CLINICAL NEWS
Adding Pharmacomechanical Thrombolysis to Anticoagulation Does Not Improve Outcomes in Proximal DVT
The objective of pharmacomechanical thrombolysis , or the delivery of a fibrinolytic drug into the thrombus with concomitant thrombus aspiration , is to diminish the thrombus burden and reduce the risk of post-thrombotic syndrome ( PTS ) in patients with proximal deep vein thrombosis ( DVT ). According to results from a randomized , controlled , phase III trial , though , the additional treatment failed to lower this risk , and increased the odds of experiencing major bleeding , compared with anticoagulation alone . The findings were published in the New England Journal of Medicine .
“ Despite the use of anticoagulant therapy , PTS [ which is associated with chronic limb pain and major disability ] develops within two years in approximately half of patients with proximal
GAZYVA ® ( obinutuzumab ) injection , for intravenous use
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 ( CLL ) GAZYVA , in combination with chlorambucil , is indicated for the treatment of patients with previously untreated chronic lymphocytic leukemia [ see Clinical Studies ( 14.1 )].
1.2 Follicular Lymphoma ( FL ) GAZYVA , in combination with bendamustine followed by GAZYVA monotherapy , is indicated for the treatment of patients with follicular lymphoma who relapsed after , or are refractory to , a rituximabcontaining regimen [ see Clinical Studies ( 14.2 )].
GAZYVA , 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 [ see Clinical Studies ( 14.2 )].
4 CONTRAINDICATIONS GAZYVA is contraindicated in patients with known hypersensitivity reactions ( e . g ., anaphylaxis ) to obinutuzumab or to any of the excipients , or serum sickness with prior obinutuzumab use [ see Warnings and Precautions Section ( 5.4 )].
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 of GAZYVA 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 , laryngeal edema ). The most frequently reported symptoms include nausea , fatigue , chest discomfort , dyspnea , dizziness , vomiting , diarrhea , rash , hypertension , hypotension , 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 Print-only preexisting cardiac content 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 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 infusion related reactions . 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 , the infusion must be stopped and treatment permanently discontinued . Patients with known hypersensitivity reactions to GAZYVA , including serum sickness , must not be retreated .
5.5 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 ( 2.3 )].
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 .
5.6 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 [ see Adverse Reactions ( 6.1 )]. 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 GALLIUM , more Grade 3 to 5 infections were reported in the recipients of GAZYVA and bendamustine ( 117 / 410 patients , 29 %), as compared to GAZYVA plus CHOP or CVP ( 43 / 281 patients , 15 %). More fatal infections were reported in patients treated with GAZYVA and bendamustine ( 3 %), as compared to GAZYVA plus CHOP or CVP (< 1 %), including during the monotherapy phase and after completion of treatment .
5.7 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 administration of granulocyte colonystimulating 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 .
5.8 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 during 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 , anticoagulants ), especially during the first cycle .
5.9 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 virus reactivation [ see Warnings and Precautions ( 5.1 )]
• Progressive multifocal leukoencephalopathy [ see Warnings and Precautions ( 5.2 )]
• Infusion reactions [ see Warnings and Precautions ( 5.3 )]
• Hypersensitivity reactions including serum sickness [ see Warnings and Precautions ( 5.4 )]
• Tumor lysis syndrome [ see Warnings and Precautions ( 5.5 )]
• Infections [ see Warnings and Precautions ( 5.6 )]
• Neutropenia [ see Warnings and Precautions ( 5.7 )]
• Thrombocytopenia [ see Warnings and Precautions ( 5.8 )]
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 in the CLL11 study . Patients were treated with chlorambucil alone , GAZYVA in combination with chlorambucil , or rituximab product 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 product in combination with chlorambucil . Adverse reactions rates and laboratory abnormalities from the Stage 2 phase are presented below and are consistent with the