ASH Clinical News May 2016 | Page 6

GAZYVA ® ( obinutuzumab ) injection , for intravenous infusion Initial U . S . Approval : 2013

This is a brief summary of information about GAZYVA . Before prescribing , please see full Prescribing Information .

WARNING : 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 [ see Warnings and Precautions ( 5.1 )].

• Progressive Multifocal Leukoencephalopathy ( PML ) including fatal PML , can occur in patients receiving GAZYVA [ see Warnings and Precautions ( 5.2 )].

1 INDICATIONS AND USAGE 1.1 Chronic Lymphocytic Leukemia GAZYVA , in combination with chlorambucil , is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia ( CLL ) [ see Clinical Studies ( 14.1 )].

1.2 Follicular Lymphoma GAZYVA , 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 rituximabcontaining regimen [ see Clinical Studies ( 14.2 )].

4 CONTRAINDICATIONS None .

5 WARNINGS AND PRECAUTIONS 5.1 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 such as GAZYVA . HBV reactivation has been reported in patients who are hepatitis B surface antigen ( HBsAg ) positive and also 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 ( i . e ., 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 , i . e ., 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 . HBV reactivation has been reported for other CD20- directed cytolytic antibodies following completion of therapy .

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 .

5.2 Progressive Multifocal Leukoencephalopathy JC virus infection resulting in progressive multifocal leukoencephalopathy ( 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 .

5.3 Infusion Reactions GAZYVA can cause severe and life-threatening infusion reactions . Sixty-five percent of patients with CLL experienced a reaction to the first 1000 mg infused of GAZYVA . Thirty-eight percent of iNHL patients 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 , laryngeal edema ). Most frequently reported symptoms include nausea , fatigue , dizziness , vomiting , diarrhea , hypertension , flushing , headache , pyrexia , and chills [ see Adverse Reactions ( 6.1 )].

Premedicate patients with acetaminophen , antihistamine , and a glucocorticoid . Institute medical management ( e . g ., glucocorticoids , epinephrine , bronchodilators , and / or oxygen ) for infusion reactions as needed . Closely monitor patients during the entire infusion . Infusion reactions within 24 hours of receiving GAZYVA have occurred [ see Dosage and Administration ( 2 )].

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 [ see Dosage and Administration ( 2 )].

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 , 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 as is suggested here .

5.4 Tumor Lysis Syndrome Tumor Lysis Syndrome ( TLS ), including fatal cases , has been reported in patients receiving GAZYVA . Patients with high tumor burden , high circulating lymphocyte count (> 25 x 10 9 / L ) or renal impairment are at greater risk for TLS and should receive appropriate tumor lysis prophylaxis with anti-hyperuricemics ( e . g ., allopurinol or rasburicase ) and hydration prior to the infusion of GAZYVA [ see Dosage and Administration ( 2.2 )].

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 .

5.5 Infections Serious bacterial , fungal , and new or reactivated viral infections can occur during and following GAZYVA therapy . Fatal infections have been reported with GAZYVA . 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 .

5.6 Neutropenia Severe and life threatening neutropenia , including febrile neutropenia , has been reported during treatment with GAZYVA . Patients with Grade 3 to 4 neutropenia should be monitored frequently with regular laboratory tests until resolution . Anticipate , evaluate , and treat any symptoms or signs of developing infection . Consider administration of granulocyte colony-stimulating factors ( G-CSF ) 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 . Antiviral and antifungal prophylaxis should be considered .

5.7 Thrombocytopenia Severe and life threatening thrombocytopenia has been reported during treatment with GAZYVA in combination with chlorambucil or bendamustine .

Fatal hemorrhagic events during Cycle 1 have also been reported in patients with CLL treated with GAZYVA . 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 , anticoagulants ), especially during the first cycle .

5.8 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 .

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

• Hepatitis B reactivation [ see Warnings and Precautions ( 5.1 )]

• Progressive multifocal leukoencephalopathy [ see Warnings and Precautions ( 5.2 )]

• Infusion reactions [ see Warnings and Precautions ( 5.3 )]

• Tumor lysis syndrome [ see Warnings and Precautions ( 5.4 )]

• Infections [ see Warnings and Precautions ( 5.5 )]

• Neutropenia [ see Warnings and Precautions ( 5.6 )]

• Thrombocytopenia [ see Warnings and Precautions ( 5.7 )]

6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice .

Summary of Clinical Trial Experience in Chronic Lymphocytic Leukemia The data described in Tables 4-5 below are based on a safety population of 773 previously untreated patients with CLL . Patients were treated with chlorambucil alone , GAZYVA in combination with chlorambucil , or rituximab in combination with chlorambucil . The Stage 1 analysis compared GAZYVA in combination with chlorambucil vs . chlorambucil alone , and Stage 2 compared GAZYVA in combination with chlorambucil vs . rituximab in combination with chlorambucil . Adverse reactions rates and laboratory abnormalities from the Stage 2 phase are presented below and 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 obinutuzumab treated patients . The incidence of Grade 3-4 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 obinutuzumab with similar incidences of Grade 3-4 abnormalities between the two arms .

Patients received three 1000 mg doses of GAZYVA on the first cycle and a single dose of 1000 mg once every 28 days for 5 additional cycles in combination with chlorambucil ( 6 cycles of 28 days each in total ). In the last 140 patients enrolled , the first dose of GAZYVA was split between day 1 ( 100 mg ) and day 2 ( 900 mg ) [ see Dosage and Administration ( 2.1 )]. In total , 81 % of patients received all 6 cycles ( of 28 days each ) of GAZYVA-based therapy .

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 .

The most common Grade 3-4 adverse reactions ( incidence ≥ 10 %) observed in patients with CLL in the GAZYVA containing arm were neutropenia , infusion reactions , and thrombocytopenia .