Indications & Important Safety Information

Indications

GAZYVA® (obinutuzumab), in combination with chlorambucil, is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia (CLL).

GAZYVA® (obinutuzumab), in combination with bendamustine followed by GAZYVA monotherapy, is indicated for the treatment of patients with follicular lymphoma (FL) who relapsed after, or are refractory to, a rituximab-containing regimen.

GAZYVA® (obinutuzumab), in combination with chemotherapy followed by GAZYVA monotherapy in patients achieving at least a partial remission, is indicated for the treatment of adult patients with previously untreated stage II bulky, III or IV follicular lymphoma (FL).

IMPORTANT SAFETY INFORMATION

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

Hepatitis B Virus Reactivation

  • Hepatitis B virus (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 physicians 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 physicians 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)

  • JC virus infection resulting in PML, which can be fatal, was observed in patients treated with GAZYVA. 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 Reactions

  • GAZYVA can cause severe and life-threatening infusion reactions. Sixty-five percent of patients with CLL experienced a reaction to the first 1,000 mg infused. Thirty-eight percent of patients with relapsed or refractory NHL and 60% of patients with previously untreated NHL experienced a reaction on Day 1 of GAZYVA infusion. Infusion reactions can also occur with subsequent infusions. Symptoms may include hypotension, tachycardia, dyspnea, and respiratory symptoms (e.g., bronchospasm, larynx and throat irritation, wheezing, and laryngeal edema). Most frequently reported symptoms include nausea, fatigue, chest discomfort, dyspnea, dizziness, vomiting, diarrhea, rash, hypertension, hypotension, flushing, headache, pyrexia, and chills
  • Premedicate patients with acetaminophen, an antihistamine, and a glucocorticoid. Institute medical management for infusion reactions as needed. Closely monitor patients during the entire infusion. Infusion reactions within 24 hours of receiving GAZYVA have occurred
  • For patients with any Grade 4 infusion reactions, including but not limited to anaphylaxis, acute life-threatening respiratory symptoms, or other life-threatening infusion reaction: Stop the GAZYVA infusion. Permanently discontinue GAZYVA therapy
  • For patients with Grade 1, 2, or 3 infusion reactions: Interrupt GAZYVA for Grade 3 reactions until resolution of symptoms. Interrupt or reduce the rate of the infusion for Grade 1 or 2 reactions and manage symptoms
  • 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 GAZYVA infusion reaction. Consider withholding antihypertensive treatments for 12 hours prior to and 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

Tumor Lysis Syndrome (TLS)

  • Tumor lysis syndrome, including fatal cases, has been reported in patients receiving GAZYVA. Patients with high tumor burden, high circulating lymphocyte count (>25 x 109/L) or renal impairment are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with antihyperuricemics (eg, allopurinol or rasburicase) and hydration prior to the infusion of GAZYVA. During the initial days of GAZYVA treatment, monitor the laboratory parameters of patients considered at risk for TLS. For treatment of TLS, correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated

Infections

  • Fatal and serious bacterial, fungal, and new or reactivated viral infections can occur during and following GAZYVA therapy. When GAZYVA is administered with chemotherapy followed by GAZYVA monotherapy, Grade 3 to 5 infections have been reported in up to 8% of patients during combination therapy, up to 13% of patients during monotherapy, and up to 8% of patients after treatment. 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

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 testing until resolution. Anticipate, evaluate, and treat any symptoms or signs of developing infection. Consider administration of granulocyte colony-stimulating factors (GCSF) 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)
  • Consider dose delays in the case of Grade 3 or 4 neutropenia. 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 NHL and CLL treated with GAZYVA in combination with chemotherapy, including Cycle 1. Monitor all patients frequently for thrombocytopenia and hemorrhagic events, especially during the first cycle. In patients with Grade 3 or 4 thrombocytopenia, monitor platelet counts more frequently until resolution and consider subsequent dose delays of GAZYVA and chemotherapy or dose reductions of chemotherapy. Transfusion of blood products (i.e., platelet transfusion) may be necessary. Consider withholding concomitant medications which may increase bleeding risk (platelet inhibitors or anticoagulants), especially during the first cycle

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 and until B-cell recovery

Pregnancy

  • There are no data with GAZYVA use in pregnant women to inform a drug-associated risk. GAZYVA is likely to cause fetal B-cell depletion. GAZYVA should be used during pregnancy and/or breastfeeding only if the potential benefit justifies the potential risk to the fetus and/or infant. 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

Geriatric Use

  • Of 336 patients with previously untreated CLL who received GAZYVA in combination with chlorambucil, 81% were 65 years and older, while 46% were 75 and older. Of the patients 75 years and older, 46% experienced serious adverse reactions and 7% experienced adverse reactions leading to death. Of the patients younger than 75, 33% experienced a serious adverse reaction and 2% an adverse reaction leading to death. No significant differences in efficacy were observed between younger and older patients
  • Of 194 patients in GADOLIN with relapsed or refractory NHL treated with GAZYVA plus bendamustine, 44% were 65 and over, while 14% were 75 and over. In patients 65 and over, 52% of patients experienced serious adverse reactions and 26% experienced adverse reactions leading to treatment withdrawal while in patients under 65, 28% and 12% experienced serious adverse reactions and adverse reactions leading to treatment withdrawal, respectively. No clinically meaningful differences in efficacy were observed between these patients and younger patients in GADOLIN
  • Of the 691 patients in GALLIUM treated with GAZYVA plus chemotherapy as first-line therapy, 33% were 65 and over, while 7% were 75 and over. Of patients 65 and over, 63% experienced serious adverse reactions and 26% experienced adverse reactions leading to treatment withdrawal, while in patients under 65, 43% experienced serious adverse reactions and 13% had an adverse reaction leading to treatment withdrawal. No clinically meaningful differences in efficacy were observed between these patients and younger patients

Additional Important Safety Information

CLL

  • The most common Grade 3 to 4 adverse reactions (incidence ≥10%) observed in patients with CLL in the GAZYVA containing arm were neutropenia, infusion reactions, and thrombocytopenia
  • The most common adverse reactions (incidence ≥10%) observed in patients with CLL in the GAZYVA containing arm were infusion reactions, neutropenia, thrombocytopenia, anemia, pyrexia, cough, nausea, and diarrhea
  • Adverse reactions rates and laboratory abnormalities from the Stage 2 phase are consistent with the rates in Stage 1. In addition to the adverse reactions observed in Stage 2, in Stage 1 back pain (5% vs. 2%), anemia (12% vs. 10%) and cough (10% vs. 7%) were observed at a higher incidence in the GAZYVA treated patients. The incidence of Grade 3 to 4 back pain (<1% vs. 0%), cough (0% vs. <1%) and anemia (5% vs. 4%) was similar in both treatment arms. With regard to laboratory abnormalities, in Stage 1 hyperkalemia (33% vs. 18%), creatinine increased (30% vs. 20%) and alkaline phosphatase increased (18% vs. 11%) were observed at a higher incidence in patients treated with GAZYVA with similar incidences of Grade 3 to 4 abnormalities between the two arms

Relapsed/Refractory NHL

  • The GADOLIN study evaluated safety in 392 patients with relapsed or refractory NHL, including FL (81%), small lymphocytic lymphoma (SLL) and marginal zone lymphoma (MZL) (a disease for which GAZYVA is not indicated), who did not respond to or progressed within 6 months of treatment with rituximab product or a rituximab product-containing regimen. In patients with follicular lymphoma, the profile of adverse reactions was consistent with the overall NHL population
  • The most common Grade 3 to 4 adverse reactions (incidence ≥10%) observed in the GAZYVA containing arm were neutropenia, thrombocytopenia and infusion reactions
  • The most common adverse reactions (incidence ≥10%) in the GAZYVA containing arm were infusion reactions, neutropenia, nausea, fatigue, cough, diarrhea, constipation, pyrexia, thrombocytopenia, vomiting, upper respiratory tract infection, decreased appetite, arthralgia, sinusitis, anemia, asthenia and urinary tract infection
  • During the monotherapy period with GAZYVA, Grade 3 to 4 adverse reactions included neutropenia (10%), and anemia, febrile neutropenia, thrombocytopenia, sepsis, upper respiratory tract infection, and urinary tract infection (all at 1%)
  • During the monotherapy period with GAZYVA, the most common adverse reactions (incidence ≥5%) were cough (15%), upper respiratory tract infections (12%), neutropenia (11%), sinusitis (10%), diarrhea (8%), infusion related reactions (8%), nausea (8%), fatigue (8%), bronchitis (7%), arthralgia (7%), pyrexia (6%), nasopharyngitis (6%), and urinary tract infections (6%)

Previously Untreated NHL

  • A randomized, open-label multicenter trial (GALLIUM) evaluated the safety of GAZYVA as compared to rituximab product in 1,385 patients with previously untreated follicular lymphoma (86%) or marginal zone lymphoma (14%)
  • Serious adverse reactions occurred in 50% of patients on the GAZYVA arm and 43% of patients on the rituximab product arm. Fatal adverse reactions were reported during treatment in 3% in the GAZYVA arm and 2% in the rituximab product arm, most often from infections in the GAZYVA arm.  During treatment and follow-up combined, fatal adverse reactions were reported in 5% of the GAZYVA arm and 4% of the rituximab product arm, with infections and second malignancies being leading causes. In the GAZYVA arm, fatal infections occurred in 2% of patients compared to <1% in the rituximab product arm
  • Neutropenia, infusion related reactions, febrile neutropenia and thrombocytopenia were the most common Grade 3 to 5 adverse reactions (incidence ≥5%) observed more frequently in the GAZYVA arm
  • Throughout treatment and follow-up, the most common adverse reactions (incidence ≥20%) observed at least 2% more in the GAZYVA arm were infusion related reactions, neutropenia, upper respiratory tract infection, cough, constipation and diarrhea
  • During the monotherapy period, the common adverse reactions (incidence ≥10%) observed at least 2% more with GAZYVA were upper respiratory infection (40%), cough (23%), musculoskeletal pain (20%), neutropenia (19%) and herpesvirus infection (13%)

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.