Gazyva Injection

Obinutuzumab is a clear, colorless to slightly brownish liquid supplied as a single 1000 mg dose in a sterile, preservative free, nonpyrogenic 50 ml glass vial containing 40 ml of liquid concentrate (25 mg/ml).

Obinutuzumab is a monoclonal antibody that targets the CD20 antigen expressed on the surface of pre-B and mature B lymphocytes. Upon binding to CD20, obinutuzumab mediates B-cell lysisthrough (1) engagement of immune effector cells (2) by directly activating intracellular death signaling pathways (direct cell death), and/or (3) activation of the complement cascade. The immune effector cell mechanisms include antibody-dependent cellular cytotoxicity (ADCC) and antibodydependent cellular phagocytosis.

As an antibody with reduced fucose content, obinutuzumab induces greater ADCC activity than rituximab in vitro using human cancer cell lines. Obinutuzumab also demonstrated an increased ability to induce direct cell death when compared to rituximab. Obinutuzumab binds to FcγRIII using purified proteins with a higher affinity than rituximab. Obinutuzumab and rituximab bind with similar affinity to overlapping epitopes on CD20.

No formal drug-drug interaction studies have been performed, although limited drug interaction sub-studies have been undertaken for Gazyva with bendamustine, CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone), FC (fludarabine, cyclophosphamide) and chlorambucil. Co administration with Gazyva had no effect on the pharmacokinetics of bendamustine, FC or the individual components of CHOP; in addition, there were no apparent effects of bendamustine, FC, chlorambucil or CHOP on the pharmacokinetics of Gazyva. A risk for interactions with concomitantly used medicinal products cannot be excluded.

Obinutuzumab is contraindicated in patients with a known hypersensitivity to obinutuzumab or to any of the 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 is likely to cause fetal B-cell depletion based on findings from animal studies and the drug’s mechanism of action. There are no data with Obinutuzumab use in pregnant women to inform a drug-associated risk. Monoclonal antibodies are transferred across the placenta. In animal reproduction studies, weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1000 mg monthly produced opportunistic infections and immune complex mediated hypersensitivity reactions. No embryo-toxic or teratogenic effects were observed in the monkeys. Consider the potential risk to the fetus when prescribing Obinutuzumab to a pregnant woman.

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

Lactation: There is no information regarding the presence of Obinutuzumab in human milk, the effects on the breastfed child, or the effects on milk production. However, low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [see Pregnancy]. Human IgG is known to be present in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and child circulations in substantial amounts. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Obinutuzumab and any potential adverse effects on the breastfed child from Obinutuzumab or from the underlying maternal condition.

In order to improve the traceability of biological medicinal products, the trade name and batch number of the administered product should be clearly recorded (or stated) in the patient file.

Pediatric Use: The safety and efficacy of Gazyva in children below 18 years of age have not been established.

Geriatric Use:

• Chronic Lymphocytic Leukemia (CLL): In the pivotal study in CLL, 46% (156 out of 336) of patients treated with Gazyva plus chlorambucil were 75 years old or older (median age was 74 years). These patients experienced more serious adverse events and adverse events leading to death than patients <75 years of age. No significant differences in efficacy were observed between patients ≥75 years of age and those <75 years of age
• Non-Hodgkin Lymphoma (NHL): In the pivotal studies in NHL, patients 65 years old or older experienced more serious adverse events, and adverse events leading to withdrawal or death than patients <65 years of age. No clinically meaningful differences in efficacy were observed.

Anti neoplastic preparations

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