Because of the risk of PML, TYSABRI^Ò is available only under a special restricted distribution program, the TOUCHÒ Prescribing Program.

Prescribing, Distribution, and Administration Program for TYSABRI^Ò

TYSABRI^Ò is available only under a special restricted distribution program called the TOUCHÒ Prescribing Program. Under the TOUCHÒ 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. In addition, TYSABRI^Ò must be administered only to patients who are enrolled in and meet all the conditions of the TOUCHÒ Prescribing Program (see BOXED WARNING and/or contact the TOUCHÒ Prescribing Program at 1-800-456-2255).

To enroll in the TOUCHÒ Prescribing Program, prescribers and patients are required to understand the risks of treatment with TYSABRI^Ò, including PML and other opportunistic infections. Prescribers are required to understand the information in the Prescribing Information and to be able to:

· Diagnose and manage opportunistic infections and PML, or be prepared to refer patients to specialists with these abilities.

· Educate patients on the benefits and risks of treatment with TYSABRI^Ò, provide them with the Medication Guide, instruct them to read it, and encourage them to ask questions when considering TYSABRI^Ò. Patients may be educated by the enrolled prescriber or a healthcare provider under that prescribers direction.

· Review the TOUCHÒ Prescriber/Patient Enrollment form for TYSABRI^Ò with the patient and answer all questions.

· As part of the initial prescription process for TYSABRI^Ò, obtain the patients signature and initials on the TOUCHÒ program enrollment form, sign it, place the original signed form in the patients medical record, send a copy to Biogen Idec, and give a copy to the patient.

· Report serious opportunistic and atypical infections with TYSABRI^Ò to Biogen Idec at 1-800-456-2255 and to the Food and Drug Administrations MedWatch Program at 1-800-FDA-1088.

· Evaluate the patient 3 months after the first infusion, 6 months after the first infusion, and every 6 months thereafter.

· Determine every 6 months whether patients should continue on treatment and if so reauthorize treatment every 6 months.

· Submit to Biogen Idec the TYSABRI^Ò Patient Status Report and Reauthorization Questionnaire 6 months after initiating treatment and every 6 months thereafter.

TYSABRI^Ò has been associated with hypersensitivity reactions, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%. These 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^Ò.

If a hypersensitivity reaction occurs, discontinue administration of TYSABRI^Ò and initiate appropriate therapy (see ADVERSE REACTIONS, Infusion-related Reactions). Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI^Ò. The possibility of antibodies to TYSABRI^Ò should be considered in patients who have hypersensitivity reactions (see ADVERSE REACTIONS, Immunogenicity).

The immune system effects of TYSABRI^Ò may increase the risk for infections. In Study 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^Ò-treated patients than in placebo-treated patients (see WARNINGS, Progressive Multifocal Leukoencephalopathy (PML); and ADVERSE REACTIONS, General and Infections). One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received TYSABRI^Ò in Study 1.

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^Ò alone (see BOXED WARNING; WARNINGS, Progressive Multifocal Leukoencephalopathy; and ADVERSE REACTIONS, Infections). The safety and efficacy of TYSABRI^Ò in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established.

Concurrent use of short courses of corticosteroids was associated with an increase in infections in Studies 1 and 2. However, the increase in infections in TYSABRI^Ò-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids.

TYSABRI^Ò induces increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persist during TYSABRI^Ò exposure, but are reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils are not observed. TYSABRI^Ò induces mild decreases in hemoglobin levels that are frequently transient.

No clastogenic or mutagenic effects of natalizumab were observed in the Ames test or in vitro chromosomal aberration assay in human lymphocytes. Natalizumab showed no effects in in vitro assays of a4-integrin positive human tumor line proliferation/cytotoxicity. Xenograft transplantation models in SCID and nude mice with two a4-integrin positive human tumor lines (leukemia, melanoma) demonstrated no increase in tumor growth rates or metastasis resulting from natalizumab treatment.

Reductions in female guinea pig fertility were observed in one study at dose levels of 30 mg/kg, but not at the 10 mg/kg dose level (2.3-fold the clinical dose). A 47% reduction in pregnancy rate was observed in guinea pigs receiving 30 mg/kg relative to control. Implantations were seen in only 36% of animals having corpora lutea in the 30 mg/kg group versus 66-72% in the other groups. Natalizumab did not affect male fertility at doses up to 7-fold the clinical dose.

There are no adequate and well-controlled studies of TYSABRI^Ò therapy in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. If a woman becomes pregnant while taking TYSABRI^Ò, discontinuation of TYSABRI^Ò should be considered.

If a woman becomes pregnant while taking TYSABRI^Ò, consider enrolling her in the TYSABRI^Ò Pregnancy Exposure Registry by calling 1-800-456-2255.

In reproductive studies in monkeys and guinea pigs, there was no evidence of teratogenic effects at doses up to 30 mg/kg (7 times the human clinical dose based on a body weight comparison). In one study where female guinea pigs were exposed to natalizumab during the second half of pregnancy, a small reduction in pup survival was noted at post-natal day 14 with respect to control (3 pups/litter for the group treated with 30 mg/kg natalizumab and 4.3 pups/litter for the control group). In one of five studies that exposed monkeys or guinea pigs during pregnancy, the number of abortions in treated (30 mg/kg) monkeys was 33% versus 17% in controls. No effects on abortion rates were noted in any other study. TYSABRI^Ò underwent trans-placental transfer and produced in utero exposure in developing guinea pigs and cynomolgus monkeys. When pregnant dams were exposed to natalizumab at approximately 7-fold the clinical dose, serum levels in fetal animals at delivery were approximately 35% of maternal serum natalizumab levels. A study in pregnant cynomolgus monkeys treated at 2.3-fold the clinical dose demonstrated natalizumab-related changes in the fetus. These changes included mild anemia, reduced platelet count, increased spleen weights, and reduced liver and thymus weights associated with increased splenic extramedullary hematopoiesis, thymic atrophy, and decreased hepatic hematopoiesis. In offspring born to mothers treated with natalizumab at 7-fold the clinical dose, platelet counts were also reduced. This effect was reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring. Offspring exposed in utero and via breast milk had no natalizumab-related changes in the lymphoid organs and had normal immune response to challenge with a T-cell dependent antigen.

It is not known whether TYSABRI^Ò is excreted in human milk. Because many drugs and immunoglobulins are excreted in human milk, and because the potential for serious adverse reactions is unknown, discontinuation of TYSABRI^Ò or alternatives to nursing should be considered.

Clinical studies of TYSABRI^Ò did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently than younger patients.

Safety and effectiveness of TYSABRI^Ò in pediatric patients with multiple sclerosis below the age of 18 have not been studied. TYSABRI^Ò is not indicated for use in pediatric patients.

No data are available on the effects of vaccination in patients receiving TYSABRI^Ò. No data are available on the secondary transmission of infection by live vaccines in patients receiving TYSABRI^Ò.

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