WARNINGS AND PRECAUTIONS
Progressive Multifocal Leukoencephalopathy (PML)
Progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC virus, 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 patients who were receiving no concomitant immunomodulatory therapy. The absolute risk for PML in patients treated with TYSABRI cannot be precisely estimated, and factors that might increase an individual patient's risk for PML have not been identified. 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. There is limited experience beyond two years of treatment. The relationship between the risk of PML and the duration of treatment is unknown, but most cases of PML were in patients who received more than one year of treatment.
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. The incidence of PML appears to be lower in patients receiving TYSABRI as monotherapy; however, the number of cases is too few and the number of patients treated too small to reliably conclude that the true risk of PML is lower in patients treated with TYSABRI alone than in patients who are receiving other drugs that decrease immune function or who are otherwise immunocompromised.
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, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended.
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.
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) ].
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.
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.
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).
Laboratory Test Abnormalities
TYSABRI induces increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persist during TYSABRI exposure, but are reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils are not observed. TYSABRI induces mild decreases in hemoglobin levels that are frequently transient.
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.
USE IN SPECIFIC POPULATIONS
Pregnancy Category C. TYSABRI has been shown to reduce pup survival in guinea pigs when given in doses 7 times the human dose, and has been shown to have hematologic effects on the fetus in monkeys when given in doses 2.3 times the human dose [see Nonclinical Toxicology (13.2) ]. There are no adequate and well-controlled studies in pregnant women. 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.
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from TYSABRI, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.
Safety and effectiveness of TYSABRI in pediatric patients with multiple sclerosis or Crohn's disease below the age of 18 years have not been established. TYSABRI is not indicated for use in pediatric patients.
Clinical studies of TYSABRI did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.