IMPORTANT SAFETY INFORMATION ( continued )
Warnings and Precautions :
• Cytokine Release Syndrome : Cytokine release syndrome ( CRS ), including fatal or life-threatening reactions , occurred following treatment with KYMRIAH . In Study 1 , CRS occurred in 79 % ( 54 / 68 ) of patients receiving KYMRIAH , including Grade 3 or 4 ( Penn grading system ) CRS in 49 % ( 33 / 68 ) patients . The median time to onset of CRS was 3 days ( range : 1-22 days ). Of the 54 patients with CRS , 27 ( 50 %) received tocilizumab ; 7 ( 13 %) patients received two doses of tocilizumab , 3 ( 6 %) patients received three doses of tocilizumab and 14 ( 26 %) patients received addition of corticosteroids ( e . g . methylprednisolone ). The median time to resolution of CRS was 8 days ( range : 1-36 days ).
Key manifestations of CRS include high fever , lower than normal blood pressure , difficulty breathing , and may be associated with hepatic , renal , and cardiac dysfunction , and coagulopathy .
Risk factors for severe CRS are high pre-infusion tumor burden ( greater than 50 % blasts in bone marrow ), uncontrolled or accelerating tumor burden following lymphodepleting chemotherapy , active infections , and / or inflammatory processes .
Delay the infusion of KYMRIAH after lymphodepleting chemotherapy if the patient has unresolved serious adverse reactions from preceding chemotherapies ( including pulmonary toxicity , cardiac toxicity , or hypotension ), active uncontrolled infection , active graft versus host disease ( GVHD ), or worsening of leukemia burden [ see Dosage and Administration ( 2.2 )].
Ensure that tocilizumab is available on site prior to infusion of KYMRIAH . Monitor patients for signs or symptoms of CRS for at least 4 weeks after treatment with KYMRIAH . Counsel patients to seek immediate medical attention should signs or symptoms of CRS occur at any time [ see Patient Counseling Information ( 17 )]. At the first sign of CRS , immediately evaluate patient for hospitalization and institute treatment with supportive care , tocilizumab and / or corticosteroids as indicated [ see Dosage and Administration ( 2.3 )].
• Neurological Toxicities : Neurological toxicities , which may be severe or life-threatening can occur following treatment with KYMRIAH . The majority of neurological toxicities occurred within 8 weeks following KYMRIAH infusion . In Study 1 , neurological toxicities within 8 weeks after KYMRIAH infusion occurred in 65 % of patients , including Grade 3 or 4 neurological toxicities in 18 % of patients , and 75 % of events resolved within 12 days . The most common neurological toxicities were headache ( 37 %), encephalopathy ( 34 %), delirium ( 21 %), anxiety ( 13 %), and tremor ( 9 %). Other manifestations of neurological toxicities included disturbances in consciousness , disorientation , confusion , agitation , seizures , mutism and aphasia . Onset of neurological toxicity can be concurrent with CRS , following resolution of CRS or in the absence of CRS .
Monitor patients for neurological events and exclude other causes for neurological symptoms . Provide supportive care as needed for KYMRIAHassociated neurological events .
• KYMRIAH REMS to Mitigate Cytokine Release Syndrome and Neurological Toxicities : Because of the risk of CRS and neurological toxicities , KYMRIAH is available only through a restricted program under a Risk Evaluation and Mitigation Strategy ( REMS ) called the KYMRIAH REMS [ see Boxed Warning and Warnings and Precautions ( 5.1 , 5.2 )]. The required components of the KYMRIAH REMS are : — Healthcare facilities that dispense and administer KYMRIAH must be enrolled and comply with the REMS requirements . Certified healthcare facilities must have on-site , immediate access to tocilizumab , and ensure that a minimum of two doses of tocilizumab are available for each patient for administration within 2 hours after KYMRIAH infusion , if needed for treatment of CRS .
— Certified healthcare facilities must ensure that healthcare providers who prescribe , dispense or administer KYMRIAH are trained about the management of CRS and neurological toxicities .
Further information is available at www . kymriah-rems . com or 1-844-4KYMRIAH .
• Hypersensitivity Reactions : Allergic reactions may occur with infusion of KYMRIAH . Serious hypersensitivity reactions , including anaphylaxis , may be due to the dimethyl sulfoxide ( DMSO ) or dextran 40 in KYMRIAH .
• Serious Infections : Serious infections , including life-threatening or fatal infections , occurred in patients after KYMRIAH infusion . In Study 1 , infections ( all Grades ) after KYMRIAH infusion occurred in 40 patients ( 59 %), including 24 patients ( 35 %) with Grade 3-4 infections and 2 patients ( 3 %) with fatal infections . Infections with an unknown pathogen occurred in 41 % of patients , viral infections in 26 %, bacterial infections in 19 %, and fungal infections in 13 %. Prior to KYMRIAH infusion , infection prophylaxis should follow local guidelines . Monitor patients for signs and symptoms of infection after treatment with KYMRIAH and treat appropriately [ see Dosage and Administration ( 2.3 )].
Febrile neutropenia ( Grade 3 or 4 ) was also observed in 37 % of patients after KYMRIAH infusion and may be concurrent with CRS . In the event of febrile neutropenia , evaluate for infection and manage with broad spectrum antibiotics , fluids and other supportive care as medically indicated .
Viral Reactivation Hepatitis B virus ( HBV ) reactivation , in some cases resulting in fulminant hepatitis , hepatic failure and death , can occur in patients treated with drugs directed against B cells . Hepatitis cases have been reported in patients who are hepatitis B surface antigen ( HBsAg ) positive , and also in patients who are HBsAg-negative but hepatitis B core antibody ( anti-HBc ) positive . HBV reactivation has occurred in patients who appear to have resolved hepatitis B infection ( i . e ., HBsAgnegative , 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 .
Perform screening for HBV , HCV , and HIV in accordance with clinical guidelines before collection of cells for manufacturing .
• Prolonged Cytopenias : Patients may exhibit cytopenias for several weeks following lymphodepleting chemotherapy and KYMRIAH infusion . Grade 3 and 4 cytopenias not resolved by Day 28 following KYMRIAH treatment included neutropenia ( 40 %) and thrombocytopenia ( 27 %) among 52 responding patients . At 56 days following KYMRIAH , 17 % and 12 % of responding patients had grade 3 and 4 neutropenia or thrombocytopenia respectively . Prolonged neutropenia has been associated with increased risk of infection . Myeloid growth factors , particularly GM-CSF , are not recommended during the first 3 weeks after KYMRIAH infusion or until CRS has resolved .
• Hypogammaglobulinemia : Hypogammaglobulinemia and agammaglobulinemia ( IgG ) can occur in patients with a complete remission after KYMRIAH infusion . In Study 1 , 43 % of patients had hypogammaglobulinemia . B-cell aplasia is an on-target effect of KYMRIAH and therefore a patient may experience hypogammaglobulinemia for as long as KYMRIAH persists [ see Clinical Pharmacology ( 12.3 )].
Monitor immunoglobulin levels after treatment with KYMRIAH and manage using infection precautions , antibiotic prophylaxis and immunoglobulin replacement standard guidelines .
The safety of immunization with live viral vaccines during or following KYMRIAH treatment has not been studied . Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of lymphodepleting chemotherapy , during KYMRIAH treatment , and until immune recovery following treatment with KYMRIAH .
Pregnant women who have received KYMRIAH may have hypogammaglobulinemia . Assess immunoglobulin levels in newborns of mothers treated with KYMRIAH .
• Secondary Malignancies : Patients treated with KYMRIAH may develop secondary malignancies or recurrence of their leukemia . Monitor life-long for secondary malignancies . In the event that a secondary malignancy occurs , contact Novartis Pharmaceuticals Corporation at 1-844-4KYMRIAH to obtain instructions on patient samples to collect for testing .
• Effects on Ability to Drive and Use Machines : Due to the potential for neurological events , including altered mental status or seizures , patients receiving KYMRIAH are at risk for altered or decreased consciousness or coordination in the 8 weeks following KYMRIAH infusion . Advise patients to refrain from driving and engaging in hazardous occupations or activities , such as operating heavy or potentially dangerous machinery , during this initial period .
Adverse Reactions The most common adverse reactions ( incidence greater than 20 %) are cytokine release syndrome , hypogammaglobulinemia , infections-pathogen unspecified , pyrexia , decreased appetite , headache , encephalopathy , bleeding , hypotension , tachycardia , nausea , diarrhea , vomiting , viral infection disorders , hypoxia , fatigue , acute kidney injury , and delirium [ see Adverse Reactions ( 6 )].
Drug Interactions HIV and the lentivirus used to make KYMRIAH have limited short spans of identical genetic material ( RNA ). Therefore , some commercial HIV nucleic acid test ( NAT ) tests may yield false positive results in patients who have received KYMRIAH .
Please see Brief Summary of full Prescribing Information for KYMRIAH , including Boxed WARNING , on following pages .