TYSABRI® (natalizumab) is a recombinant humanized IgG4k monoclonal antibody produced in murine myeloma cells. Natalizumab contains human framework regions and the complementarity-determining regions of a murine antibody that binds to a4-integrin. The molecular weight of natalizumab is 149 kilodaltons. TYSABRI® is supplied as a sterile, colorless, and clear to slightly opalescent concentrate for intravenous (IV) infusion.

Each 15 mL dose contains 300 mg natalizumab; 123 mg sodium chloride, USP; 17.0 mg sodium phosphate, monobasic, monohydrate, USP; 7.24 mg sodium phosphate, dibasic, heptahydrate, USP; 3.0 mg polysorbate 80, USP/NF, in water for injection, USP at pH 6.1.

TYSABRI^Ò is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis to delay the accumulation of physical disability and reduce the frequency of clinical exacerbations. The safety and efficacy of TYSABRI^Ò beyond two years are unknown.

Because TYSABRI^Ò increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability (see BOXED WARNING and WARNINGS, Progressive Multifocal Leukoencephalopathy), TYSABRI^Ò is generally recommended for patients who have had an inadequate response to, or are unable to tolerate, alternate multiple sclerosis therapies.

Safety and efficacy in patients with chronic progressive multiple sclerosis have not been studied.

Only prescribers registered in the TOUCHÒ Prescribing Program may prescribe TYSABRI^Ò (see BOXED WARNING).

The recommended dose of TYSABRI^Ò is 300 mg IV infusion every four weeks. Dilute TYSABRI^Ò concentrate 300 mg/15 mL in 100 mL 0.9% Sodium Chloride Injection, USP, and infuse over approximately one hour. Do not administer TYSABRI^Ò as an IV push or bolus injection (see Preparation Instructions) .

Observe patients during the infusion and for 1 hour after the infusion is complete. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction (see WARNINGS, Hypersensitivity).

Use aseptic technique when preparing TYSABRI^Ò solution for IV infusion. Each vial is intended for single use only.

TYSABRI^Ò is a colorless, clear to slightly opalescent concentrate. Inspect the TYSABRI^Ò vial for particulate material prior to dilution and administration. If visible particulates are observed and/or the liquid in the vial is discolored, the vial must not be used. Do not use TYSABRI^Ò beyond the expiration date stamped on the carton or vial.

To prepare the solution, withdraw 15 mL of TYSABRI^Ò concentrate from the vial using a sterile needle and syringe. Inject the concentrate into 100 mL 0.9% Sodium Chloride Injection, USP. No other IV diluents may be used to prepare the TYSABRI^Ò solution.

Gently invert the TYSABRI^Ò solution to mix completely. Do not shake. Inspect the solution visually for particulate material prior to administration.

Following dilution, infuse TYSABRI^Ò solution immediately, or refrigerate solution at 2-8° C, and use within 8 hours. If stored at 2-8° C, allow the solution to warm to room temperature prior to infusion. DO NOT FREEZE.

Infuse TYSABRI^Ò 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP over approximately one hour. After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP.

Use of filtration devices during administration has not been evaluated. Other medications should not be injected into infusion set side ports or mixed with TYSABRI^Ò.

TYSABRI^Ò concentrate is supplied as 300 mg natalizumab in a sterile, single-use vial free of preservatives. Each package contains a single-use vial. NDC 59075-730-15

TYSABRI^Ò is available only through registered infusion centers participating in the TOUCHÒ Prescribing Program. To locate these infusion centers, contact Biogen Idec at 1-800-456-2255.

TYSABRI^Ò single-use vials must be refrigerated between 2-8°C (36°-46°F). Do not use beyond the expiration date stamped on the carton and vial label. DO NOT SHAKE OR FREEZE. Protect from light.

If not used immediately, store the TYSABRI^Ò solution for infusion at 2-8°C (36°-46°F). TYSABRI^Ò solution for infusion must be administered within 8 hours of preparation.

The most frequently reported serious adverse events in Study 1 (see CLINICAL STUDIES) with TYSABRI^Ò were infections (3.2% versus 2.6% in placebo, including urinary tract infection [0.8% versus 0.3%] and pneumonia [0.6% versus 0%]), acute hypersensitivity reactions (1.1% versus 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% versus 0%]), depression (1.0% versus 1.0%, including suicidal ideation or attempt [0.6% versus 0.3%]), and cholelithiasis (1.0% versus 0.3%). In Study 2, serious adverse events of appendicitis were also more common in patients who received TYSABRI^Ò (0.8% versus 0.2% in placebo) (see WARNINGS, Hypersensitivity and ADVERSE REACTIONS, Infections).

The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of TYSABRI^Ò), were urticaria (1%) and other hypersensitivity reactions (1%) (see WARNINGS, Hypersensitivity).

Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in clinical trials of TYSABRI^Ò cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. The adverse reaction information does, however, provide a basis for identifying the adverse events that appear to be related to drug use and a basis for approximating rates.

A total of 1617 multiple sclerosis patients in controlled studies received TYSABRI^Ò, with a median duration of exposure of 28 months.

Table 3 enumerates adverse events and selected laboratory abnormalities that occurred in Study 1 at an incidence of at least 1 percentage point higher in TYSABRI^Ò-treated patients than was observed in placebo-treated patients.

In Study 2, peripheral edema was more common in patients who received TYSABRI^Ò (5% versus 1% in placebo).

Progressive Multifocal Leukoencephalopathy (PML) has occurred in 3 patients who received TYSABRI^Ò in clinical trials (see BOXED WARNING and WARNINGS, Progressive Multifocal Leukoencephalopathy). Two cases of PML were observed in the 1869 patients with multiple sclerosis who were treated for a median of 120 weeks. These 2 patients had received TYSABRI in addition to interferon beta-1a (see BOXED WARNING and WARNINGS, Progressive Multifocal Leukoencephalopathy). The third case occurred after 8 doses in one of the 1043 patients with Crohns disease who were evaluated for PML.

In Studies 1 and 2, the rate of any type of infection was approximately 1.5 per patient-year in bothTYSABRI ^Ò-treated patients and placebo-treated patients. The infections were predominately upper respiratory tract infections, influenza, and urinary tract infections.

In Study 1, the incidence of serious infection was approximately 3% in TYSABRI^Ò-treated patients and placebo-treated patients. Most patients did not interrupt treatment with TYSABRI^Ò during infections.

The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course.

In clinical studies for indications other than multiple sclerosis, opportunistic infections (e.g., pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been uncommonly observed in TYSABRI^Ò-treated patients; some of these patients were receiving concurrent immunosuppressants (see WARNINGS, Immunosuppression). Two serious non-bacterial meningitides occurred in TYSABRI^Ò-treated patients compared to none in placebo-treated patients.

In post-marketing experience, one patient who received TYSABRI^Ò developed herpes encephalitis and died; a second patient developed herpes meningitis and recovered with appropriate treatment.

An infusion-related reaction was defined in clinical trials as any adverse event occurring within 2 hours of the start of an infusion. Approximately 24% of TYSABRI^Ò-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebo-treated patients. Events more common in the TYSABRI^Ò-treated patients included headache, dizziness, fatigue, urticaria, pruritus, and rigors. Acute urticaria was observed in approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients receiving TYSABRI^Ò. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients. All patients recovered with treatment and/or discontinuation of the infusion.

Patients who became persistently positive for antibodies to TYSABRI^Ò were more likely to have an infusion-related reaction than those who were antibody-negative (see ADVERSE REACTIONS, Immunogenicity).

Patients in Study 1 were tested for antibodies to natalizumab every 12 weeks. The assays used were unable to detect low to moderate levels of antibodies to natalizumab. Approximately 9% of patients receiving TYSABRI^Ò developed detectable antibodies at least once during treatment. Approximately 6% of patients had positive antibodies on more than one occasion. Approximately 82% of patients who became persistently antibody-positive developed detectable antibodies by 12 weeks. Anti-natalizumab antibodies were neutralizing in vitro.

The presence of anti-natalizumab antibodies was correlated with a reduction in serum natalizumab levels. In Study 1, the Week 12 pre-infusion mean natalizumab serum concentration in antibody-negative patients was 14.9 mcg/mL compared to 1.3 mcg/mL in antibody-positive patients. Persistent antibody-positivity was associated with a substantial decrease in the effectiveness of TYSABRI^Ò. The risk of increased disability and the annualized relapse rate were similar in persistently antibody-positive TYSABRI^Ò-treated patients and patients who received placebo. A similar phenomenon was also observed in Study 2.

Infusion-related reactions most often associated with persistent antibody-positivity included urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia. Additional adverse events more common in persistently antibody-positive patients included myalgia, hypertension, dyspnea, anxiety, and tachycardia.

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 6 months) may be transient and disappear with continued dosing. Repeat testing at 3 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^Ò in a patient with persistent antibodies.

The long-term immunogenicity of TYSABRI^Ò and the effects of low to moderate levels of antibody to natalizumab are unknown. Experience with other monoclonal antibodies suggests that patients who receive therapeutic antibodies after an extended period without treatment may be at higher risk of hypersensitivity reactions than patients who received regularly scheduled treatment. It is not known if this will occur with TYSABRI^Ò(see WARNINGS, Hypersensitivity and ADVERSE REACTIONS, Infusion-related Reactions) .

Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody-positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to TYSABRI^Ò with the incidence of antibodies to other products may be misleading.

See BOXED WARNING and WARNINGS, Immunosuppression.

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.

Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of TYSABRI^Ò that can be safely administered has not been determined.

TYSABRI^Ò should not be administered to patients with known hypersensitivity to TYSABRI^Ò or any of its components.

TYSABRI^Ò is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) (see BOXED WARNING and WARNINGS).

TYSABRI^Ò binds to the a4-subunit of a4b1 and a4b7 integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the a4-mediated adhesion of leukocytes to their counter-receptor(s). The receptors for the a4 family of integrins include vascular cell adhesion molecule-1 (VCAM-1), which is expressed on activated vascular endothelium, and mucosal addressin cell adhesion molecule-1 (MadCAM-1) present on vascular endothelial cells of the gastrointestinal tract. Disruption of these molecular interactions prevents transmigration of leukocytes across the endothelium into inflamed parenchymal tissue. In vitro, anti-a4-integrin antibodies also block a4-mediated cell binding to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting segment-1 (CS-1). In vivo, TYSABRI^Ò may further act to inhibit the interaction of a4-expressing leukocytes with their ligand(s) in the extracellular matrix and on parenchymal cells, thereby inhibiting further recruitment and inflammatory activity of activated immune cells.

The specific mechanism(s) by which TYSABRI^Ò exerts its effects in multiple sclerosis have not been fully defined. In multiple sclerosis, lesions are believed to occur when activated inflammatory cells, including T-lymphocytes, cross the blood-brain barrier (BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules on inflammatory cells and their counter-receptors present on endothelial cells of the vessel wall. The clinical effect of natalizumab in multiple sclerosis may be secondary to blockade of the molecular interaction of a4b1-integrin expressed by inflammatory cells with VCAM-1 on vascular endothelial cells, and with CS-1 and/or osteopontin expressed by parenchymal cells in the brain. Data from an experimental autoimmune encephalitis animal model of multiple sclerosis demonstrate reduction of leukocyte migration into brain parenchyma and reduction of plaque formation detected by magnetic resonance imaging (MRI) following repeated administration of natalizumab. The clinical significance of these animal data is unknown.

Following the repeat intravenous administration of a 300 mg dose of natalizumab to patients with multiple sclerosis, the mean maximum observed serum concentration was 110 ± 52 mcg/mL. Mean average steady-state trough concentrations ranged from 23 mcg/mL to 29 mcg/mL. The observed time to steady-state was approximately 24 weeks after every 4 weeks of dosing. The mean half-life, volume of distribution, and clearance of natalizumab were 11 ± 4 days, 5.7 ± 1.9 L, and 16 ± 5 mL/hour, respectively.

The effects of covariates such as body weight, age, gender, and presence of anti-natalizumab antibodies on natalizumab pharmacokinetics were investigated in a population pharmacokinetic study. Natalizumab clearance increased with body weight in a less than proportional manner such that a 43% increase in body weight resulted in a 32% increase in clearance. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold (see ADVERSE REACTIONS, Immunogenicity). Age (18 to 62 years) and gender did not influence natalizumab pharmacokinetics .

Pharmacokinetics of TYSABRI^Ò in pediatric patients with multiple sclerosis or patients with renal or hepatic insufficiency have not been studied.

TYSABRI^Ò administration increases the number of circulating leukocytes (including lymphocytes, monocytes, basophils, and eosinophils) due to inhibition of transmigration out of the vascular space. TYSABRI^Ò does not affect the number of circulating neutrophils (see PRECAUTIONS, Laboratory Tests).

TYSABRI^Ò was evaluated in two randomized, double-blind, placebo-controlled trials in patients with multiple sclerosis. Both studies enrolled patients who experienced at least one clinical relapse during the prior year and had a Kurtzke Expanded Disability Status Scale (EDSS) score between 0 and 5.0.

In both studies, neurological evaluations were performed every 12 weeks and at times of suspected relapse. Magnetic resonance imaging evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.

Study 1 enrolled patients who had not received any interferon-beta or glatiramer acetate for at least the previous 6 months; approximately 94% had never been treated with these agents. Median age was 37, with a median disease duration of 5 years. Patients were randomized in a 2:1 ratio to receive TYSABRI^Ò 300 mg IV infusion (n=627) or placebo (n=315) every 4 weeks for up to 28 months (30 infusions).

Study 2 enrolled patients who had experienced one or more relapses while on treatment with AVONEX^Ò (Interferon beta-1a) 30 mcg intramuscularly (IM) once weekly during the year prior to study entry. Median age was 39, with a median disease duration of 7 years. Patients were evenly randomized to receive TYSABRI^Ò 300 mg (n=589) or placebo (n=582) every 4 weeks for up to 28 months (30 infusions). All patients continued to receive AVONEX^Ò 30 mcg IM once weekly.

The efficacy of TYSABRI^Ò alone was not compared with the efficacy of TYSABRI^Ò plus AVONEX^Ò.

Results for each study are shown in Tables 1 and 2. Median time on study drug was 120 weeks in each study. Safety and efficacy of treatment with TYSABRI^Ò beyond two years are not known.

The primary endpoint at 2 years was time to onset of sustained increase in disability, defined as an increase of at least 1 point on the EDSS from baseline EDSS ≥1.0 that was sustained for 12 weeks, or at least a 1.5 point increase on the EDSS from baseline EDSS=0 that was sustained for 12 weeks. Time to onset of sustained increase in disability was longer in TYSABRI^Ò-treated patients than in placebo-treatedpatients in Studies 1 (Figure 1) and 2. The proportion of patients with increased disability and the annualized relapse rate were also lower in TYSABRI^Ò-treated patients than in placebo-treated patients in Studies 1 and 2 (Tables 1 and 2).

Changes in MRI findings often do not correlate with changes in the clinical status of patients (e.g., disability progression). The prognostic significance of the MRI findings in these studies has not been evaluated.

Figure 1. Time to Increase in Disability Sustained for 12 Weeks in Study 1

Patients should be fully counseled on and understand the risks and benefits of TYSABRI^Ò before an initial prescription is written. The patient may be educated by either the enrolled prescriber or a healthcare provider under that prescribers direction.

PATIENTS WHO ARE PRESCRIBED TYSABRI^Ò SHOULD BE INSTRUCTED TO:

· Read the Medication Guide before starting TYSABRI^Ò and before each TYSABRI^Ò infusion.

· Promptly report any continuously worsening symptoms that persist over several days to their prescriber (see BOXED WARNING and WARNINGS, Progressive Multifocal Leukoencephalopathy).

· Inform all of their physicians that they are receiving TYSABRI^Ò.

· Plan to see their prescriber 3 months after the first infusion, 6 months after the first infusion, and at least as frequently as every 6 months thereafter.

If patients experience symptoms consistent with a hypersensitivity reaction (e.g., urticaria with or without associated symptoms) during or following an infusion of TYSABRI^Ò, they should report these symptoms to their prescriber immediately (see WARNINGS, Hypersensitivity).

TYSABRI^Ò (tie-SA-bree) (natalizumab)

Read the Medication Guide given to you before you start TYSABRI^Ò and before each infusion. There may be new information. This Medication Guide does not take the place of talking to your doctor about your medical condition or your treatment. Ask your doctor or nurse if you have any questions.

What is the most important information I should know about TYSABRI^Ò?

· TYSABRI^Ò increases your chance of getting a rare brain infection that usually causes death or severe disability. This infection is called progressive multifocal leukoencephalopathy (PML). PML usually happens in people with weakened immune systems.

· No one can predict who will get PML.

· There is no known treatment, prevention, or cure for PML.

· Your chance of getting PML may be higher if you are also being treated with other medicines that can weaken your immune system, including other MS treatments.

· Even if you use TYSABRI^Ò alone to treat your MS, it is not known if your chance of getting PML will be lower. It is also not known if treatment for a long period of time with TYSABRI^Ò can increase your chance of getting PML.

· TYSABRI^Ò is available only through a restricted distribution program called the TOUCHÒ Prescribing Program. In order to receive TYSABRI^Ò, you must talk to your doctor and understand the benefits and risks of TYSABRI^Ò and agree to all of the instructions in the TOUCHÒ Prescribing Program.

· If you take TYSABRI^Ò, it is important that you call your doctor right away if you get any new or worsening medical problems (such as a new or sudden change in your thinking, eyesight, balance, or strength or other problems) that have lasted over several days. Tell all of your doctors that you are getting treatment with TYSABRI^Ò.

Also, see "What are the possible side effects with TYSABRI^Ò?" for other serious side effects with TYSABRI^Ò.

What is TYSABRI^Ò?

TYSABRI^Ò is a prescription medicine approved for patients with relapsing forms of MS to:

· slow the worsening of disability that is common in patients with MS and,

· decrease the number of flare-ups (relapses)

· Because of the chance of getting PML, TYSABRI^Ò is generally recommended for patients that have not been helped enough by, or cannot tolerate other treatments for MS.

· TYSABRI^Ò does not cure MS.

· TYSABRI^Ò has not been studied for use longer than 2 years. Also, TYSABRI^Ò has not been studied in patients with chronic progressive MS, or in children. It is not known if patients older than 65 years have a different response to TYSABRI^Ò.

TYSABRI^Ò is only:

· prescribed by doctors who are enrolled in the TOUCHÒ Prescribing Program

· infused at an infusion center that is enrolled in the TOUCHÒ Prescribing Program

· given to patients who are enrolled in the TOUCHÒ Prescribing Program

Who should not receive TYSABRI^Ò?

Do not receive TYSABRI^Ò if you:

· have PML

· are allergic to TYSABRI^Ò

· have a medical condition that can weaken your immune system such as HIV infection or AIDS, leukemia or lymphoma, or an organ transplant, and others.

· are taking medicines that can weaken your immune system. Talk with your doctor about all of the medicines you take or have taken.

If you have questions about any of the above, talk to your doctor.

What should I tell my doctor and nurse before receiving each infusion of TYSABRI^Ò?

Tell your doctor and nurse about all of your medical conditions. Tell them if you:

· have any new or worsening medical problems (such as a new or sudden change in your thinking, eyesight, balance, or strength or other problems) that have lasted several days

· have had hives, itching or trouble breathing during or after an infusion of TYSABRI^Ò

· have a fever or infection (including shingles or any unusually long lasting infection)

· are pregnant or plan to become pregnant

· are breastfeeding

Tell your doctor and nurse about all of the medicines you are taking, including prescription and non-prescription medicines, vitamins and herbal supplements.

· Know the medicines you take. Keep a list of them with you to show your doctor and nurse. The nurse may ask to see this list before every TYSABRI^Ò infusion.

How do I receive TYSABRI^Ò?

· TYSABRI^Ò is given once every four weeks through a needle placed in a vein (IV infusion).

· You must follow all the instructions of the TOUCHÒ Prescribing Program. Before you can begin to receive TYSABRI^Ò, your doctor or nurse will:

· explain the TOUCHÒ Prescribing Program to you

· have you sign the TOUCHÒ Prescriber/Patient Enrollment Form

· Before every TYSABRI^Ò infusion you will be asked a series of questions to confirm that TYSABRI^Ò is still right for you.

· Call your doctor who prescribes TYSABRI^Ò right away to report any medical problems that keep getting worse and last several days.

What are the possible side effects of TYSABRI^Ò?

TYSABRI^Ò increases your chance of getting a rare brain infection that usually causes death or severe disability. This infection is called progressive multifocal leukoencephalopathy (PML). PML usually happens in people with weakened immune systems. (see "What is the most important information I should know about TYSABRI^Ò?")

Other serious side effects with TYSABRI^Ò include:

· Allergic reactions including serious allergic reactions. Symptoms can include:

· Serious allergic reactions usually happen within 2 hours of the start of the infusion, but they can happen at any time after receiving TYSABRI^Ò.

· Tell your doctor or nurse right away if you have any symptom of an allergic reaction, even if it happens after you leave the infusion center. You may need treatment if you are having an allergic reaction.

· Infections. TYSABRI^Ò may increase your chance of getting an unusual or serious infection because TYSABRI^Ò can affect your immune system.

Other side effects with TYSABRI^Ò include:

Tell your doctor about any side effect that bothers you or that does not go away.

These are not all the side effects with TYSABRI^Ò. Ask your doctor for more information.

General information about the safe and effective use of TYSABRI^Ò

This Medication Guide provides a summary of the most important information about TYSABRI^Ò. If you would like more information or have any questions, talk with your doctor or nurse. You can ask your doctor or nurse for information about TYSABRI that is written for healthcare professionals. You can also call 1-800-456-2255 or visit www.TYSABRI.com.

What are the ingredients in TYSABRI^Ò?

Each dose of TYSABRI^Ò contains natalizumab; sodium chloride; sodium phosphate, monobasic, monohydrate; sodium phosphate, dibasic, heptahydrate; polysorbate 80; and water for injection.

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

NATALIZUMAB - INJECTION

(nay-tal-IZ-oo-mab)

COMMON BRAND NAME(S): Tysabri

WARNING: Natalizumab increases your risk of getting a rare but very serious (sometimes fatal) brain infection (progressive multifocal leukoencephalopathy-PML). This risk may be higher if you are also using other medications that weaken the immune system, such as other multiple sclerosis (MS) treatments (such as interferon) or immunosuppressants (such as azathioprine). (See also Side Effects and Drug Interactions sections.) Because this medication increases the risk of PML, it is usually used alone and only when other treatments have not worked or you are unable to use them.

Natalizumab is available only to patients enrolled in the TOUCH Prescribing Program. There are two different TOUCH prescribing programs: MS TOUCH for patients with multiple sclerosis, and CD TOUCH for patients with Crohn's disease. Only doctors, infusion centers, and pharmacies enrolled in these programs may prescribe, inject, or provide this medication to patients. Talk with your doctor about the risks and benefits of this medication and other treatment choices. If you and your doctor decide that this is the best treatment for you, your doctor can help you enroll in the TOUCH program. Your doctor will monitor you very closely while you are using this medication, usually at least 3 times during the first year and every 6 months from then on.

USES: This medication is used to treat a type of multiple sclerosis that occurs when symptoms appear in cycles of worsening and improvement (relapsing/remitting multiple sclerosis-MS). It is not a cure for MS, but it is thought to help by preventing your immune system from attacking the nerves in your brain and spinal cord. It helps decrease the number of episodes of worsening and may prevent or delay disability.

Natalizumab is also used to treat a bowel condition called Crohn's disease (CD) when it is moderate to severe and/or keeps coming back. It is not a cure for CD, but it is thought to work by preventing your immune system from causing inflammation/swelling within your bowels.

Natalizumab is a protein called a monoclonal antibody.

HOW TO USE: This medicine comes with a Medication Guide. Read it carefully before you start using natalizumab and each time you receive another dose. Ask your doctor, nurse, or pharmacist any questions that you may have about this medicine.

This medication is given by a health care professional in an infusion center, usually every 4 weeks or as directed by your doctor. This medication is mixed in a solution and injected slowly into a vein, usually over 1 hour. It should not be given as a rapid injection. You will be monitored for 1 hour after your treatment is finished to make sure you do not have a serious reaction to the medication. (See also Side Effects section.)

It is important to use this medication regularly to get the most benefit from it. Do not miss any doses without your doctor's approval.

Tell your doctor if your condition worsens. When using this medication for Crohn's disease, if your condition does not improve after 12 weeks of treatment, your doctor will need to switch your treatment plan.

SIDE EFFECTS: Headache, joint pain, redness/irritation at the injection site, swelling hands/feet/ankles, or changes in menstrual cycle may occur. If any of these effects persist or worsen, tell your doctor or pharmacist promptly.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

Tell your doctor immediately if you have any side effects while this drug is being given or shortly after your treatment is finished. Examples of these side effects (infusion reaction) may include chills, fever, flushing, nausea, dizziness, tiredness, and chest pain.

Tell your doctor immediately if any of these unlikely but serious side effects occur: severe headache, fast/pounding heartbeat, signs of infection (such as fever, persistent sore throat, breathing problems, unusual vaginal discharge, painful/frequent urination), mood changes (such as depression, suicidal thoughts), severe stomach/abdominal pain.

This drug increases the risk of a possibly fatal brain infection (see Warning section for more details). In MS patients, the symptoms of PML can seem like an attack of worsening MS. Therefore, whether you are using this drug for MS or CD, tell your doctor immediately of any worsening symptoms that persist for several days such as: clumsiness, sudden change in your thinking (such as confusion, difficulty concentrating), difficulty moving muscles, seizure, problems with speech, vision changes.

This drug may rarely cause serious liver problems. If you notice any of the following rare but very serious side effects, tell your doctor immediately: persistent nausea/vomiting, dark urine, yellowing eyes/skin, feeling tired/weak.

A very serious allergic reaction to this drug is rare. However, seek immediate medical attention if you notice any of the following symptoms: rash, itching/swelling (especially of the face/tongue/throat), severe dizziness, trouble breathing.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before using this medication, tell your doctor or pharmacist if you are allergic to it; or if you have any other allergies.

This medication should not be used if you have ever had a certain medical condition. Before using this medicine, consult your doctor or pharmacist if you have ever had: a certain virus infection (progressive multifocal leukoencephalopathy-PML).

Before using this medication, tell your doctor or pharmacist your medical history, especially of: weakened immune system (such as leukemia, lymphoma, HIV infection, organ transplant), current infections, history of certain virus infections that keep coming back (such as herpes, shingles), mental/mood disorders (such as depression).

During pregnancy, this medication should be used only when clearly needed. Discuss the risks and benefits with your doctor.

It is not known if this drug passes into breast milk. Because of the possible risk to the infant, breast-feeding is not recommended while using this drug. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your doctor or pharmacist may already be aware of any possible drug interactions and may be monitoring you for them. Do not start, stop, or change the dosage of any medicine before checking with your doctor or pharmacist first.

This drug should not be used with the following medications because very serious interactions may occur: long-term use of drugs that may weaken the immune system (such as azathioprine, cyclosporine, 6-mercaptopurine, methotrexate, TNF blockers such as adalimumab, etanercept, infliximab), immunomodulators (such as interferon beta).

If you are currently using any of these medications listed above, tell your doctor or pharmacist before starting natalizumab.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: short-term use of corticosteroids (such as prednisone).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US National Poison Hotline at 1-800-222-1222. Canada residents can call a provincial poison control center.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (such as MRI, liver function tests) may be performed before you start treatment and repeated periodically to monitor your progress or check for side effects. Consult your doctor for more details.

Talk to your doctor or pharmacist about lifestyle changes that might benefit you. Examples of lifestyle changes include stress reduction programs and maintaining a healthy diet. A doctor-approved exercise program may also help MS patients maintain strength, balance, and muscle tone. Consult your doctor or pharmacist for more details.

MISSED DOSE: It is very important to use this medication as directed. If you miss a dose, contact your doctor or pharmacist immediately to set up a new dosing schedule.

STORAGE: Refrigerate between 36-46 degrees F (2-8 degrees C). Do not shake or freeze the liquid. Protect from light.

After mixing in the correct IV fluid, it is best to use this drug immediately. If it is not used immediately, refrigerate the mixed liquid between 36-46 degrees F (2-8 degrees C) and use within 8 hours. Do not freeze or shake. Throw away any unused solution.

Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For information about enrolling in MedicAlert, call 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.