Mabthera10 mg/ml

Mabthera is a chimeric monoclonal antibody directed against the CD20 antigen on B-lymphocytes. It is used, alone or in combination with other agents, for the following conditions:

FDA-approved / established indications

• Non-Hodgkin's Lymphoma (NHL): Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; also used in combination with chemotherapy for previously untreated follicular NHL and diffuse large B-cell lymphoma (DLBCL), and as single-agent maintenance therapy.
• Chronic Lymphocytic Leukemia (CLL): Previously untreated and previously treated CD20-positive CLL, in combination with fludarabine and cyclophosphamide.
• Rheumatoid Arthritis (RA): Moderately to severely active RA in adults with an inadequate response to one or more tumor necrosis factor (TNF) antagonist therapies — must be used in combination with methotrexate.
• Granulomatosis with Polyangiitis (GPA) and Microscopic Polyangiitis (MPA): Induction and maintenance of remission in adult and pediatric patients (2 years and older), in combination with glucocorticoids.
• Pemphigus Vulgaris (PV): Moderate-to-severe disease in adults.
• Pediatric B-cell malignancies: Previously untreated, advanced-stage CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma, Burkitt-like lymphoma, or mature B-cell acute leukemia in pediatric patients 6 months of age and older, in combination with chemotherapy.

Guideline-supported / commonly used off-label indications

Guidelines and clinical experience also support use of Mabthera (off-label with respect to the original FDA label) in certain B-cell-mediated or autoantibody-mediated conditions, such as refractory idiopathic thrombocytopenic purpura (ITP), certain forms of vasculitis-associated glomerulonephritis, and select autoimmune cytopenias, generally reserved for cases refractory to first-line therapy and under specialist supervision.

All uses of Mabthera require administration by a healthcare professional in a setting equipped to manage severe infusion reactions.

Each vial contains Rituximab (rituximab), a genetically engineered chimeric murine/human monoclonal IgG1 antibody directed against the CD20 antigen, as a sterile, preservative-free, clear-to-opalescent concentrate for solution for intravenous infusion.

Typical marketed strength: 10 mg/mL, supplied in single-use vials (e.g., 100 mg/10 mL and 500 mg/50 mL) that must be diluted prior to administration.

Mabthera is a chimeric monoclonal antibody that targets the CD20 antigen, a cell-surface protein expressed on normal and malignant B-lymphocytes but not on stem cells, pro-B-cells, normal plasma cells, or other normal tissues. By binding CD20, Mabthera depletes circulating and tissue B-cells, which underlies its efficacy in B-cell malignancies, rheumatoid arthritis, ANCA-associated vasculitis, and pemphigus vulgaris.

Mabthera is administered only as an intravenous infusion in a monitored clinical setting; it is not available as an oral or self-administered formulation.

Monoclonal antibody (anti-CD20 antibody); Antineoplastic biologic agent; Disease-modifying antirheumatic biologic used for Mabthera therapy in B-cell mediated autoimmune disease.

Mechanism

Rituximab binds specifically to the CD20 antigen on the surface of B-lymphocytes. The Fab domain of Rituximab binds the CD20 antigen, and the Fc domain recruits immune effector functions to mediate B-cell lysis through:

• Complement-dependent cytotoxicity (CDC)
• Antibody-dependent cell-mediated cytotoxicity (ADCC)
• Induction of apoptosis in the targeted B-cell

Pharmacokinetics

Following intravenous infusion, Rituximab is detectable in serum for 3–6 months after completion of treatment. B-cell depletion in peripheral blood occurs rapidly and B-cell recovery typically begins within 6 months, with normal levels returning by 9–12 months after completion of therapy in most patients. Clearance is variable and influenced by tumor/CD20 antigen burden.

Mabthera concentrate must be diluted in 0.9% Sodium Chloride or 5% Dextrose injection to a final concentration of 1–4 mg/mL before infusion. It is administered exclusively via a dedicated intravenous line and must never be given as an IV push or bolus injection.

• Premedicate with antipyretic and antihistamine before each infusion; add glucocorticoid premedication where indicated for the specific condition.
• Begin the first infusion at a slow initial rate (e.g., 50 mg/hour) and increase in increments only if no infusion reaction occurs.
• Monitor vital signs closely, especially during and immediately after the first infusion, when the risk of severe infusion reaction is highest.
• Interrupt the infusion immediately for any hypotension, bronchospasm, dyspnea, angioedema, or other signs of a severe infusion reaction, and manage supportively; resume at a reduced rate only once symptoms have fully resolved and if judged safe to continue.
• Administer only in a facility equipped with resuscitation equipment and staff trained in managing anaphylaxis/infusion reactions.

Clinically significant interactions with Mabthera include:

• Live/attenuated vaccines: Should be avoided during and for an extended period after Mabthera therapy because of profound B-cell depletion and an inadequate, potentially unsafe, immune response; complete any needed live-vaccine series before starting Mabthera whenever possible.
• Other immunosuppressants and biologic DMARDs (e.g., other biologic agents for RA, cytotoxic chemotherapy): Concurrent or sequential use increases the cumulative risk of serious infection; combinations should be used cautiously and only when clinically necessary.
• Cisplatin: Concomitant use with Mabthera in some chemotherapy regimens has been associated with an increased risk of renal toxicity; the combination is not recommended outside of established protocols.
• Cardiotoxic agents: Because infusion reactions can precipitate arrhythmia or angina, caution is warranted when Mabthera is combined with other agents that affect cardiac conduction or in patients with pre-existing cardiac disease (see Precautions and Warnings).

Adverse effects associated with Mabthera vary by indication but commonly include:

• Infusion-related reactions (most common, especially with the first infusion): fever, chills, rigors, pruritus, urticaria, angioedema, hypotension, bronchospasm, dyspnea, and headache — see Precautions and Warnings for the serious/fatal form of this reaction.
• Hematologic: lymphopenia, neutropenia, thrombocytopenia, anemia.
• Infections: upper respiratory tract infections, urinary tract infections, nasopharyngitis, bronchitis, sinusitis; serious infections including reactivation of viral infections (see Precautions and Warnings for hepatitis B reactivation and PML).
• General: fatigue, nausea, diarrhea, arthralgia, muscle spasms.
• Mucocutaneous reactions: rash and, rarely, severe/fatal mucocutaneous reactions (see Precautions and Warnings).

Mabthera can cross the placenta and cause B-cell lymphopenia in infants exposed in-utero; it should be used during pregnancy only if clearly needed and the potential benefit to the mother justifies the potential risk to the fetus, and only under close specialist supervision. Women of reproductive potential should use effective contraception during treatment with Mabthera and for 12 months after the final dose. A pregnancy exposure registry may be available; consult a physician if pregnancy occurs during or after treatment.

It is not known whether Mabthera is excreted in human milk; because maternal IgG is excreted in milk and B-cell depletion in the infant is a potential risk, breastfeeding is generally not recommended during treatment with Mabthera and for several months after the last dose. Consult a physician before breastfeeding.

Boxed Warnings

• Fatal infusion-related reactions: Severe, including fatal, infusion reactions can occur during or within 24 hours of an infusion of Mabthera, most frequently with the first infusion. Premedication and close monitoring are required; discontinue the infusion immediately for severe reactions and institute supportive treatment.
• Severe mucocutaneous reactions: Rare but potentially fatal reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported with Mabthera. Discontinue permanently if a severe reaction occurs.
• Hepatitis B virus (HBV) reactivation: Can occur in patients treated with Mabthera, in some cases resulting in fulminant hepatitis, hepatic failure, and death. Screen all patients for HBV infection before starting Mabthera; monitor carriers during and for months after treatment and manage in consultation with a liver disease specialist if reactivation occurs.
• Progressive multifocal leukoencephalopathy (PML): A rare, often fatal, JC virus brain infection has been reported with Mabthera. Consider PML in any patient with new-onset neurologic symptoms and discontinue Mabthera if PML is confirmed.

Other precautions

• Avoid use in patients with active severe infections; Mabthera increases susceptibility to infection through B-cell depletion.
• Use with caution in patients with pre-existing cardiac disease, as infusion reactions may precipitate angina or arrhythmia; monitor cardiac patients closely during infusion.
• Tumor lysis syndrome has been reported in patients with high tumor burden or high circulating malignant cell counts; consider prophylaxis and closely monitor renal function, electrolytes, and uric acid in at-risk patients.
• Avoid administration of live/attenuated vaccines during and for an extended period after treatment (see Interactions).
• Must be administered only in a facility with immediate access to resuscitation equipment and medications for management of anaphylaxis and severe infusion reactions.

There is no established antidote for Mabthera overdose. Clinical experience with doses above the recommended amount is limited. In the event of suspected overdose, discontinue the infusion immediately, seek immediate medical attention, and manage supportively with close monitoring of vital signs, blood counts, and signs of infusion reaction or infection. Contact a poison control center or emergency services for further guidance if needed.

Store vials of Mabthera refrigerated at 2°C to 8°C (36°F to 46°F). Protect vials from direct light. Do not freeze and do not shake. Once diluted for infusion, the solution should be used promptly; if not used immediately, diluted solutions may be refrigerated as directed by the manufacturer's instructions. Keep out of reach of children and handle only under healthcare professional supervision.

• Renal impairment: No formal dose adjustment of Mabthera has been established; use with caution and monitor renal function, particularly in combination regimens associated with tumor lysis syndrome risk.
• Hepatic impairment: No formal dose adjustment established; screen for hepatitis B before use (see Precautions and Warnings) and use cautiously in patients with underlying liver disease.
• Elderly: No overall differences in safety or efficacy have been reported compared with younger patients, though the incidence of serious adverse reactions may be higher; use with appropriate monitoring.
• Pregnancy and lactation: See Pregnancy and Lactation section.
• Pediatric use: See Pediatric Uses section.

Duration of Mabthera therapy is indication-specific: a single course is typically 4 doses (RA, GPA/MPA induction context varies) to 8 weekly doses (NHL) or 6 monthly cycles (CLL, combined with chemotherapy). For rheumatoid arthritis and pemphigus vulgaris, re-treatment/maintenance courses are given based on clinical and laboratory response, generally not more often than every 24 weeks (RA) or per specialist-directed maintenance schedule (PV). The treating physician determines the total duration and number of courses based on disease response, B-cell counts, and tolerability.

Monoclonal antibody; Anti-CD20 antibody; Antineoplastic biologic agent; Biologic disease-modifying antirheumatic drug (bDMARD)

Rituximab is a chimeric IgG1 monoclonal antibody with a murine variable region and human constant region, engineered to bind specifically to the CD20 transmembrane protein expressed on pre-B and mature B-lymphocytes. Upon binding, Rituximab triggers B-cell depletion via three principal mechanisms: complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC) through Fc-receptor-bearing effector cells, and direct induction of apoptosis. Because CD20 is not expressed on hematopoietic stem cells or plasma cells, B-cell populations are able to regenerate from stem cells after treatment is completed, typically over 6–12 months.

Approved pediatric use of Mabthera is limited to specific indications and age groups:

• Pediatric B-cell malignancies (6 months and older): Previously untreated, advanced-stage CD20-positive diffuse large B-cell lymphoma, Burkitt lymphoma/leukemia, or mature B-cell acute leukemia, in combination with chemotherapy.
• GPA and MPA (2 years and older): In combination with glucocorticoids, using weight-based dosing per protocol.

Safety and efficacy of Mabthera have not been established in children for rheumatoid arthritis, chronic lymphocytic leukemia, or pemphigus vulgaris. Pediatric use outside these established indications should occur only under specialist supervision, with close monitoring for infusion reactions, infection, and growth/immune development given the systemic B-cell depletion produced by Mabthera.