IMPORTANT SAFETY INFORMATION
TYSABRI increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Cases of PML have been reported in patients taking TYSABRI who were recently or concomitantly treated with immunomodulators or immunosuppressants, as well as in patients receiving TYSABRI as monotherapy. Longer treatment duration (especially beyond 2 years), prior immunosuppressant use (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil), and the presence of anti-JC virus antibodies are three known risk factors identified thus far that increase risk of PML in TYSABRI treated patients. The risks and benefits of continuing treatment with TYSABRI should be carefully considered in patients who are anti-JCV antibody positive and have one or more additional risk factors. 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.
Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be 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. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML.
For diagnosis, 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.
Important Safety Information
Progressive Multifocal Leukoencephalopathy (PML)
- PML developed in 3 patients who received TYSABRI in clinical trials. Two cases of PML were observed in 1869 patients with MS treated for a median of 120 weeks. The third case occurred among 1043 patients with Crohn's disease after the patient received 8 doses. Both MS 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.
- Anti-JCV antibody testing should not be used to diagnose PML.
- 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.
- In MS 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.
- 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.
- TYSABRI is contraindicated in patients who have or have had PML.
- TYSABRI should not be administered to a patient who has had a hypersensitivity reaction to TYSABRI.
Distribution Program for TYSABRI
- Because of the risk of PML, TYSABRI is only available in the US through a special restricted distribution program called the TOUCH Prescribing Program. Under the TOUCH Prescribing Program, only prescribers, patients, infusion centers, and pharmacies associated with infusion centers registered with the program are able to prescribe, receive, infuse, or distribute the product. In addition, TYSABRI must be administered only to patients who are enrolled in and meet all the conditions of the TOUCH Prescribing Program.
- 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 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.
- Hypersensitivity reactions have occurred in patients receiving TYSABRI, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%.
- Reactions usually occur within 2 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.
- Patients who receive TYSABRI after an extended period without treatment may be at higher risk of hypersensitivity reactions.
- The immune system effects of TYSABRI may increase the risk for infections.
- In Study MS1, 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. 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.
- Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections over the risk observed with use of TYSABRI alone. The safety and efficacy of TYSABRI in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established.
- In Study MS1 and Study MS2, the rate of any type of infection was approximately 1.5 per patient-year in both TYSABRI-treated patients and placebo-treated patients.
- In Study MS1, the incidence of serious infections was approximately 3% in TYSABRI-treated patients and in placebo-treated patients. Most patients did not interrupt treatment with TYSABRI during infections.
- In postmarketing experience, serious herpes infections have occurred.
- Clinically significant liver injury has been reported in patients treated with TYSABRI in the postmarketing setting. In some patients, liver injury recurred upon rechallenge, providing evidence that TYSABRI caused the injury.
- TYSABRI should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).
- 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.
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.
*Percentage based on female patients only
- The most frequently reported serious adverse reactions in Study MS1 were infections (3.2% vs 2.6% placebo), including urinary tract infection (0.8% versus 0.3%) and pneumonia (0.6% versus 0%), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% versus 0%]), depression (1.0% vs 1.0%, including suicidal ideation or attempt [0.6% versus 0.3%]), and cholelithiasis (1.0% vs 0.3%).
- Based on animal data, TYSABRI may cause fetal harm. TYSABRI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. If a woman becomes pregnant while taking TYSABRI, consider enrolling her in the TYSABRI Pregnancy Exposure Registry by calling 1-800-456-2255.