Obinutuzumab

• Approved Indications:
• Treatment of previously untreated chronic lymphocytic leukemia (CLL), in combination with chlorambucil.
• Treatment of follicular lymphoma (FL) in adult patients who have received at least one prior therapy.
• Treatment of diffuse large B-cell lymphoma (DLBCL) in combination with chemotherapy for patients who are not candidates for autologous stem cell transplant.
• Off-label and Investigational Uses:
• Investigated in other B-cell malignancies including mantle cell lymphoma and marginal zone lymphoma.
• Used in clinical trials for autoimmune disorders such as rheumatoid arthritis (not FDA approved for these uses).

• Chronic Lymphocytic Leukemia (CLL):
• Induction: 100 mg IV infusion on Day 1 (Cycle 1), followed by 900 mg IV on Day 2 (Cycle 1), then 1000 mg IV on Day 8 and Day 15 (Cycle 1), and 1000 mg IV on Day 1 of subsequent cycles.
• Administered in combination with chlorambucil.
• Cycles repeat every 28 days for up to 6 cycles.
• Follicular Lymphoma (FL):
• 1000 mg IV on Days 1, 8, and 15 of Cycle 1, then Day 1 of subsequent 21-day cycles for 6 cycles.
• Maintenance: 1000 mg IV every 2 months for up to 2 years.
• Diffuse Large B-Cell Lymphoma (DLBCL):
• 1000 mg IV on Day 1 of each 21-day cycle, combined with chemotherapy.
• Number of cycles varies based on regimen.
• Special Populations:
• No established dose adjustments for renal or hepatic impairment; caution advised.
• Pediatric use not established.
• Elderly patients generally tolerate standard dosing but require monitoring.
• Administration Notes:
• Intravenous infusion only.
• Pre-medication with corticosteroids, antihistamines, and antipyretics is recommended to reduce infusion-related reactions.
• Infusion rate should be adjusted based on tolerance.

Obinutuzumab is a humanized, glycoengineered type II anti-CD20 monoclonal antibody. It binds selectively to the CD20 antigen expressed on the surface of B-lymphocytes. This binding induces direct cell death through a non-apoptotic mechanism and enhances antibody-dependent cellular cytotoxicity (ADCC) by increasing affinity for Fcγ receptors on immune effector cells. It also induces complement-dependent cytotoxicity (CDC) to a lesser extent. These combined effects result in effective depletion of malignant and normal B cells.

• Absorption: Not applicable (intravenous administration).
• Distribution: Volume of distribution approximates plasma volume; limited extravascular distribution.
• Metabolism: Catabolized by proteolytic enzymes into small peptides and amino acids.
• Elimination: Half-life is dose- and time-dependent; approximately 28 days at steady state.
• Clearance: Clearance decreases over time due to depletion of CD20-positive B cells.
• Onset: B-cell depletion occurs rapidly after initial doses.

• Pregnancy:
• Classified as FDA Pregnancy Category C.
• Animal studies have shown fetal harm; no adequate human data.
• Use only if potential benefit justifies potential risk.
• Lactation:
• Unknown if excreted in human milk.
• Breastfeeding not recommended during treatment and for 6 months following last dose due to potential immunosuppression in the infant.
• Caution: Limited data; avoid use unless clearly necessary.

• Primary Class: Monoclonal antibody
• Subclass: Anti-CD20 B-cell depleting agent

• Known hypersensitivity to obinutuzumab or any component of the formulation.
• History of severe infusion-related reactions to obinutuzumab.
• Active severe infections that contraindicate immunosuppressive therapy.

• Infusion-Related Reactions (IRRs): Can be severe or life-threatening, especially during the first infusion; monitor closely and premedicate.
• Infections: Increased risk of bacterial, viral, and fungal infections; monitor for signs of infection.
• Hepatitis B Reactivation: Screen all patients for HBV infection before initiation; monitor and provide prophylaxis if needed.
• Progressive Multifocal Leukoencephalopathy (PML): Rare but fatal brain infection reported; discontinue if suspected.
• Neutropenia and Thrombocytopenia: Monitor blood counts regularly; may require dose adjustments or supportive therapy.
• Immunization: Avoid live vaccines during and after treatment until immune recovery.

• Common:
• Infusion-related reactions (fever, chills, rash, hypotension)
• Neutropenia
• Thrombocytopenia
• Anemia
• Upper respiratory tract infections
• Pyrexia
• Fatigue
• Serious:
• Severe infusion reactions including anaphylaxis
• Infections (including sepsis)
• Hepatitis B virus reactivation
• PML
• Tumor lysis syndrome
• Rare:
• Cardiac arrhythmias
• Cytokine release syndrome

• Immunosuppressants and Chemotherapy Agents: Additive immunosuppression; monitor for infection.
• Live Vaccines: Avoid due to risk of reduced vaccine efficacy and potential infection.
• No significant CYP450 enzyme interactions as obinutuzumab is a monoclonal antibody.

• Recent oncology guidelines recommend obinutuzumab combined with chlorambucil as a first-line treatment for CLL in patients unsuitable for more intensive therapy.
• Obinutuzumab maintenance therapy is recommended post-induction in follicular lymphoma to prolong remission.
• Updated safety monitoring guidelines emphasize vigilance for infusion reactions and HBV reactivation.
• EMA and FDA continue to review data for expanded indications.

• Store in a refrigerator at 2°C to 8°C (36°F to 46°F).
• Do not freeze.
• Protect from light; keep in original carton until use.
• Do not shake.
• Use reconstituted or diluted solutions promptly as per prescribing information.