tyruko

Important safety information

Herpes infections: Life-threatening and fatal cases have occurred with herpes encephalitis and meningitis infections. Blindness has occurred in patients developing acute retinal necrosis. Discontinue TYRUKO if these infections occur and treat appropriately. ( 5.3 ) • Hepatotoxicity: Significant liver injury, including liver failure requiring transplant, has occurred. Discontinue TYRUKO in patients with evidence of liver injury. ( 5.4 ) • Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have occurred. Permanently discontinue TYRUKO if such a reaction occurs. ( 5.5 ) • Immunosuppression/Infections: Natalizumab products may increase the risk for certain infections. Monitor patients for development of infections due to increased risk with use of TYRUKO. ( 5.6 ) • Hematological abnormalities: Natalizumab products may cause thrombocytopenia. Monitor patients for bleeding abnormalities. Discontinue TYRUKO in patients with thrombocytopenia. Neonatal thrombocytopenia and anemia have also occurred. Obtain a complete blood count in neonates exposed to TYRUKO in utero. ( 5.8 ) 5.1 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability, has occurred in patients who have received natalizumab products. Three factors that are known to increase the risk of PML in natalizumab-treated patients have been identified: • The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML. • Longer treatment duration, especially beyond 2 years. • Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil). These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYRUKO. Table 1: Estimated United States Incidence of PML Stratified by Risk Factor Anti-JCV Antibody Negative Natalizumab Exposure Anti-JCV Antibody Positive No Prior Immunosuppressant Use Prior Immunosuppressant Use 1/10,000 1-24 months <1/1,000 1/1,000 25-48 months 2/1,000 6/1,000 49-72 months 4/1,000 7/1,000 73-96 months 2/1,000 6/1,000 Notes: The risk estimates are based on postmarketing data in the United States from approximately 100,000 natalizumab exposed patients. The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA) that has been analytically and clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific antibodies with an analytical false negative rate of 3%. Retrospective analyses of postmarketing data from various sources, including observational studies and spontaneous reports obtained worldwide, suggest that the risk of developing PML may be associated with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often described as an anti-JCV antibody index value). Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with TYRUKO. Infection by the JC virus is required for the development of PML. Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates that antibodies to the JC virus have not been detected. Patients who are anti-JCV antibody negative have a lower risk of PML than those who are positive. Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. The reported rate of seroconversion in patients with MS (changing from anti-JCV antibody negative to positive and remaining positive in subsequent testing) is 3 to 8 percent annually. In addition, some patients’ serostatus may change intermittently. Therefore, patients with a negative anti-JCV antibody test result should be retested periodically. For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay. After plasma exchange (PLEX), wait at least two weeks to test for anti-JCV antibodies to avoid false negative test results caused by the removal of serum antibodies. After infusion of intravenous immunoglobulin (IVIg), wait at least 6 months (5 half-lives) for the IVIg to clear in order to avoid false positive anti-JCV antibody test results. Healthcare professionals should monitor patients on TYRUKO for any new sign or symptom suggestive of PML. Symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold TYRUKO dosing immediately and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following natalizumab products discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of natalizumab products or due to differences in disease in these patients. There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs. PML has been reported following discontinuation of natalizumab products in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least six months following discontinuation of TYRUKO. Because of the risk of PML, TYRUKO is available only under a restricted distribution program, the TYRUKO REMS Program. In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with TYRUKO. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML. In Crohn’s disease patients, a baseline brain MRI may also be helpful to distinguish pre-existent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on natalizumab product therapy are uncommon. For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. If the initial evaluations for PML are negative but clinical suspicion for PML remains, continue to withhold TYRUKO dosing, and repeat the evaluations. There are no known interventions that can adequately treat PML if it occurs. Three sessions of PLEX over 5 to 8 days were shown to accelerate natalizumab clearance in a study of 12 patients…