: Asthenia, throat irritation, flushing, tachycardia, anorexia, leukopenia, thrombocytopenia, anemia, peripheral edema, dizziness, depression, respiratory symptoms, night sweats, pruritus.

There has been no experience with overdosage in human clinical trials; single doses higher than 500 mg/m² have not been tested

Store vials at refrigeration (2°C to 8°C/36°F to 46°F); protect vials from direct sunlight

Withdraw the necessary amount of rituximab and dilute to a final concentration of 1-4 mg/mL into an infusion bag containing either 0.9% sodium chloride or 5% dextrose in water. Gently invert the bag to mix the solution. 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 12 hours.

Genetically engineered chimeric murine/human monoclonal antibody directed against the CD20 antigen found on the surface of normal and malignant B lymphocytes. The antibody is an IgG₁ kappa immunoglobulin. It binds specifically to the antigen CD20. The antigen is also expressed on >90% of B-cell non-Hodgkin's lymphomas (NHL) but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells, or other normal tissues. CD20 regulates an early step(s) in the activation process for cell-cycle initiation and differentiation, and possibly functions as a calcium ion channel. CD20 is not shed from the cell surface and does not internalize upon antibody binding. The Fab domain of rituximab binds to the CD20 antigen on B-lymphocytes and the Fc domain recruits immune effector functions to mediate B-cell lysis in vitro. Possible mechanisms of cell lysis include complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. The antibody induces apoptosis in the DHL-4 human B-cell lymphoma line.

Absorption: I.V.: Immediate and results in a rapid and sustained depletion of circulating and tissue-based B cells

Half-life, mean serum: 59.8 hours after the first infusion and 174 hours after the fourth infusion

Duration: Detectable in the serum of patients 3-6 months after completion of treatment. B-cell recovery began ~6 months following completion of treatment. Median B-cell levels returned to normal by 12 months following completion of treatment.

Adults: I.V. (refer to individual protocols): Do not administer I.V. push or bolus (hypersensitivity reactions may occur). Consider premedication (consisting of acetaminophen and diphenhydramine) before each infusion of rituximab. Premedication may attenuate infusion-related events. Because transient hypotension may occur during infusion, give consideration to withholding antihypertensive medications 12 hours prior to rituximab infusion.

Obtain complete blood counts and platelet counts at regular intervals during rituximab therapy and more frequently in patients who develop cytopenia. Human antimurine antibody (HAMA) was not detected in 57 patients evaluated. Less than 1% of patients evaluated for human antichimeric antibody (HACA) was positive. Patients who develop HAMA/HACA titers may have an allergic or hypersensitivity reaction when treated with this or other murine or chimeric monoclonal antibodies. Monitor peripheral CD20+ cells.

Peripheral CD20+ cells: High level pretreatment (500-1600 cells/mL, malignant or normal) may indicate risk of more severe infusional reactions

May cause dizziness or depression

Leukopenia is common; avoid concurrent use with clozapine or carbamazepine

No information available to require special precautions

No effects or complications reported

You may experience a reaction during the infusion of this medication including high fever, chills, difficulty breathing, or congestion. You will be closely monitored and comfort measures provided. Maintain adequate hydration (2-3 L/day of fluids unless instructed to restrict fluid intake) during entire course of therapy. You will be susceptible to infection and people may wear masks and gloves while caring for you to protect you as much as possible (ie, avoid crowds and people with infections or contagious diseases). You may experience dizziness or trembling (use caution until response to medication is known); or nausea or vomiting (frequent small meals, frequent mouth care may help). Report persistent dizziness, swelling of extremities, unusual weight gain, difficulty breathing, chest pain or tightness; symptoms of respiratory infection, wheezing or bronchospasms, or difficulty breathing; unresolved gastrointestinal effects; skin rash or redness; sore or irritated throat; fatigue, chills, fever, unhealed sores, white plaques in mouth or genital area; unusual bruising or bleeding; or other unusual effects related to this medication. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to be pregnant. Do not breast-feed until approved by prescriber.

Injection, preservative free: 100 mg (10 mL); 500 mg (10 mL)

Coiffier B, Haioun C, Ketterer N, et al, "Rituximab (Anti-CD20 Monoclonal Antibody) for the Treatment of Patients With Relapsing or Refractory Aggressive Lymphoma: A Multicenter Phase II Study," Blood, 1998, 92(6):1927-32.

Maloney DG, Grillo-Lopez AJ, White CA, et al, "IDEC-C2B8 (Rituximab) Anti-CD20 Monoclonal Antibody Therapy in Patients With Relapsed Low-Grade Non-Hodgkin's Lymphoma," Blood, 1997, 90(6):2188-95.

McLaughlin P, Grillo-Lopez AJ, Link BK, et al, "Rituximab Chimeric Anti-CD20 Monoclonal Antibody Therapy for Relapsed Indolent Lymphoma: Half of Patients Respond to a Four-Dose Treatment Program," J Clin Oncol, 1998, 16(8):2825-33.

Scott SD, "Rituximab: A New Therapeutic Monoclonal Antibody for Non-Hodgkin's Lymphoma," Cancer Pract, 1998, 6(3):195-7.

Tobinai K, Kobayashi Y, Narabayashi M, et al, "Feasibility and Pharmacokinetic Study of a Chimeric Anti-CD20 Monoclonal Antibody (IDEC-C2B8, Rituximab) in Relapsed B-Cell Lymphoma. The IDEC-C2B8 Study Group," Ann Oncol, 1998, 9(5):527-34.