Rituxan I.V.

General

Rituximab binds specifically to the antigen CD20 (human B-lymphocyte-restricted differentiation antigen, Bp35), a hydrophobic transmembrane protein with a molecular weight of approximately 35 kD located on pre-B and mature B lymphocytes. 1,2 The antigen is also expressed on > 90% of B-cell non-Hodgkin's lymphomas (NHL), 3 but is not found on hematopoietic stem cells, pro-B cells, normal plasma cells or other normal tissues. 4 CD20 regulates an early step(s) in the activation process for cell cycle initiation and differentiation, 4 and possibly functions as a calcium ion channel. 5 CD20 is not shed from the cell surface and does not internalize upon antibody binding. 6 Free CD20 antigen is not found in the circulation. 2

Preclinical Pharmacology and Toxicology

Mechanism of Action: 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 (CDC) 7 and antibody-dependent cell mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line. 8

Normal Tissue Cross-reactivity: Rituximab binding was observed on lymphoid cells in the thymus, the white pulp of the spleen, and a majority of B lymphocytes in peripheral blood and lymph nodes. Little or no binding was observed in the non-lymphoid tissues examined.

Human Pharmacokinetics/Pharmacodynamics

In patients given single doses at 10, 50, 100, 250 or 500 mg/m 2 as an IV infusion, serum levels and the half-life of Rituximab were proportional to dose. 9 In 14 patients given 375 mg/m 2 as an IV infusion for 4 weekly doses, the mean serum half-life was 76.3 hours (range, 31.5 to 152.6 hours) after the first infusion and 205.8 hours (range, 83.9 to 407.0 hours); after the fourth infusion. 10,11,12 The wide range of half-lives may reflect the variable tumor burden among patients and the changes in CD20-positive (normal and malignant) B-cell populations upon repeated administrations.

RITUXAN at a dose of 375 mg/m 2 was administered as an IV infusion at weekly intervals for 4 doses to 203 patients naive to RITUXAN. The mean C max following the fourth infusion was 486 µg/mL (range, 77.5 to 996.6 µg/mL). The peak and trough serum levels of Rituximab were inversely correlated with baseline values for the number of circulating CD20-positive B cells and measures of disease burden. Median steady-state serum levels were higher for responders compared with nonresponders; however, no difference was found in the rate of elimination as measured by serum half-life. Serum levels were higher in patients with International Working Formulation (IWF) subtypes B, C, and D as compared with those with subtype A. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment.

RITUXAN at a dose of 375 mg/m 2 was administered as an IV infusion at weekly intervals for 8 doses to 37 patients. The mean C max after 8 infusions was 550 µg/mL (range, 171 to 1177 µg/mL). The mean C max increased with each successive infusion through the eighth infusion (Table 1).

The pharmacokinetic profile of RITUXAN when administered as 6 infusions of 375 mg/m 2 in combination with 6 cycles of CHOP chemotherapy was similar to that seen with RITUXAN alone.

Administration of RITUXAN resulted in a rapid and sustained depletion of circulating and tissue-based B cells. Lymph node biopsies performed 14 days after therapy showed a decrease in the percentage of B cells in seven of eight patients who had received single doses of Rituximab >/=100 mg/m 2 . 9 Among the 166 patients in the pivotal study, circulating B cells (measured as CD19-positive cells) were depleted within the first three doses with sustained depletion for up to 6 to 9 months post-treatment in 83% of patients. Of the responding patients assessed (n = 80), 1% failed to show significant depletion of CD19- positive cells after the third infusion of Rituximab as compared to 19% of the nonresponding patients. B-cell recovery began at approximately 6 months following completion of treatment. Median B-cell levels returned to normal by 12 months following completion of treatment.

There were sustained and statistically significant reductions in both IgM and IgG serum levels observed from 5 through 11 months following Rituximab administration. However, only 14% of patients had reductions in IgM and/or IgG serum levels, resulting in values below the normal range.

RITUXAN is contraindicated in patients with known anaphylaxis or IgE-mediated hypersensitivity to murine proteins or to any component of this product. (See WARNINGS .)

WARNINGS (See BOXED WARNINGS )

Severe Infusion Reactions (See BOXED WARNINGS , ADVERSE REACTIONS and Hypersensitivity Reactions ): RITUXAN has caused severe infusion reactions. In some cases, these reactions were fatal. These severe reactions typically occurred during the first infusion with time to onset of 30 to 120 minutes. Signs and symptoms of severe infusion reactions may include hypotension, angioedema, hypoxia or bronchospasm, and may require interruption of RITUXAN administration. The most severe manifestations and sequelae include pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, and cardiogenic shock. In the reported cases, the following factors were more frequently associated with fatal outcomes: female gender, pulmonary infiltrates, and chronic lymphocytic leukemia or mantle cell lymphoma.

Management of severe infusion reactions:   The RITUXAN infusion should be interrupted for severe reactions and supportive care measures instituted as medically indicated (e.g., intravenous fluids, vasopressors, oxygen, bronchodilators, diphenhydramine, and acetaminophen). In most cases, the infusion can be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have completely resolved. Patients requiring close monitoring during first and all subsequent infusions include those with pre-existing cardiac and pulmonary conditions, those with prior clinically significant cardiopulmonary adverse events and those with high numbers of circulating malignant cells (>/= 25,000/mm 3 ) with or without evidence of high tumor burden.

Tumor Lysis Syndrome [TLS] (See BOXED WARNINGS and ADVERSE REACTIONS ):   Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatasemia, have been reported within 12 to 24 hours after the first RITUXAN infusion. Rare instances of fatal outcome have been reported in the setting of TLS following treatment with RITUXAN. The risks of TLS appear to be greater in patients with high numbers of circulating malignant cells (>/= 25,000/mm 3 ) or high tumor burden. Prophylaxis for TLS should be considered for patients at high risk. Correction of electrolyte abnormalities, monitoring of renal function and fluid balance, and administration of supportive care, including dialysis, should be initiated as indicated. Following complete resolution of the complications of TLS, RITUXAN has been tolerated when re-administered in conjunction with prophylactic therapy for TLS in a limited number of cases.

Hepatitis B Reactivation with Related Fulminant Hepatitis:   Hepatitis B virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death has been reported in some patients with hematologic malignancies treated with RITUXAN. The majority of patients received RITUXAN in combination with chemotherapy. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of RITUXAN and approximately one month after the last dose.

Persons at high risk of HBV infection should be screened before initiation of RITUXAN. Carriers of hepatitis B should be closely monitored for clinical and laboratory signs of active HBV infection and for signs of hepatitis during and for up to several months following RITUXAN therapy.

In patients who develop viral hepatitis, RITUXAN and any concomitant chemotherapy should be discontinued and appropriate treatment including antiviral therapy initiated. There are insufficient data regarding the safety of resuming RITUXAN therapy in patients who develop hepatitis subsequent to HBV reactivation.

Hypersensitivity Reactions:

RITUXAN has been associated with hypersensitivity reactions (non-IgE-mediated reactions) which may respond to adjustments in the infusion rate and in medical management. Hypotension, bronchospasm, and angioedema have occurred in association with RITUXAN infusion (see Severe Infusion Reactions ). RITUXAN infusion should be interrupted for severe hypersensitivity reactions and can be resumed at a 50% reduction in rate (e.g., from 100 mg/hr to 50 mg/hr) when symptoms have completely resolved. Treatment of these symptoms with diphenhydramine and acetaminophen is recommended; additional treatment with bronchodilators or IV saline may be indicated. In most cases, patients who have experienced non-life-threatening hypersensitivity reactions have been able to complete the full course of therapy. (See DOSAGE and ADMINISTRATION .) Medications for the treatment of hypersensitivity reactions, e.g., epinephrine, antihistamines and corticosteroids, should be available for immediate use in the event of a reaction during administration.

Cardiovascular:   Infusions should be discontinued in the event of serious or life-threatening cardiac arrhythmias. Patients who develop clinically significant arrhythmias should undergo cardiac monitoring during and after subsequent infusions of RITUXAN. Patients with pre-existing cardiac conditions including arrhythmias and angina have had recurrences of these events during RITUXAN therapy and should be monitored throughout the infusion and immediate post-infusion period.

Renal:   RITUXAN administration has been associated with severe renal toxicity including acute renal failure requiring dialysis and in some cases, has led to a fatal outcome. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (>25,000/mm 3 ) or high tumor burden who experience tumor lysis syndrome (see Tumor Lysis Syndrome ) and in patients administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and RITUXAN is not an approved treatment regimen. If this combination is used in clinical trials extreme caution should be exercised; patients should be monitored closely for signs of renal failure. Discontinuation of RITUXAN should be considered for those with rising serum creatinine or oliguria.

Severe Mucocutaneous Reactions (See BOXED WARNINGS and ADVERSE REACTIONS ):   Mucocutaneous reactions, some with fatal outcome, have been reported in patients treated with RITUXAN. These reports include paraneoplastic pemphigus (an uncommon disorder which is a manifestation of the patient's underlying malignancy), 16 Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of the reaction in the reported cases has varied from 1 to 13 weeks following RITUXAN exposure. Patients experiencing a severe mucocutaneous reaction should not receive any further infusions and seek prompt medical evaluation. Skin biopsy may help to distinguish among different mucocutaneous reactions and guide subsequent treatment. The safety of readministration of RITUXAN to patients with any of these mucocutaneous reactions has not been determined.

The most serious adverse reactions caused by RITUXAN include infusion reactions, tumor lysis syndrome, mucocutaneous reactions, hypersensitivity reactions, cardiac arrhythmias and angina, and renal failure. Please refer to the BOXED WARNINGS and WARNINGS sections for detailed descriptions of these reactions. Infusion reactions and lymphopenia are the most commonly occurring adverse reactions.

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Additional adverse reactions have been identified during postmarketing use of RITUXAN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to RITUXAN exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to RITUXAN.

Where specific percentages are noted, these data are based on 356 patients treated in nonrandomized, single-arm studies of RITUXAN administered as a single agent. Most patients received RITUXAN 375 mg/m 2 weekly for 4 doses. These include 39 patients with bulky disease (lesions >/= 10 cm) and 60 patients who received more than 1 course of RITUXAN. Thirty-seven patients received 375 mg/m 2 for 8 doses and 25 patients received doses other than 375 mg/m 2 for 4 doses and up to 500 mg/m 2 single dose in the Phase 1 setting. Adverse events of greater severity are referred to as "Grade 3 and 4 events" defined by the commonly used National Cancer Institute Common Toxicity Criteria. 17

Risk Factors Associated with Increased Rates of Adverse Events:   Administration of RITUXAN weekly for 8 doses resulted in higher rates of Grade 3 and 4 adverse events 17 overall (70%) compared with administration weekly for 4 doses (57%). The incidence of Grade 3 or 4 adverse events was similar in patients retreated with RITUXAN compared with initial treatment (58% and 57%, respectively). The incidence of the following clinically significant adverse events was higher in patients with bulky disease (lesions >/=10 cm) (N = 39) versus patients with lesions < 10 cm (N = 195): abdominal pain, anemia, dyspnea, hypotension, and neutropenia.

Infusion Reactions (See BOXED WARNINGS and WARNINGS ):   Mild to moderate infusion reactions consisting of fever and chills/rigors occurred in the majority of patients during the first RITUXAN infusion. Other frequent infusion reaction symptoms included nausea, pruritus, angioedema, asthenia, hypotension, headache, bronchospasm, throat irritation, rhinitis, urticaria, rash, vomiting, myalgia, dizziness, and hypertension. These reactions generally occurred within 30 to 120 minutes of beginning the first infusion, and resolved with slowing or interruption of the RITUXAN infusion and with supportive care (diphenhydramine, acetaminophen, IV saline, and vasopressors). In an analysis of data from 356 patients with relapsed or refractory, low-grade NHL who received 4 (N = 319) or 8 (N = 37) weekly infusions of RITUXAN, the incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion (30% with fourth infusion and 14% with eighth infusion).

Infectious Events:   RITUXAN induced B-cell depletion in 70% to 80% of patients and was associated with decreased serum immunoglobulins in a minority of patients; the lymphopenia lasted a median of 14 days (range, 1 to 588 days). Infectious events occurred in 31% of patients: 19% of patients had bacterial infections, 10% had viral infections, 1% had fungal infections, and 6% were unknown infections. Incidence is not additive because a single patient may have had more than one type of infection. Serious infectious events (Grade 3 or 4), 17 including sepsis, occurred in 2% of patients.

Hematologic Events:   In clinical trials, Grade 3 and 4 cytopenias 17 were reported in 48% of patients treated with RITUXAN; these include: lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1 to 588 days) and of neutropenia was 13 days (range, 2 to 116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following RITUXAN therapy were reported.

In addition, there have been a limited number of postmarketing reports of prolonged pancytopenia, marrow hypoplasia, and late onset neutropenia (defined as occurring 40 days after the last dose of RITUXAN) in patients with hematologic malignancies. In reported cases of late onset neutropenia (NCI-CTC Grade 3 and 4), the median duration of neutropenia was 10 days (range 3 to 148 days). Documented resolution of the neutropenia was described in approximately one-half of the reported cases; of those with documented recovery, approximately half received growth factor support. In the remaining cases, information on resolution was not provided. More than half of the reported cases of delayed onset neutropenia occurred in patients who had undergone a prior autologous bone marrow transplantation. In an adequately designed, controlled, clinical trial, the reported incidence of NCI-CTC Grade 3 and 4 neutropenia was higher in patients receiving RITUXAN in combination with fludarabine as compared to those receiving fludarabine alone (76% [39/51] vs.39% [21/53]). 18

Cardiac Events (See BOXED WARNINGS ):   Grade 3 or 4 cardiac-related events include hypotension. Rare, fatal cardiac failure with symptomatic onset weeks after RITUXAN has also been reported. Patients who develop clinically significant cardiopulmonary events should have RITUXAN infusion discontinued.

Pulmonary Events (See BOXED WARNINGS ):   135 patients (38%) experienced pulmonary events in clinical trials. The most common respiratory system adverse events experienced were increased cough, rhinitis, bronchospasm, dyspnea, and sinusitis. In both clinical studies and post-marketing surveillance, there have been a limited number of reports of bronchiolitis obliterans presenting up to 6 months post-RITUXAN infusion and a limited number of reports of pneumonitis (including interstitial pneumonitis) presenting up to 3 months post-RITUXAN infusion, some of which resulted in fatal outcomes. The safety of resumption or continued administration of RITUXAN in patients with pneumonitis or bronchiolitis obliterans is unknown.

Immune/Autoimmune Events: Immune/autoimmune events have been reported, including uveitis, optic neuritis in a patient with systemic vasculitis, pleuritis in a patient with a lupus-like syndrome, serum sickness with polyarticular arthritis, and vasculitis with rash.

Less Commonly Observed Events:   In clinical trials, < 5% and > 1% of the patients experienced the following events regardless of causality assessment: agitation, anorexia, arthritis, conjunctivitis, depression, dyspepsia, edema, hyperkinesia, hypertonia, hypesthesia, hypoglycemia, injection site pain, insomnia, lacrimation disorder, malaise, nervousness, neuritis, neuropathy, paresthesia, somnolence, vertigo, weight decrease.

There has been no experience with overdosage in human clinical trials. Single doses of up to 500 mg/m 2 have been given in controlled clinical trials. 10

Initial Therapy:

RITUXAN is given at 375 mg/m 2 IV infusion once weekly for 4 or 8 doses.

Retreatment Therapy:   Patients who subsequently develop progressive disease may be safely retreated with RITUXAN 375 mg/m 2 IV infusion once weekly for 4 doses. Currently there are limited data concerning more than 2 courses.

RITUXAN as a Component of Zevalin™ (Ibritumomab Tiuxetan) Therapeutic Regimen:   As a required component of the Zevalin therapeutic regimen, RITUXAN 250 mg/m 2 should be infused within 4 hours prior to the administration of Indium-111- (In-111-) Zevalin and within 4 hours prior to the administration of Yttrium-90- (Y-90-) Zevalin. Administration of RITUXAN and In-111-Zevalin should precede RITUXAN and Y-90-Zevalin by 7-9 days. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.

RITUXAN may be administered in an outpatient setting. DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS. (See Administration .)

Instructions for Administration

Preparation for Administration:   Use appropriate aseptic technique. Withdraw the necessary amount of RITUXAN and dilute to a final concentration of 1 to 4 mg/mL into an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. Gently invert the bag to mix the solution. Discard any unused portion left in the vial. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration.

RITUXAN solutions for infusion may be stored at 2-8°C (36-46°F) for 24 hours. RITUXAN solutions for infusion have been shown to be stable for an additional 24 hours at room temperature. However, since RITUXAN solutions do not contain a preservative, diluted solutions should be stored refrigerated (2-8°C). No incompatibilities between RITUXAN and polyvinylchloride or polyethylene bags have been observed.

Administration: DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.

Infusion and hypersensitivity reactions may occur (see BOXED WARNINGS , WARNINGS , and ADVERSE REACTIONS ). Premedication consisting of acetaminophen and diphenhydramine should be considered before each infusion of RITUXAN. Premedication may attenuate infusion reactions. Since transient hypotension may occur during RITUXAN infusion, consideration should be given to withholding antihypertensive medications 12 hours prior to RITUXAN infusion.

First Infusion: The RITUXAN solution for infusion should be administered intravenously at an initial rate of 50 mg/hr. RITUXAN should not be mixed or diluted with other drugs. If hypersensitivity or infusion reactions do not occur, escalate the infusion rate in 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. If a hypersensitivity (non-IgE-mediated) or an infusion reaction develops, the infusion should be temporarily slowed or interrupted (see BOXED WARNINGS and WARNINGS ). The infusion can continue at one-half the previous rate upon improvement of patient symptoms.

Subsequent Infusions: If the patient tolerated the first infusion well, subsequent RITUXAN infusions can be administered at an initial rate of 100 mg/hr, and increased by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr as tolerated. If the patient did not tolerate the first infusion well, follow the guidelines under First Infusion.

Stability and Storage:   RITUXAN vials are stable at 2-8°C (36-46°F). Do not use beyond expiration date stamped on carton. RITUXAN vials should be protected from direct sunlight. Refer to the "Preparation and Administration" section for information on the stability and storage of solutions of RITUXAN diluted for infusion.

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