Rituximab – Rituxan®

Rituximab - Rituxan®

Usual Diluents

Dilution Data

Preparation for Administration:   Do not use vial if particulates or discoloration is present. Withdraw the necessary amount of Rituxan and dilute to a final concentration of 1 to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial.

Rituxan vials [100 mg (NDC 50242-051-21) and 500 mg (NDC 50242-053-06)] are stable at 2°C - 8°C (36°F - 46°F). Do not use beyond expiration date stamped on carton. Rituxan vials should be protected from direct sunlight. Do not freeze or shake.    Rituxan solutions for infusion may be stored at 2°C - 8°C (36°F - 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°C - 8°C). No incompatibilities between Rituxan and polyvinylchloride or polyethylene bags have been observed.

Initial U.S. Approval: 1997

DESCRIPTION
Rituxan® (rituximab) is a genetically engineered chimeric murine/human monoclonal IgG1 kappa antibody directed against the CD20 antigen. Rituximab has an approximate molecular weight of 145 kD. Rituximab has a binding affinity for the CD20 antigen of approximately 8.0 nM.

Rituximab 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. Rituxan is a sterile, clear, colorless, preservative-free liquid concentrate for intravenous 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 in 9 mg/mL sodium chloride, 7.35 mg/mL sodium citrate dihydrate, 0.7 mg/mL polysorbate 80, and Water for Injection. The pH is 6.5.

CLINICAL PHARMACOLOGY

Mechanism of Action
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. The antigen is expressed on >90% of B-cell non-Hodgkin’s lymphomas (NHL), but the antigen 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. Free CD20 antigen is not found in the circulation.

B cells are believed to play a role in the pathogenesis of rheumatoid arthritis (RA) and associated chronic synovitis. In this setting, B cells may be acting at multiple sites in the autoimmune/inflammatory process, including through production of rheumatoid factor (RF) and other autoantibodies, antigen presentation, T-cell activation, and/or pro-inflammatory cytokine production.

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) and antibody-dependent cell-mediated cytotoxicity (ADCC). The antibody has been shown to induce apoptosis in the DHL-4 human B-cell lymphoma line.

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.

Pharmacodynamics
In NHL patients, administration of Rituxan resulted in depletion of circulating and tissue-based B cells. Among 166 patients in Study 1, circulating CD19-positive B cells were depleted within the first three weeks with sustained depletion for up to 6 to 9 months posttreatment in 83% of patients. B-cell recovery began at approximately 6 months and 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 14% of patients had IgM and/or IgG serum levels below the normal range.

In RA patients, treatment with Rituxan induced depletion of peripheral B lymphocytes, with the majority of patients demonstrating near complete depletion (CD19 counts below the lower limit of quantification, 20 cells/µl) within 2 weeks after receiving the first dose of Rituxan. The majority of patients showed peripheral B-cell depletion for at least 6 months. A small proportion of patients (~4%) had prolonged peripheral B-cell depletion lasting more than 3 years after a single course of treatment.

Total serum immunoglobulin levels, IgM, IgG, and IgA were reduced at 6 months with the greatest change observed in IgM. At Week 24 of the first course of Rituxan treatment, small proportions of patients experienced decreases in IgM (10%), IgG (2.8%), and IgA (0.8%) levels below the lower limit of normal (LLN). In the experience with Rituxan in RA patients during repeated Rituxan treatment, 23.3%, 5.5%, and 0.5% of patients experienced decreases in IgM, IgG, and IgA concentrations below LLN at any time after receiving Rituxan, respectively. The clinical consequences of decreases in immunoglobulin levels in RA patients treated with Rituxan are unclear.

Treatment with rituximab in patients with RA was associated with reduction of certain biologic markers of inflammation such as interleukin-6 (IL-6), C-reactive protein (CRP), serum amyloid protein (SAA), S100 A8/S100 A9 heterodimer complex (S100 A8/9), anti-citrullinated peptide (anti-CCP), and RF.

Pharmacokinetics
Pharmacokinetics were characterized in 203 NHL patients receiving 375 mg/m2 Rituxan weekly by IV infusion for 4 doses. Rituximab was detectable in the serum of patients 3 to 6 months after completion of treatment.

The pharmacokinetic profile of rituximab when administered as 6 infusions of 375 mg/m2 in combination with 6 cycles of CHOP chemotherapy was similar to that seen with rituximab alone.

Based on a population pharmacokinetic analysis of data from 298 NHL patients who received rituximab once weekly or once every three weeks, the estimated median terminal elimination half life was 22 days (range, 6.1 to 52 days). Patients with higher CD19–positive cell counts or larger measurable tumor lesions at pretreatment had a higher clearance. However, dose adjustment for pretreatment CD19 count or size of tumor lesion is not necessary. Age and gender had no effect on the pharmacokinetics of rituximab.

Pharmacokinetics were characterized in 21 patients with CLL receiving rituximab according to the recommended dose and schedule. The estimated median terminal half-life of rituximab was 32 days (range, 14 to 62 days).

Following administration of 2 doses of Rituxan in patients with RA, the mean (+/- S.D.; % CV) concentrations after the first infusion (Cmax first) and second infusion (Cmax second) were 157 (+/- 46; 29%) and 183 (+/- 55; 30%) mcg/mL, and 318 (+/- 86; 27%) and 381 (+/- 98; 26%) mcg/mL for the 2 x 500 mg and 2 x 1000 mg doses, respectively.

Based on a population pharmacokinetic analysis of data from 2005 RA patients who received Rituxan, the estimated clearance of rituximab was 0.335 L/day; volume of distribution was 3.1 L and mean terminal elimination half life was 18.0 days (range, 5.17 to 77.5 days). Age, weight and gender had no effect on the pharmacokinetics of rituximab in RA patients.

The pharmacokinetics of rituximab have not been studied in children and adolescents. No formal studies were conducted to examine the effects of either renal or hepatic impairment on the pharmacokinetics of rituximab.

1. INDICATIONS AND USAGE

1.1 Non-Hodgkin’s Lymphoma (NHL)
Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy Non-progressing (including stable disease), low-grade, CD20-positive, B-cell NHL, as a single agent, after first-line CVP chemotherapy Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens 1.2 Chronic Lymphocytic Leukemia (CLL)
Rituxan® (rituximab) is indicated, in combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.

1.3 Rheumatoid Arthritis (RA)
Rituxan® (rituximab) in combination with methotrexate is indicated for the treatment of adult patients with moderately-to severely- active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

1.4 Limitations of Use
Rituxan is not recommended for use in patients with severe, active infections.

2. DOSAGE AND ADMINISTRATION

2.1 Administration
DO NOT ADMINISTER AS AN INTRAVENOUS PUSH OR BOLUS.
Premedicate before each infusion [see Dosage and Administration (2.6)]. Administer only as an intravenous (IV) infusion [see Dosage and Administration (2.6)].
First Infusion: Initiate infusion at a rate of 50 mg/hr. In the absence of infusion toxicity, increase infusion rate by 50 mg/hr increments every 30 minutes, to a maximum of 400 mg/hr. Subsequent Infusions: Initiate infusion at a rate of 100 mg/hr. In the absence of infusion toxicity, increase rate by 100 mg/hr increments at 30-minute intervals, to a maximum of 400 mg/hr. Interrupt the infusion or slow the infusion rate for infusion reactions [see Boxed Warning, Warnings and Precautions (5.1)]. Continue the infusion at one half the previous rate upon improvement of symptoms. 2.2   Recommended Dose for Non-Hodgkin’s Lymphoma (NHL)
The recommended dose is 375 mg/m2 as an IV infusion according to the following schedules: Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
Administer once weekly for 4 or 8 doses. Retreatment for Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL
Administer once weekly for 4 doses. Previously Untreated, Follicular, CD20-Positive, B-Cell NHL
Administer on Day 1 of each cycle of CVP chemotherapy, for up to 8 doses. Non-progressing, Low-Grade, CD20-Positive, B-cell NHL, after first-line CVP chemotherapy
Following completion of 6–8 cycles of CVP chemotherapy, administer once weekly for 4 doses at 6-month intervals to a maximum of 16 doses. Diffuse Large B-Cell NHL
Administer on Day 1 of each cycle of chemotherapy for up to 8 infusions. 2.3 Recommended Dose for Chronic Lymphocytic Leukemia (CLL)
The recommended dose is:
     375 mg/m2 the day prior to the initiation of FC chemotherapy, then 500 mg/m2 on Day 1 of cycles 2-6 (every 28 days).

2.4 Recommended Dose as a Component of Zevalin® Infuse rituximab 250 mg/m2 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. Administer Rituxan and In-111-Zevalin 7–9 days prior to Rituxan and Y-90- Zevalin. Refer to the Zevalin package insert for full prescribing information regarding the Zevalin therapeutic regimen.
2.5 Recommended Dose for Rheumatoid Arthritis (RA) Administer Rituxan as two-1000 mg intravenous infusions separated by 2 weeks. Glucocorticoids administered as methylprednisolone 100 mg intravenous or its equivalent 30 minutes prior to each infusion are recommended to reduce the incidence and severity of infusion reactions. Subsequent courses should be administered every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks. Rituxan is given in combination with methotrexate
2.6 Recommended Concomitant Medications
Premedicate before each infusion with acetaminophen and an antihistamine.

For RA patients, methylprednisolone 100 mg IV or its equivalent is recommended 30 minutes prior to each infusion.

Pneumocystis jiroveci pneumonia (PCP) and anti-herpetic viral prophylaxis is recommended for patients with CLL during treatment and for up to 12 months following treatment as appropriate.

2.7 Preparation for Administration
Use appropriate aseptic technique. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use vial if particulates or discoloration is present. Withdraw the necessary amount of Rituxan and dilute to a final concentration of 1 to 4 mg/mL in an infusion bag containing either 0.9% Sodium Chloride, USP, or 5% Dextrose in Water, USP. Gently invert the bag to mix the solution. Do not mix or dilute with other drugs. Discard any unused portion left in the vial.

3. DOSAGE FORMS AND STRENGTHS
100 mg/10 mL single-use vial

500 mg/50 mL single-use vial

4. CONTRAINDICATIONS
None.

HOW SUPPLIED/STORAGE AND HANDLING
Rituxan vials [100 mg (NDC 50242-051-21) and 500 mg (NDC 50242-053-06)] are stable at 2°C - 8°C (36°F - 46°F). Do not use beyond expiration date stamped on carton. Rituxan vials should be protected from direct sunlight. Do not freeze or shake.

Rituxan solutions for infusion may be stored at 2°C - 8°C (36°F - 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°C - 8°C). No incompatibilities between Rituxan and polyvinylchloride or polyethylene bags have been observed.

©2010 Biogen Idec Inc. and Genentech, Inc.