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Rituxan I.V.

Warnings

Fatal Infusion Reactions:   Deaths within 24 hours of RITUXAN infusion have been reported. These fatal reactions followed an infusion reaction complex which included hypoxia, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation or cardiogenic shock. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. (See WARNINGS and ADVERSE REACTIONS .)

Patients who develop severe infusion reactions should have RITUXAN infusion discontinued and receive medical treatment.

Tumor Lysis Syndrome (TLS):   Acute renal failure requiring dialysis with instances of fatal outcome has been reported in the setting of TLS following treatment with RITUXAN. (See WARNINGS .)

Severe Mucocutaneous Reactions:   Severe mucocutaneous reactions, some with fatal outcome, have been reported in association with RITUXAN treatment. (See WARNINGS and ADVERSE REACTIONS .)

Description

The RITUXAN (Rituximab) antibody is a 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 IgG 1 kappa immunoglobulin containing murine light- and heavy-chain variable region sequences and human constant region sequences. Rituximab is composed of two heavy chains of 451 amino acids and two light chains of 213 amino acids (based on cDNA analysis) and has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM.

The chimeric anti-CD20 antibody is produced by mammalian cell (Chinese Hamster Ovary) suspension culture in a nutrient medium containing the antibiotic gentamicin. Gentamicin is not detectable in the final product. The anti-CD20 antibody is purified by affinity and ion exchange chromatography. The purification process includes specific viral inactivation and removal procedures. Rituximab drug product is manufactured from either bulk drug substance manufactured by Genentech, Inc. (US License No. 1048) or utilizing formulated bulk Rituximab supplied by IDEC Pharmaceuticals Corporation (US License No. 1235) under a shared manufacturing arrangement.

RITUXAN is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous (IV) administration. RITUXAN is supplied at a concentration of 10 mg/mL in either 100 mg (10 mL) or 500 mg (50 mL) single-use vials. The product is formulated for IV administration in 9.0 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Sterile Water for Injection. The pH is adjusted to 6.5.

Clinical Pharmacology

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).

Table 1
Rituximab C max Values
Infusion Number Mean C max
µg/mL
Range
µg/mL
1 242.6 16.1-581.9
2 357.5 106.8-948.6
3 381.3 110.5-731.2
4 460.0 138.0-835.8
5 475.3 156.0-929.1
6 515.4 152.7-865.2
7 544.6 187.0-936.8
8 550.0  170.6-1177.0

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.

Clinical Studies

Studies with a collective enrollment of 296 patients having relapsed or refractory low-grade or follicular B-cell NHL are described below (Table 2). RITUXAN regimens tested include treatment weekly for 4 doses and treatment weekly for 8 doses. Clinical settings studied were initial treatment, initial treatment of bulky disease, and retreatment.

Table 2
Summary of RITUXAN Efficacy Data by Schedule and Clinical Setting
(See
ADVERSE REACTIONS for Risk Factors
Associated with Increased Rates of Adverse Events.)
   Initial,
Weekly × 4
N = 166
Initial,
Weekly × 8
N = 37
Initial, Bulky,
Weekly × 4
N = 39
1
Retreatment,
Weekly × 4
N = 60
Overall Response Rate
48% 57% 36% 38%
Complete Response Rate
6% 14% 3% 10%
Median Duration Of Response 2 , 3 , 4 (Months)
11.2 13.4 6.9 15.0
[Range]
[1.9 to 42.1+] [2.5 to 36.5+] [2.8 to 25.0+] [3.0 to 25.1+]
1 Six of these patients are included in the first column. Thus, data from 296 intent to treat patients are provided in this table.
2 Kaplan-Meier projected with observed range.
3 "+" indicates an ongoing response.
4 Duration of response: interval from the onset of response to disease progression.

Initial Treatment, Weekly for 4 Doses

A multicenter, open-label, single-arm study was conducted in 166 patients with relapsed or refractory low-grade or follicular B-cell NHL who received 375 mg/m 2 of RITUXAN given as an IV infusion weekly for 4 doses. 13 Patients with tumor masses >10 cm or with >5,000 lymphocytes/µL in the peripheral blood were excluded from the study. The overall response rate (ORR) was 48% with 6% complete response (CR) and 42% partial response (PR) rates. The median time to onset of response was 50 days and the median duration of response was 11.2 months (range, 1.9 to 42.1+). Disease-related signs and symptoms (including B-symptoms) were present in 23% (39/166) of patients at study entry and resolved in 64% (25/39) of those patients.

In a multivariate analysis, the ORR was higher in patients with IWF B, C, and D histologic subtypes as compared to IWF subtype A (58% vs. 12%), higher in patients whose largest lesion was <5 cm vs. >7 cm (maximum, 21 cm) in greatest diameter (53% vs. 38%), and higher in patients with chemosensitive relapse as compared with chemoresistant (defined as duration of response <3 months) relapse (53% vs. 36%). ORR in patients previously treated with autologous bone marrow transplant was 78% (18/23). The following adverse prognostic factors were not associated with a lower response rate: age >/=60 years, extranodal disease, prior anthracycline therapy, and bone marrow involvement.

Initial Treatment, Weekly for 8 Doses

In a multicenter, single-arm study, 37 patients with relapsed or refractory, low-grade NHL received 375 mg/m 2 of RITUXAN weekly for 8 doses. The ORR was 57% (CR 14%, PR 43%) with a projected median duration of response of 13.4 months (range, 2.5 to 36.5+). 14 (For information on the higher incidence of Grade 3 and 4 adverse events, see ADVERSE REACTIONS , Risk Factors Associated with Increased Rates of Adverse Events .)

Initial Treatment, Bulky Disease, Weekly for 4 Doses

In pooled data from multiple studies of RITUXAN, 39 patients with relapsed or refractory, bulky disease (single lesion >10 cm in diameter), low-grade NHL received 375 mg/m 2 of RITUXAN weekly for 4 doses. The ORR was 36% (CR 3%, PR 33%) with a median duration of response of 6.9 months (range 2.8 to 25.0+). (For information on the higher incidence of Grade 3 and 4 adverse events, see ADVERSE REACTIONS , Risk Factors Associated with Increased Rates of Adverse Events .)

Retreatment, Weekly for 4 Doses

In a multi-center, single-arm study, 60 patients received 375 mg/m 2 of RITUXAN weekly for 4 doses. 15 All patients had relapsed or refractory, low-grade or follicular B-cell NHL and had achieved an objective clinical response to a prior course of RITUXAN. Of these 60 patients, 55 received their second course of RITUXAN, 3 patients received their third course and 2 patients received their second and third courses of RITUXAN in this study. The ORR was 38% (10% CR and 28% PR) with a projected median duration of response of 15 months (range, 3.0 to 25.1+ months).

Indications and Usage

RITUXAN (Rituximab) is indicated for the treatment of patients with relapsed or refractory, low-grade or follicular, CD20-positive, B-cell non-Hodgkin's lymphoma.

Contraindications

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.

Precautions

Laboratory Monitoring:   Because RITUXAN targets all CD20-positive B lymphocytes, malignant and nonmalignant, complete blood counts (CBC) and platelet counts should be obtained at regular intervals during RITUXAN therapy and more frequently in patients who develop cytopenias (see ADVERSE REACTIONS ). The duration of cytopenias caused by RITUXAN can extend well beyond the treatment period.

Drug/Laboratory Interactions:   There have been no formal drug interaction studies performed with RITUXAN. However, renal toxicity was seen with this drug in combination with cisplatin in clinical trials. (See WARNINGS , Renal .)

HACA Formation:   Human antichimeric antibody (HACA) was detected in 4 of 356 patients and 3 had an objective clinical response. The data reflect the percentage of patients whose test results were considered positive for antibodies to RITUXAN using an enzyme-linked immunosorbant assay (limit of detection = 7 ng/mL). The observed incidence of antibody positivity in an assay is highly dependent on the sensitivity and specificity of the assay and may be influenced by several factors including sample handling, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to RITUXAN with the incidence of antibodies to other products may be misleading.

Immunization:   The safety of immunization with live viral vaccines following RITUXAN therapy has not been studied. The ability to generate a primary or anamnestic humoral response to vaccination is currently being studied.

Carcinogenesis, Mutagenesis, Impairment of Fertility:   No long-term animal studies have been performed to establish the carcinogenic or mutagenic potential of RITUXAN, or to determine its effects on fertility in males or females. Individuals of childbearing potential should use effective contraceptive methods during treatment and for up to 12 months following RITUXAN therapy.

Pregnancy Category C:   Animal reproduction studies have not been conducted with RITUXAN. It is not known whether RITUXAN can cause fetal harm when administered to a pregnant woman or whether it can affect reproductive capacity. Human IgG is known to pass the placental barrier, and thus may potentially cause fetal B-cell depletion; therefore, RITUXAN should be given to a pregnant woman only if clearly needed.

Nursing Mothers:   It is not known whether RITUXAN is excreted in human milk. Because human IgG is excreted in human milk and the potential for absorption and immunosuppression in the infant is unknown, women should be advised to discontinue nursing until circulating drug levels are no longer detectable. (See CLINICAL PHARMACOLOGY .)

Pediatric Use:   The safety and effectiveness of RITUXAN in pediatric patients have not been established.

Geriatric Use:   Among the 331 patients enrolled in clinical studies of single agent RITUXAN, 24% were 65 to 75 years old and 5% were 75 years old and older. The overall response rates were higher in older (age >/= 65 years) vs. younger (age < 65 years) patients (52% vs. 44%, respectively). However, the median duration of response, based on Kaplan-Meier estimates, was shorter in older vs. younger patients: 10.1 months (range, 1.9 to 36.5+) vs. 11.4 months (range, 2.1 to 42.1+), respectively. This shorter duration of response was not statistically significant. Adverse reactions, including incidence, severity and type of adverse reaction were similar between older and younger patients.

Adverse Reactions

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

Table 3
Incidence of Adverse Events >/= 5% of Patients in Clinical
Trials (N = 356) (Adverse Events were followed for a
period of 12 months following RITUXAN therapy)
  
All Grades (%) Grade 3 and 4 (%)
Any Adverse Events
99 57
Body as a Whole
86 10
  Fever
53 1
  Chills
33 3
  Infection
31 4
  Asthenia
26 1
  Headache
19 1
  Abdominal Pain
14 1
  Pain
12 1
  Back Pain
10 1
  Throat Irritation
9 0
  Flushing
5 0
Cardiovascular System
25 3
  Hypotension
10 1
  Hypertension
6 1
Digestive System
37 2
  Nausea
23 1
  Diarrhea
10 1
  Vomiting
10 1
Hemic and Lymphatic System
67 48
  Lymphopenia
48 40
  Leukopenia
14 4
  Neutropenia
14 6
  Thrombocytopenia
12 2
  Anemia
8 3
Metabolic and Nutritional Disorders
38 3
  Angioedema
11 1
  Hyperglycemia
9 1
  Peripheral Edema
8 0
  LDH Increase
7 0
Musculoskeletal System
26 3
  Myalgia
10 1
  Arthralgia
10 1
Nervous System
32 1
  Dizziness
10 1
  Anxiety
5 1
Respiratory System
38 4
  Increased Cough
13 1
  Rhinitis
12 1
  Bronchospasm
8 1
  Dyspnea
7 1
  Sinusitis
6 0
Skin and Appendages
44 2
  Night Sweats
15 1
  Rash
15 1
  Pruritus
14 1
  Urticaria
8 1

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.

Overdosage

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

Dosage and Administration

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.

How Supplied

RITUXAN (Rituximab) is supplied as 100 mg and 500 mg of sterile, preservative-free, single-use vials.

Single unit 100 mg carton: Contains one 10 mL vial of RITUXAN (10 mg/mL).

NDC 50242-051-21

Single unit 500 mg carton: Contains one 50 mL vial of RITUXAN (10 mg/mL).

NDC 50242-053-06

References

  1. Valentine MA, Meier KE, Rossie S, et al. Phosphorylation of the CD20 phosphoprotein in resting B lymphocytes. J Biol Chem 1989 264(19):11282-11287.
  2. Einfeld DA, Brown JP, Valentine MA, et al. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J 1988 7(3):711-717.
  3. Anderson KC, Bates MP, Slaughenhoupt BL, et al. Expression of human B cell-associated antigens on leukemias and lymphomas: A model of human B cell differentiation. Blood 1984 63(6):1424-1433.
  4. Tedder TF, Boyd AW, Freedman AS, et al. The B cell surface molecule B1 is functionally linked with B cell activation and differentiation. J Immunol 1985 135(2):973-979.
  5. Tedder TF, Zhou LJ, Bell PD, et al. The CD20 surface molecule of B lymphocytes functions as a calcium channel. J Cell Biochem 1990 14D:195.
  6. Press OW, Applebaum F, Ledbetter JA, Martin PJ, Zarling J, Kidd P, et al. Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B-cell lymphomas. Blood 1987 69(2):584-591.
  7. Reff ME, Carner C, Chambers KS, Chinn PC, Leonard JE, Raab R, et al. Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20. Blood 1994 83(2):435-445.
  8. Demidem A, Lam T, Alas S, Hariharan K, Hanna N, and Bonavida B. Chimeric anti-CD20 (IDEC-C2B8) monoclonal antibody sensitizes a B cell lymphoma cell line to cell killing by cytotoxic drugs. Cancer Biotherapy & Radiopharmaceuticals 1997 12(3):177-186.
  9. Maloney DG, Liles TM, Czerwinski C, Waldichuk J, Rosenberg J, Grillo-López A, et al. Phase I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma. Blood 1994 84(8):2457-2466.
  10. Berinstein NL, Grillo-López AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, et al. Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma. Annals of Oncology 1998, 9:995-1001.
  11. Maloney DG, Grillo-López AJ, Bodkin D, White CA, Liles T-M, Royston I, et al. IDEC-C2B8: Results of a phase I multiple-dose trial in patients with relapsed non-Hodgkin's lymphoma. J Clin Oncol 1997 15(10):3266-3274.
  12. Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 1997 90(6):2188-2195.
  13. McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, 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):2825-2833.
  14. Piro LD, White CA, Grillo-López AJ, Janakiraman N, Saven A, Beck TM, et al. Extended Rituximab (anti-CD20 monoclonal antibody) therapy for relapsed or refractory low-grade or follicular non-Hodgkin's lymphoma. Annals of Oncology 1999 10:655-661.
  15. Davis TA, Grillo-López AJ, White CA, McLaughlin P, Czuczman MS, Link BK, Maloney DG, Weaver RL, Rosenberg J, Levy R. Rituximab anti-CD20 monoclonal antibody therapy in non-hodgkin's lymphoma: safety and efficacy of re-treatment. J Clin Oncol 2000 18(17):3135-3143.
  16. Anhalt GJ, Kim SC, Stanley JR, Korman NJ, Jabs DA, Kory M, Izumi H, Ratrie H, Mutasim D, Ariss-Abdo L, Labib RS. Paraneoplastic Pemphigus, an autoimmune mucocutaneous disease associated with neoplasia. NEJM 1990 323(25):1729-1735.
  17. National Institutes of Health (US), National Cancer Institute. Common Toxicity Criteria. [Bethesda, MD.]: National Institutes of Health, National Cancer Institute; c1998. 73p.
  18. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E, Vardiman JW, Rai K, Schiffer CA, Larson RA. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 2003 101(1):6-14.

Jointly Marketed by:

IDEC Pharmaceuticals Corporation

11011 Torreyana Road

San Diego, CA 92121

Genentech, Inc.

1 DNA Way

South San Francisco, CA 94080-4990

4809705

Revised June 2004

PRODUCT PHOTO(S):

NOTE: These photos can be used only for identification by shape, color, and imprint. They do not depict actual or relative size.

The product samples shown here have been supplied by the manufacturer. While every effort has been made to assure accurate reproduction, please remember that any visual identification should be considered preliminary. In cases of poisoning or suspected overdosage, the drug's identity should be verified by chemical analysis.
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