BOXED WARNINGS: HEPATITIS B VIRUS REACTIVATION AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

• Hepatitis B Virus (HBV) reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients receiving CD20-directed cytolytic antibodies, including GAZYVA. Screen all patients for HBV infection before treatment initiation. Monitor HBV-positive patients during and after treatment with GAZYVA. Discontinue GAZYVA and concomitant medications in the event of HBV reactivation
• Progressive Multifocal Leukoencephalopathy (PML), including fatal PML, can occur in patients receiving GAZYVA

Contraindications

• GAZYVA is contraindicated in patients with known hypersensitivity reactions (eg, anaphylaxis) to obinutuzumab or to any of the excipients, or serum sickness with prior obinutuzumab use

Warnings and Precautions

Hepatitis B Virus Reactivation

• GAZYVA can cause hepatitis B virus (HBV) reactivation. HBV reactivation, in some cases resulting in fulminant hepatitis, hepatic failure, and death, can occur in patients treated with anti-CD20 antibodies, including GAZYVA. HBV reactivation has been reported in patients who are hepatitis B surface antigen (HBsAg) positive and in patients who are HBsAg negative but are hepatitis B core antibody (anti-HBc) positive. Reactivation has also occurred in patients who appear to have resolved hepatitis B infection (ie, HBsAg negative, anti-HBc positive, and hepatitis B surface antibody [anti-HBs] positive)
• HBV reactivation is defined as an abrupt increase in HBV replication manifesting as a rapid increase in serum HBV DNA level, or detection of HBsAg in a person who was previously HBsAg negative and anti-HBc positive. Reactivation of HBV replication is often followed by hepatitis, ie, increase in transaminase levels and in severe cases, increase in bilirubin levels, liver failure, and death
• Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with GAZYVA. For patients who show evidence of hepatitis B infection (HBsAg positive [regardless of antibody status] or HBsAg negative but anti-HBc positive), consult healthcare providers with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy
• Monitor patients with evidence of current or prior HBV infection for clinical and laboratory signs of hepatitis or HBV reactivation during and for several months following treatment with GAZYVA
• In patients who develop reactivation of HBV while receiving GAZYVA, immediately discontinue GAZYVA and any concomitant chemotherapy and institute appropriate treatment. Resumption of GAZYVA in patients whose HBV reactivation resolves should be discussed with healthcare providers with expertise in managing hepatitis B. Insufficient data exist regarding the safety of resuming GAZYVA in patients who develop HBV reactivation

Progressive Multifocal Leukoencephalopathy (PML)

• John Cunningham (JC) virus infection resulting in PML, which can be fatal, occurred in patients treated with GAZYVA in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). Consider the diagnosis of PML in any patient presenting with new onset or changes to, preexisting neurologic manifestations. Evaluation of PML includes, but is not limited to, consultation with a neurologist, brain MRI, and lumbar puncture. Discontinue GAZYVA therapy and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML

Infusion-Related Reactions

• GAZYVA can cause severe and life-threatening infusion-related reactions (IRRs)
• In patients with LN, IRRs occurred predominantly during infusion of the first 1,000 mg. IRRs were generally mild to moderate and could be managed by slowing or temporarily halting the infusion. Severe and life-threatening IRRs requiring symptomatic treatment were also reported. The most common IRR signs/symptoms reported in the REGENCY study included headache, nausea and vomiting. In the NOBILITY study, the most common IRR symptoms were pyrexia and tachycardia
• Premedicate patients with acetaminophen, an antihistamine, and a glucocorticoid. Closely monitor patients during the entire infusion. Reduce infusion rate, interrupt infusion, or permanently discontinue GAZYVA for IRRs based on severity. Institute medical management (eg, glucocorticoids, epinephrine, bronchodilators, and/or oxygen) for IRRs as needed
• For patients with preexisting cardiac or pulmonary conditions, monitor more frequently throughout the infusion and the post-infusion period, since they may be at greater risk of experiencing more severe reactions. Hypotension may occur as part of the IRR to GAZYVA. Consider withholding antihypertensive treatments for 12 hours prior to, during each GAZYVA infusion, and for the first hour after administration until blood pressure is stable. For patients at increased risk of hypertensive crisis, consider the benefits versus the risks of withholding their antihypertensive medication

Hypersensitivity Reactions Including Serum Sickness

• Hypersensitivity reactions have been reported in patients treated with GAZYVA. Signs of immediate-onset hypersensitivity included dyspnea, bronchospasm, hypotension, urticaria and tachycardia. Late-onset hypersensitivity diagnosed as serum sickness has also been reported, with symptoms that include chest pain, diffuse arthralgia, and fever. Hypersensitivity reactions may be difficult to clinically distinguish from IRRs. However, hypersensitivity very rarely occurs with the first infusion and, when observed, often occurs after previous exposure
• If a hypersensitivity reaction is suspected during or after an infusion, stop the infusion and permanently discontinue treatment. GAZYVA is contraindicated in patients with known hypersensitivity reactions to GAZYVA, including serum sickness with prior GAZYVA use

Serious, Including Fatal, Infections

• Fatal and serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy
• In the pooled double-blind periods of REGENCY (Week 76) and NOBILITY (Week 52), the incidence of Grade 3-5 infections was 11% (22/200) in patients treated with GAZYVA and standard therapy compared to 9% (18/193) in patients receiving placebo and standard therapy, corresponding to an exposure-adjusted incidence rate (EAIR) of 8.9 and 7.9 per 100 patient years, respectively. The incidence of fatal infections was 1% (2/200) in patients treated with GAZYVA and 0.5% (1/193) in patients receiving placebo, corresponding to an EAIR of 0.8 and 0.4 per 100 patient years, respectively
•  In 40 patients who crossed-over from placebo to GAZYVA and standard therapy at Week 76 in the REGENCY study, and patients who continued treatment with GAZYVA and standard therapy, including additional treatment after Week 76, the EAIR of Grade 3-5 infections for the GAZYVA arm was 9.0 per 100 patient years while the EAIR of fatal infections for the GAZYVA arm was 1.8 per 100 patient years
• Do not administer GAZYVA to patients with an active infection. Patients with a history of recurring or chronic infections may be at increased risk of infection. In patients who develop a serious infection while receiving GAZYVA, immediately discontinue GAZYVA and institute appropriate treatment. Consider the risk and benefit of resuming treatment with GAZYVA following resolution of serious infections

Neutropenia

• Severe and life-threatening neutropenia, including febrile neutropenia, has been reported during treatment with GAZYVA. Monitor patients with Grade 3 to 4 neutropenia frequently with regular laboratory tests until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection. Consider dose delays for Grade 3 or 4 neutropenia. Consider administration of granulocyte colony-stimulating factors (GCSFs) in patients with Grade 3 or 4 neutropenia
• Neutropenia can also be of late onset (occurring more than 28 days after completion of treatment) and/or prolonged (lasting longer than 28 days)
• Patients with severe and long-lasting (>1 week) neutropenia are strongly recommended to receive antimicrobial prophylaxis until resolution of neutropenia to Grade 1 or 2. Consider antiviral and antifungal prophylaxis

Thrombocytopenia

• Severe and life-threatening thrombocytopenia has been reported during treatment with GAZYVA in combination with chemotherapy. Fatal hemorrhagic events have been reported in patients with CLL treated with GAZYVA in combination with chemotherapy
• Monitor patients frequently for thrombocytopenia and hemorrhagic events, and if clinically indicated, evaluate laboratory coagulation parameters. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider dose delays of GAZYVA and chemotherapy or dose reductions of chemotherapy. Transfusion of blood products (ie, platelet transfusion) may be necessary. Consider withholding concomitant medications that may increase bleeding risk (platelet inhibitors or anticoagulants), especially during the first cycle

Disseminated Intravascular Coagulation (DIC)

• Fatal and severe DIC has been reported in patients receiving GAZYVA for CLL and NHL. The majority of DIC cases have involved changes in platelets and laboratory coagulation parameters following the first infusion, with spontaneous resolution usually occurring by Day 8. In some cases, DIC was associated with IRRs
• In patients with suspected DIC, evaluate potential causes and monitor coagulation parameters, platelet counts, and for signs and symptoms of bleeding or thrombosis. Manage according to standard guidelines for DIC. Supportive care, including transfusion of blood products and other medical management, may be necessary

Immunization

• The safety and efficacy of immunization with live or attenuated viral vaccines during or following GAZYVA therapy have not been studied. Immunization with live virus vaccines is not recommended during treatment with GAZYVA and until B-cell recovery

Embryo-Fetal Toxicity

• Based on its mechanism of action and findings in animals, GAZYVA can cause B-cell depletion in infants exposed to obinutuzumab in utero. Advise pregnant women of the potential risk to the fetus. Mothers who have been exposed to GAZYVA during pregnancy should discuss the safety and timing of live virus vaccinations for their infants with their child’s healthcare providers. Advise females of reproductive potential to use effective contraception while receiving GAZYVA and for 6 months after the last dose

Lactation

• Human IgG is known to be present in human milk. Because of the potential of serious adverse reactions in the breastfed child, advise women not to breastfeed during treatment with GAZYVA and for 6 months after the last dose

Additional Important Safety Information

• The most common adverse reactions (incidence ≥5%) observed in patients with LN in the GAZYVA arm were upper respiratory tract infection, COVID-19, and urinary tract infection, bronchitis, pneumonia, infusion-related reactions and neutropenia 
• The most common serious adverse reactions in the GAZYVA arm were: COVID-19 (5.5%), pneumonia (4.5%), neutropenia (3.5%), urinary tract infections (2.5%), and infusion-related reactions (0.5%). No serious adverse reactions were reported for bronchitis, herpes simplex and upper respiratory tract infections. Two fatal adverse reactions of COVID-19 were reported in the GAZYVA arm

You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088.

Please see the full Prescribing Information for additional Important Safety Information, including BOXED WARNINGS.