Chronic Lymphocytic Leukemia (CLL): Obinutuzumab in combination with chlorambucil is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia.

Follicular Lymphoma (FL): Obinutuzumab in combination with chemotherapy, followed by Obinutuzumab maintenance, is indicated for the treatment of patients with previously untreated follicular lymphoma. Obinutuzumab in combination with bendamustine, followed by Obinutuzumab maintenance, is indicated for the treatment of patients with FL who did not respond to, or who progressed during or after treatment with rituximab or a rituximab-containing regimen.

Obinutuzumab is supplied as a clear, colorless to slightly brownish liquid in a sterile, preservative-free, non-pyrogenic 50 ml glass vial. Each vial contains 40 ml of liquid concentrate at a strength of 25 mg/ml, providing a single 1000 mg dose.

Obinutuzumab is a monoclonal antibody directed against the CD20 antigen present on the surface of pre-B and mature B lymphocytes. After binding to CD20, it causes B-cell destruction through (1) recruitment of immune effector cells, (2) direct activation of intracellular death signaling pathways leading to direct cell death, and/or (3) activation of the complement cascade. These immune mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis.

Due to its reduced fucose content, Obinutuzumab produces greater ADCC activity than rituximab in vitro using human cancer cell lines. It also shows a stronger ability to induce direct cell death compared to rituximab. Obinutuzumab binds to FcγRIII with higher affinity than rituximab when tested with purified proteins. Both Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.

No formal drug-drug interaction studies have been conducted with Obinutuzumab. However, limited interaction sub-studies have been carried out with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), FC (fludarabine, cyclophosphamide), and chlorambucil. Co-administration of Obinutuzumab did not affect the pharmacokinetics of bendamustine, FC, or the individual components of CHOP. Likewise, bendamustine, FC, chlorambucil, or CHOP showed no apparent effect on the pharmacokinetics of Obinutuzumab. However, the possibility of interaction with other concurrently used medicines cannot be completely excluded.

Obinutuzumab is contraindicated in patients with known hypersensitivity to Obinutuzumab or to any of its excipients.

The following adverse reactions are discussed in greater detail in other sections of the label:

• Hepatitis B reactivation
• Progressive multifocal leukoencephalopathy
• Infusion reactions
• Tumor lysis syndrome
• Infections
• Neutropenia
• Thrombocytopenia

Pregnancy: Obinutuzumab may cause fetal B-cell depletion based on animal study findings and its mechanism of action. There are no adequate data regarding its use in pregnant women to determine drug-associated risk. Monoclonal antibodies can cross the placenta. In animal reproduction studies, weekly intravenous administration of Obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until delivery, including the organogenesis period, at exposures up to 2.4 times the clinical exposure of 1000 mg monthly, caused opportunistic infections and immune complex-mediated hypersensitivity reactions. No embryo-toxic or teratogenic effects were observed. The potential risk to the fetus should be considered before prescribing to pregnant women.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects is 2% to 4%, and miscarriage is 15% to 20% of clinically recognized pregnancies.

Lactation: There is no information on the presence of Obinutuzumab in human milk, its effects on the breastfed child, or its effects on milk production. Low levels were detected in the milk of lactating cynomolgus monkeys. Human IgG is known to be present in breast milk, but published data suggest that antibodies in breast milk do not significantly enter neonatal or child circulation. The developmental and health benefits of breastfeeding should be weighed against the mother’s clinical need for Obinutuzumab and any possible adverse effects on the breastfed child.

To improve the traceability of biological medicinal products, the brand name and batch number of the administered product should be clearly documented in the patient’s medical records.

Pediatric Use: The safety and effectiveness of Obinutuzumab in patients below 18 years of age have not been established.

Geriatric Use:

• Chronic Lymphocytic Leukemia (CLL): In the main CLL study, 46% (156 out of 336) of patients receiving Obinutuzumab plus chlorambucil were 75 years or older (median age 74 years). These patients experienced more serious adverse events and deaths related to adverse events compared to patients younger than 75 years. However, no significant differences in efficacy were observed between the two age groups.
• Non-Hodgkin Lymphoma (NHL): In pivotal NHL studies, patients aged 65 years or older experienced more serious adverse events and more treatment discontinuation or death compared to younger patients. However, no clinically meaningful differences in efficacy were observed.

Antineoplastic preparations

Store the vials in a refrigerator at 2°C to 8°C. Keep the vial in the original outer carton to protect from light. Do not freeze. Do not shake.