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.

In patients given single doses at 10, 50, 100, 250, or 500 mg/m² as an IV infusion, serum levels and the half-life of Rituximab were proportional to the dose. In 14 patients given 375 mg/m² as an IV infusion for four 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. 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.

Rituximab at a dose of 375 mg/m² was administered as an IV infusion at weekly intervals for four doses to 203 patients naïve to Rituximab. The mean Cmax 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 non-responders; 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 three to six months after completion of treatment. Rituximab at a dose of 375 mg/m² was administered as an IV infusion at weekly intervals for eight doses to 37 patients. The mean Cmax after eight infusions was 550 µg/mL (range, 171 to 1177 µg/mL). The mean Cmax increased with each successive infusion through the eighth infusion.

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

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 six to nine 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 non-responding patients.

B-cell recovery began at approximately six 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 five 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.

Recelbia® is indicated for the treatment of:

Non-Hodgkin's Lymphoma (NHL): 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 first-line chemotherapy and, in patients achieving a complete or partial response to Recelbia® in combination with chemotherapy, as single-agent maintenance therapy.

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.

Chronic Lymphocytic Leukemia (CLL): In combination with fludarabine and cyclophosphamide (FC), for the treatment of patients with previously untreated and previously treated CD20-positive CLL.

Rheumatoid Arthritis (RA): In combination with methotrexate, 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.

Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA): In combination with glucocorticoids, indicated for the treatment of adult patients with Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA).

Non-Hodgkin’s Lymphoma (NHL): The recommended dose is 375 mg/m² as an intravenous infusion according to the following schedules:

Relapsed or Refractory, Low-Grade or Follicular, CD20-Positive, B-Cell NHL: Administer once weekly for four or eight doses.

Previously Untreated, Follicular, CD20-Positive, B-Cell NHL: Administer on Day 1 of each cycle of chemotherapy for up to eight doses. In patients with complete or partial response, initiate Recelbia® maintenance eight weeks following completion of Recelbia® in combination with chemotherapy. Administer Recelbia® as a single agent every eight weeks for 12 doses.

Diffuse Large B-Cell NHL: Administer on Day 1 of each cycle of chemotherapy for up to eight infusions.

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).

Rheumatoid Arthritis (RA): The recommended dose in combination with methotrexate is two 1000 mg intravenous infusions separated by two weeks every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks.

Wegener’s Granulomatosis (WG) and Microscopic Polyangiitis (MPA): Administer Recelbia® as a 375 mg/m² intravenous infusion once weekly for four weeks.

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.

Formal drug interaction studies have not been performed with Recelbia. In patients with CLL, Recelbia did not alter systemic exposure to fludarabine or cyclophosphamide.

It is contraindicated in patients with known hypersensitivity to Rituximab or any other components of this product.

Reactivation of hepatitis B virus. Fever and rigors. Pruritus, skin rashes, dyspnoea, bronchospasm, angioedema, transient hypotension, and flushing, asthenia, headache, rhinitis, thrombocytopenia, neutropenia, anaemia, abdominal pain, bowel obstruction, and perforation. Exacerbation of heart failure and angina pectoris. Reversible interstitial pneumonia and interstitial fibrosis. Depletion of immunoglobulin concentrations.

Rituximab can cause fetal harm when administered to a pregnant woman. Rituximab can cause adverse developmental outcomes including B-cell lymphocytopenia in infants exposed to Rituximab in-utero. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The background risk of major birth defects and miscarriage for the indicated populations is unknown. Lactation: There are limited data on the presence of Rituximab in human milk and the effect on the breastfed child, and there are no data on the effect on milk production. Rituximab has also been reported to be excreted at low concentrations in human breast milk. Given that the clinical significance of this finding for children is not known, Women should not be advised to breastfeed during treatment with Rituximab and for 6 months after the last dose due to the potential of serious adverse reactions in breastfed children.

Infusion-Related Reactions: Recelbia can cause severe, including fatal, infusion-related reactions. Recelbia -induced infusion-related reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, anaphylactoid events, or death. For pediatric patients with mature B-cell NHL/B-AL, prednisone should be administerd as part of chemotherapy regimen prior to Recelbia during induction and as needed for subsequent cycles.

Severe Mucocutaneous Reactions: Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Recelbia. These reactions include paraneoplastic pemphigus, Stevens-John-son syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has been variable and includes reports with onset on the first day of Recelbia exposure. Recelbia should be discontinued in patients who experience a severe mucocutaneous reaction.

Progressive Multifocal Leukoencephalopathy (PML): The diagnosis of PML should be considered in any patient presenting with new-onset neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Recelbia should be discontinued and considered discontinuation or reduction of any concomitant chemothera- py or immunosuppressive therapy in patients who develop PML.

Tumor Lysis Syndrome (TLS): It should be administered aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administered supportive care, including dialysis as indicated.

Infections: Serious, including fatal, bacterial, fungal, and new or reactivated viral infections can occur during and following the completion of Recelbia-based therapy. Recelbia should be discontinued for serious infections and institute appropriate anti-infective therapy. Recelbia is not recommended for use in patients with severe, active infections.

Store the vial in original carton at 2°C-8°C in a refrigerator. Do not freeze. Protect from light. Keep out of the reach of children.