IMPORTANT SAFETY INFORMATION
TYSABRI® (natalizumab) increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti-JCV antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI.
Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. 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.
Because of the risk of PML, TYSABRI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH Prescribing Program.
Progressive Multifocal Leukoencephalopathy (PML)
- Infection by the JC Virus (JCV) is required for the development of PML.
- Anti-JCV antibody testing should not be used to diagnose PML.
- There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs. It is not known whether early detection of PML and discontinuation of TYSABRI will mitigate the disease.
- PML has been reported after discontinuation of TYSABRI 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 approximately 6 months after discontinuation of TYSABRI.
- In MS patients, an MRI scan should be obtained before initiating therapy with TYSABRI. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML.
- Three sessions of plasma exchange over the course of 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 that 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 2 weeks after, plasma exchange because of 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 available only through a restricted program under a REMS called the TOUCH® Prescribing Program.
- 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).
- Prescribers must be certified and must comply with the following:
- Review the TOUCH Prescribing Program prescriber educational materials, including the Full Prescribing Information.
- Educate patients on the benefits and risks of treatment with TYSABRI, ensure that patients receive the Medication Guide, and encourage them to ask questions.
- Review, complete, and sign the Patient-Prescriber Enrollment Form.
- Evaluate patients 3 months after the first infusion, 6 months after the first infusion, every 6 months thereafter, and for at least 6 months after discontinuing TYSABRI.
- Determine every 6 months whether patients should continue on treatment, and if so, authorize treatment for another 6 months.
- Submit to Biogen Idec the "TYSABRI Patient Status Report and Reauthorization Questionnaire" 6 months after initiating treatment and every 6 months thereafter.
- Complete an "Initial Discontinuation Questionnaire" when TYSABRI is discontinued, and complete a "6-Month Discontinuation Questionnaire" after discontinuation of TYSABRI.
- Report cases of PML, hospitalizations due to opportunistic infections, or deaths to Biogen Idec at 1-800-456-2255 and to the Food and Drug Administration's MedWatch Program at 1-800-FDA-1088 as soon as possible.
- Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide, understand the risks associated with TYSABRI and complete and sign the Patient-Prescriber Enrollment Form.
- To dispense or infuse TYSABRI, pharmacies and infusion centers must be specially certified.
Herpes Encephalitis and Meningitis
- TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses.
- Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI.
- Monitor patients receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered.
- Clinically significant liver injury, including acute liver failure requiring transplant, 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.
- 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).
- 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 with 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 Studies MS1 and 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.
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.
- The most common adverse reactions reported at an incidence of ≥10% with TYSABRI and ≥2% difference with placebo were headache (38% vs 33%), fatigue (27% vs 21%), infusion reactions (24% vs 18%), urinary tract infections (21% vs 17%), arthralgia (19% vs 14%), depression (19% vs 16%), pain in extremity (16% vs 14%), rash (12% vs 9%), gastroenteritis (11% vs 9%), and vaginitis* (10% vs 6%).
*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% vs 0.3%) and pneumonia (0.6% vs 0%), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% vs 0%]), depression (1.0% vs 1.0%, including suicidal ideation or attempt [0.6% vs 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.