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warnings and cautions
5 WARNINGS AND PRECAUTIONS Progressive Multifocal Leukoencephalopathy (PML): Has occurred in patients who received TYSABRI. Patients who have significantly compromised immune system function should not ordinarily be treated with TYSABRI. Obtain an MRI scan in MS patients prior to initiating TYSABRI. Monitor MS and CD patients and withhold TYSABRI at the first sign or symptom suggestive of PML. Treatment duration, prior immunosuppressant use, and presence of anti-JC virus antibodies are associated with increased risk of PML in TYSABRI-treated patients ( 5.1 ). Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have occurred. Permanently discontinue TYSABRI if such a reaction occurs ( 5.3 ). Immunosuppression/Infections: TYSABRI may increase the risk for certain infections. Monitor patients for development of infections due to increased risk with use of TYSABRI ( 5.4 ). Hepatotoxicity: Clinically significant liver injury has occurred. Discontinue TYSABRI in patients with jaundice or evidence of liver injury ( 5.5 ). 5.1 Progressive Multifocal Leukoencephalopathy (PML) Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, developed in three patients who received TYSABRI in clinical trials [see Boxed Warning ]. Two cases of PML were observed among 1869 patients with multiple sclerosis treated for a median of 120 weeks. The third case occurred among 1043 patients with Crohn's disease after the patient received eight doses. Both multiple sclerosis patients were receiving concomitant immunomodulatory therapy and the Crohn's disease patient had been treated in the past with immunosuppressive therapy. In the postmarketing setting, additional cases of PML have been reported in multiple sclerosis and Crohn's disease patients who were receiving no concomitant immunomodulatory therapy. Three factors that are known to increase the risk of PML in TYSABRI-treated patients have been identified: Longer treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 4 years of TYSABRI treatment. Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil). The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML. The risks and benefits of continuing treatment with Tysabri should be carefully considered in patients who are found to be anti-JCV antibody positive and have one or more additional risk factors. Patients with all three known risk factors have an estimated risk of PML of 11/1,000. Consideration should be given to testing patients for anti-JCV antibody status prior to treatment or during treatment if antibody status is unknown. Infection by the JC virus is required for the development of PML. Anti-JCV antibody negative status indicates that exposure to the JC virus has not been detected. 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. Therefore, patients with a negative anti-JCV antibody test result should be retested every 6 months. 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. Table 1: Estimated Incidence of PML Stratified by Risk Factor Notes: Based on postmarketing PML data as of September 5, 2012 and TYSABRI use data as of August 31, 2012. † Data beyond 4 years of treatment are limited. *Risk in anti-JCV antibody positive patients was estimated based on the assumptions that 18% of Tysabri-treated MS patients have a history of prior immunosuppressant treatment and that 55% of Tysabri-treated MS patients are anti-JCV antibody positive. 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 a false negative rate of 3%. Tysabri Exposure † Anti-JCV Antibody Positive* No Prior Immunosuppressant Use Prior Immunosuppressant Use 1-24 months <1/1,000 2/1,000 25-48 months 5/1,000 11/1,000 Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody testing should not be performed for at least two weeks following plasma exchange due to the removal of antibodies from the serum. There are no known interventions that can reliably prevent PML or adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of TYSABRI will mitigate the disease. 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 TYSABRI. Because of the risk of PML, TYSABRI is available only under a special restricted distribution program, the TOUCH ® Prescribing Program. In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with TYSABRI. 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 TYSABRI therapy are uncommon. Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom suggestive of PML. Typical 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 TYSABRI dosing immediately at the first sign or symptom suggestive of PML. 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 TYSABRI dosing and repeat the evaluations. There are no known interventions that can adequately treat PML if it occurs. Three sessions of plasma exchange over 5 to 8 days were shown to accelerate TYSABRI clearance in a study of 12 patients with MS who did not have PML, although in the majority of patients alpha-4 integrin receptor binding remained high. Adverse events which may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although plasma exchange has not been studied in TYSABRI treated patients with PML, it has been used in such patients in the postmarketing setting to remove TYSABRI more quickly from the circulation. Anti-JCV antibody testing should not be performed during or for at least two weeks following plasma exchange due to the removal of antibodies from the serum. Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI treated patients who developed PML and subsequently discontinued TYSABRI. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating TYSABRI. It presents as a clinical decline in the patient's condition after TYSABRI removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death and is often associated with characteristic changes in the MRI. TYSABRI has not been associated with IRIS in patients discontinuing treatment with TYSABRI for reasons unrelated to PML. In TYSABRI-treated patients with PML, IRIS has been reported within days to several weeks after plasma exchange. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken. 5.2 Distribution Program for TYSABRI TYSABRI is available only under a special restricted distribution program called the TOUCH ® Prescribing Program. Under the TOUCH ® Prescribing Program, only prescribers, infusion centers, and pharmacies associated with infusion centers registered with the program are able to prescribe, distribute, or infuse the product. For prescribers and patients, the TOUCH ® Prescribing Program has two components: MS TOUCH ® (for patients with multiple sclerosis) and CD TOUCH ® (for patients with Crohn's disease). TYSABRI must be administered only to patients who are enrolled in and meet all the conditions of the MS or CD TOUCH ® Prescribing Program. Contact the TOUCH ® Prescribing Program at 1-800-456-2255 [see Boxed Warning ]. To enroll in the TOUCH ® Prescribing Program, prescribers and patients are required to understand the risks of treatment with TYSABRI, including PML and other opportunistic infections. Prescribers are required to understand the information in the Prescribing Information and to be able to: Educate patients on the benefits and risks of treatment with TYSABRI, ensure that the patient receives the Medication Guide, instruct them to read it, and encourage them to ask questions when considering TYSABRI. Patients may be educated by the enrolled prescriber or a healthcare provider under that prescriber's direction. Review the TOUCH ® Prescriber/Patient Enrollment form for TYSABRI with the patient and answer all questions. As part of the initial prescription process for TYSABRI, obtain the patient's signature and initials on the TOUCH ® program enrollment form, sign it, place the original signed form in the patient's medical record, send a copy to Biogen Idec, and give a copy to the patient. Report serious opportunistic and atypical infections with TYSABRI to Biogen Idec or Elan at 1-800-456-2255 and to the Food and Drug Administration's MedWatch Program at 1-800-FDA-1088. Evaluate the patient three months after the first infusion, six months after the first infusion, and every six months thereafter. Determine every six months whether patients should continue on treatment and if so reauthorize treatment every six months. Submit to Biogen Idec the TYSABRI Patient Status Report and Reauthorization Questionnaire six months after initiating treatment and every six months thereafter. 5.3 Hypersensitivity/Antibody Formation Hypersensitivity reactions have occurred in patients receiving TYSABRI, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%. These reactions usually occur within two hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain. Generally, these reactions are associated with antibodies to TYSABRI. If a hypersensitivity reaction occurs, discontinue administration of TYSABRI and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI. Hypersensitivity reactions were more frequent in patients with antibodies to TYSABRI compared to patients who did not develop antibodies to TYSABRI in both MS and CD studies. Therefore, the possibility of antibodies to TYSABRI should be considered in patients who have hypersensitivity reactions [see Adverse Reactions ( 6.2 ) ]. Antibody testing: If the presence of persistent antibodies is suspected, antibody testing should be performed. Antibodies may be detected and confirmed with sequential serum antibody tests. Antibodies detected early in the treatment course (e.g., within the first six months) may be transient and disappear with continued dosing. Repeat testing at three months after the initial positive result is recommended in patients in whom antibodies are detected to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of TYSABRI in a patient with persistent antibodies. Experience with monoclonal antibodies, including TYSABRI, suggests that patients who receive therapeutic monoclonal antibodies after an extended period without treatment may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled treatment. Given that patients with persistent antibodies to TYSABRI experience reduced efficacy, and that hypersensitivity reactions are more common in such patients, consideration should be given to testing for the presence of antibodies in patients who wish to recommence therapy following a dose interruption. Following a period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of antibody development with re-treatment that is similar to TYSABRI naïve patients [see Adverse Reactions ( 6.2 ) ]. 5.4 Immunosuppression/Infections The immune system effects of TYSABRI may increase the risk for infections. In Study MS1 [see Clinical Studies ( 14.1 ) ], certain types of infections, including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections, occurred more often in TYSABRI-treated patients than in placebo-treated patients [see Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 ) ]. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received TYSABRI in Study MS1. In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in TYSABRI-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. In CD clinical studies, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of TYSABRI-treated patients; some of these patients were receiving concurrent immunosuppressants [see Boxed Warning , Warnings and Precautions ( 5.1 , 5.4 ), Adverse Reactions ( 6.1 ) ]. In Studies CD1 and CD2, an increase in infections was seen in patients concurrently receiving corticosteroids. However, the increase in infections was similar in placebo-treated and TYSABRI-treated patients who received steroids. Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections, including PML and other opportunistic infections, over the risk observed with use of TYSABRI alone [see Boxed Warning , Warnings and Precautions ( 5.1 ), Adverse Reactions ( 6.1 ) ]. The safety and efficacy of TYSABRI in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not ordinarily be treated with TYSABRI. The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving TYSABRI [see Warnings and Precautions ( 5.1 ) ]. For patients with Crohn's disease who start TYSABRI while on chronic corticosteroids, commence steroid withdrawal as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within six months, discontinue TYSABRI. 5.5 Hepatotoxicity Clinically significant liver injury has been reported in patients treated with TYSABRI in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses. In some patients, liver injury recurred upon rechallenge, providing evidence that TYSABRI caused the injury. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. TYSABRI should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence). 5.6 Laboratory Test Abnormalities In clinical trials, TYSABRI was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during TYSABRI exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. TYSABRI induces mild decreases in hemoglobin levels that are frequently transient. 5.7 Immunizations No data are available on the effects of vaccination in patients receiving TYSABRI. No data are available on the secondary transmission of infection by live vaccines in patients receiving TYSABRI.