IMPORTANT SAFETY INFORMATION ( cont ’ d ) Infusion-Related Reactions ( IRR )
• Rituximab products can cause severe , including fatal , infusionrelated reactions . Severe reactions typically occurred during the first infusion with time to onset of 30 – 120 minutes
• Rituximab product−induced infusion-related reactions and sequelae include urticaria , hypotension , angioedema , hypoxia , bronchospasm , pulmonary infiltrates , acute respiratory distress syndrome , myocardial infarction , ventricular fibrillation , cardiogenic shock , anaphylactoid events , or death
• Premedicate patients with an antihistamine and acetaminophen prior to dosing . Institute medical management ( e . g ., glucocorticoids , epinephrine , bronchodilators , or oxygen ) for infusion-related reactions as needed . Depending on the severity of the infusionrelated reaction and the required interventions , temporarily or permanently discontinue RUXIENCE . Resume infusion at a minimum 50 % reduction in rate after symptoms have resolved
• Closely monitor the following patients : those with preexisting cardiac or pulmonary conditions , those who experienced prior cardiopulmonary adverse reactions , and those with high numbers of circulating malignant cells ( ≥25,000 / mm 3 )
Severe Mucocutaneous Reactions
• Mucocutaneous reactions , some with fatal outcome , can occur in patients treated with rituximab products . These reactions include paraneoplastic pemphigus , Stevens-Johnson syndrome , lichenoid dermatitis , vesiculobullous dermatitis , and toxic epidermal necrolysis
• The onset of these reactions has been variable and includes reports with onset on the first day of rituximab exposure . Discontinue RUXIENCE in patients who experience a severe mucocutaneous reaction . The safety of readministration of rituximab products to patients with severe mucocutaneous reactions has not been determined
Hepatitis B Virus ( HBV ) Reactivation
• HBV reactivation , in some cases resulting in fulminant hepatitis , hepatic failure , and death , can occur in patients treated with drugs classified as CD20-directed cytolytic antibodies , including rituximab products . Cases have 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 . In severe cases , increase in bilirubin levels , liver failure , and death can occur
• Screen all patients for HBV infection by measuring HBsAg and anti-HBc before initiating treatment with RUXIENCE . For patients who show evidence of prior hepatitis B infection ( HBsAg positive [ regardless of antibody status ] or HBsAg negative but anti-HBc positive ), consult with physicians with expertise in managing hepatitis B regarding monitoring and consideration for HBV antiviral therapy before and / or during RUXIENCE treatment
• 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 RUXIENCE therapy . HBV reactivation has been reported up to 24 months following completion of rituximab therapy
• In patients who develop reactivation of HBV while on RUXIENCE , immediately discontinue RUXIENCE and any concomitant chemotherapy , and institute appropriate treatment . Insufficient data exist regarding the safety of resuming rituximab product treatment in patients who develop HBV reactivation . Resumption of RUXIENCE treatment in patients whose HBV reactivation resolves should be discussed with physicians with expertise in managing HBV
Progressive Multifocal Leukoencephalopathy ( PML )
• JC virus infection resulting in progressive multifocal leukoencephalopathy ( PML ) and death can occur in rituximab product−treated patients with hematologic malignancies or with autoimmune diseases . The majority of patients with hematologic malignancies diagnosed with PML received rituximab in combination with chemotherapy or as part of a hematopoietic stem cell transplant . The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy . Most cases of PML were diagnosed within 12 months of their last infusion of rituximab
• Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations . Evaluation of PML includes , but is not limited to , consultation with a neurologist , brain MRI , and lumbar puncture . Discontinue RUXIENCE and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML Tumor Lysis Syndrome ( TLS )
• Acute renal failure , hyperkalemia , hypocalcemia , hyperuricemia , or hyperphosphatemia from tumor lysis , some fatal , can occur within 12 – 24 hours after the first infusion of RUXIENCE in patients with non-Hodgkin ’ s lymphoma ( NHL ). A high number of circulating malignant cells ( ≥25,000 / mm 3 ), or high tumor burden , confers a greater risk of TLS
• Administer aggressive intravenous hydration and anti-hyperuricemic therapy in patients at high risk for TLS . Correct electrolyte abnormalities , monitor renal function and fluid balance , and administer supportive care , including dialysis as indicated
Infections
• Serious , including fatal , bacterial , fungal , and new or reactivated viral infections can occur during and following the completion of rituximab product−based therapy . Infections have been reported in some patients with prolonged hypogammaglobulinemia ( defined as hypogammaglobulinemia > 11 months after rituximab exposure )
• New or reactivated viral infections included cytomegalovirus , herpes simplex virus , parvovirus B19 , varicella zoster virus , West Nile virus , and hepatitis B and C . Discontinue RUXIENCE for serious infections and institute appropriate anti-infective therapy
• RUXIENCE is not recommended for use in patients with severe , active infections
Please see continued Important Safety Information on next page .
Please see the Brief Summary of Prescribing Information , including BOXED WARNINGS , on the following pages .