`
`
`
`TYSABRI® (natalizumab)
`
`DESCRIPTION
`
`TYSABRI® (natalizumab) is a recombinant humanized IgG4κ monoclonal antibody produced in
`murine myeloma cells. Natalizumab contains human framework regions and the
`complementarity-determining regions of a murine antibody that binds to α4-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.
`
`CLINICAL PHARMACOLOGY
`
`General
`
`TYSABRI® binds to the α4-subunit of α4β1 and α4β7 integrins expressed on the surface of all
`leukocytes except neutrophils, and inhibits the α4-mediated adhesion of leukocytes to their counter-
`receptor(s). The receptors for the α4 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-α4-integrin antibodies also block α4-mediated cell binding
`to ligands such as osteopontin and an alternatively spliced domain of fibronectin, connecting
`segment-1 (CS-1). In vivo, TYSABRI® may further act to inhibit the interaction of α4-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® 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 α4β1-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.
`
`Pharmacokinetics
`
`Following the repeat intravenous administration of a 300 mg dose of natalizumab to multiple sclerosis
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`patients, the mean maximum observed serum concentration was 98 ± 34 mcg/mL. Mean average
`steady-state natalizumab concentrations over the dosing period were approximately 30 mcg/mL.
`The mean half-life of 11 ± 4 days was observed with a clearance of 16 ± 5 mL/hour. The
`distribution volume of 5.7 ± 1.9 L was consistent with plasma volume.
`
`Pharmacokinetics of TYSABRI® in pediatric multiple sclerosis patients or patients with renal or
`hepatic insufficiency have not been studied.
`
`Pharmacodynamics
`
`TYSABRI® administration increases the number of circulating leukocytes, (including lymphocytes,
`monocytes, basophils, and eosinophils) due to inhibition of transmigration out of the vascular space.
`TYSABRI® does not affect the number of circulating neutrophils (see PRECAUTIONS,
`Laboratory Tests).
`
`CLINICAL STUDIES
`
`TYSABRI® was evaluated in two ongoing 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® 300 mg IV infusion (n=627) or placebo (n=315) every 4 weeks for
`up to 28 months.
`
`Study 2 enrolled patients who had experienced one or more relapses while on treatment with
`AVONEX® (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® 300 mg (n=589) or placebo (n=582) every 4 weeks for up to 28
`months. All patients continued to receive AVONEX® 30 mcg IM once weekly.
`
`Results for each study were analyzed at a pre-specified time and are shown in Tables 1 and 2.
`Median patient time on study was 13 months in both studies. Safety and efficacy of treatment
`with TYSABRI® beyond one year are not known.
`
`The exact relationship between MRI findings and the clinical status of patients is unknown.
`Changes in lesion area often do not correlate with changes in disability progression. The
`prognostic significance of the MRI findings in these studies has not been evaluated.
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`Table 1. 13-Month Clinical and 1-Year MRI Endpoints in Study 1 (Monotherapy Study)
`
`
`
` TYSABRI® Placebo
`n=627 n=315
`
`Clinical Endpoints
`Annualized relapse rate
` Relative reduction (percentage)
`Percentage of patients remaining relapse-free
`
`
`
`
`
`0.25
`
`76%
`
`66%
`
`0.74
`
`53%
`
`
`
`0.0
`
`60%
`18%
` 6%
`16%
`
`0.0
`
`
`
`
`
`3.0
`
`22%
`13%
` 7%
`58%
`
`0.0
`
`MRI Endpoints
`New or newly enlarging T2-hyperintense lesions
` Median
` Percentage of patients with:
`
` 0 lesions
`
` 1 lesion
`
` 2 lesions
`
` 3 or more lesions
`Gd-enhancing lesions
`
` Median
`
` Percentage of patients with:
`
` 0 lesions
`68%
`96%
`
` 1 lesion
`13%
` 3%
`
` 2 or more lesions
`19%
` 1%
`
`All analyses were intent-to-treat. For each endpoint, p<0.001. Determination of p-values: relapse rate by Poisson regression
`adjusting for baseline relapse rate, EDSS, presence of Gd-enhancing lesions, age; percentage relapse-free by logistic regression
`adjusting for baseline relapse rate; and MRI endpoints by ordinal logistic regression adjusting for baseline lesion number.
`
`
`Table 2. 13-Month Clinical and 1-Year MRI Endpoints in Study 2 (Add-On Study)
`
`
`
` TYSABRI® Placebo
`plus AVONEX® plus AVONEX®
`n=589 n=582
`
`Clinical Endpoints
`Annualized relapse rate
` Relative reduction (percentage)
`Percentage of patients remaining relapse-free
`
`
`
`
`
`0.36
` 54%
`67%
`
`0.78
`
`46%
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` TYSABRI® Placebo
`plus AVONEX® plus AVONEX®
`n=589 n=582
`
`1.0
`
`40%
`29%
`10%
`21%
`
`0.0
`
`0.0
`
`67%
`26%
` 4%
` 3%
`
`0.0
`
`MRI Endpoints
`
`New or newly enlarging T2-hyperintense lesions
`
` Median
`
` Percentage of patients with:
`
` 0 lesions
`
` 1 lesion
`
` 2 lesions
`
` 3 or more lesions
`
`Gd-enhancing lesions
`
` Median
`
` Percentage of patients with:
`76%
`96%
`
` 0 lesions
`12%
` 3%
`
` 1 lesion
`12%
` 1%
`
` 2 or more lesions
`All analyses were intent-to-treat. For each endpoint, p<0.001. Determination of p-values: relapse rate by Poisson regression
`adjusting for baseline relapse rate, EDSS, presence of Gd-enhancing lesions, age; percentage relapse-free by logistic regression
`adjusting for baseline relapse rate; and MRI endpoints by ordinal logistic regression adjusting for baseline lesion number.
`
`
`INDICATIONS AND USAGE
`
`TYSABRI® is indicated for the treatment of patients with relapsing forms of multiple sclerosis to
`reduce the frequency of clinical exacerbations. This indication is based on results achieved after
`approximately one year of treatment in ongoing controlled trials of two years in duration. The
`safety and efficacy of TYSABRI® beyond one year are unknown.
`
`Safety and efficacy in patients with chronic progressive multiple sclerosis have not been established.
`
`CONTRAINDICATIONS
`
`TYSABRI® should not be administered to patients with known hypersensitivity to TYSABRI® or any
`of its components.
`
`WARNINGS
`
`Hypersensitivity
`
`TYSABRI® 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®.
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`If a hypersensitivity reaction occurs, discontinue administration of TYSABRI® and initiate
`appropriate therapy (see ADVERSE REACTIONS, Infusion-related Reactions). Patients who
`have experienced a hypersensitivity reaction should not be re-treated with TYSABRI®. The
`possibility of antibodies to TYSABRI® should be considered in patients who have
`hypersensitivity reactions (see ADVERSE REACTIONS, Immunogenicity).
`
`PRECAUTIONS
`
`Immunosuppression
`
`In Studies 1 and 2, concomitant treatment of relapses with a short course of corticosteroids was
`not associated with an increased rate of infection. The safety and efficacy of TYSABRI® in
`combination with other immunosuppressive agents have not been evaluated. Patients receiving
`these agents should not receive concurrent therapy with TYSABRI® because of the possibility of
`increased risk of infections.
`
`Information to Patients
`
`If patients experience symptoms consistent with a hypersensitivity reaction (e.g., urticaria with
`or without associated symptoms) during or following an infusion of TYSABRI®, they should
`report these symptoms to their physician immediately (see WARNINGS, Hypersensitivity).
`
`Laboratory Tests
`
`TYSABRI® induces increases in circulating lymphocytes, monocytes, eosinophils, basophils,
`and nucleated red blood cells. Observed increases 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.
`
`Drug Interactions
`
`After multiple dosing, interferon beta-1a (AVONEX® 30 mcg IM once weekly) reduced
`TYSABRI® clearance by approximately 30%. The similarity of the TYSABRI®-associated
`adverse event profile between Study 1 (without co-administered AVONEX®) and Study 2 (with
`co-administered AVONEX®) indicates that this alteration in clearance does not necessitate
`reduction of the TYSABRI® dose to maintain safety (see ADVERSE REACTIONS, General).
`
`Results of studies in multiple sclerosis patients taking TYSABRI® and concomitant interferon beta-
`1a (AVONEX® 30 mcg IM once weekly) or glatiramer acetate were inconclusive with regard to
`the need for dose adjustment of the beta-interferon or glatiramer acetate.
`
`Carcinogenesis, Mutagenesis, and Impairment of Fertility
`
`No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human
`chromosomal aberration assays. Natalizumab showed no effects on in vitro assays of α4-integrin
`positive tumor line proliferation/cytotoxicity. Xenograft transplantation models in SCID and nude
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`mice with two α4-integrin positive 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.
`
`Pregnancy (Category C)
`
`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® 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.
`
`There are no adequate and well-controlled studies of TYSABRI® 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®, discontinuation of TYSABRI® should be considered.
`
`Nursing Mothers
`
`It is not known whether TYSABRI® 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, a decision should be made whether to discontinue nursing or TYSABRI® taking into
`account the importance of therapy to the mother.
`
`Geriatric Use
`
`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.
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`Pediatric Use
`
`Safety and effectiveness of TYSABRI® in pediatric multiple sclerosis patients below the age of 18
`have not been studied. TYSABRI® is not indicated for use in pediatric patients.
`
`Immunizations
`
`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®.
`
`ADVERSE REACTIONS
`
`General
`
`The most frequently reported serious adverse reactions with TYSABRI® were infections (2.1%
`versus 1.3% in placebo, including pneumonia [0.6%]), hypersensitivity reactions (1.3%,
`including anaphylaxis/anaphylactoid reaction [0.8%]), depression (0.8%, including suicidal
`ideation [0.5%]), and cholelithiasis (0.8%) (see WARNINGS, Hypersensitivity and
`ADVERSE REACTIONS, Infections).
`
`The most frequently reported adverse reactions resulting in clinical intervention (i.e.,
`discontinuation of TYSABRI®), 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® 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.
`
` total of 1,617 multiple sclerosis patients, in both controlled and uncontrolled studies, have been
`exposed to TYSABRI® with a median duration of exposure of 20 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®-treated patients than was observed in
`the placebo group. The adverse event profile in Study 2 was similar.
`
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`Table 3. Adverse Reactions in Study 1
`
`
`Adverse Events
`(Preferred Term)
`
`General
`Headache
`Fatigue
`Arthralgia
`Allergic reaction
`Urinary urgency/frequency
`Chest discomfort
`Local bleeding
`Rigors
`Syncope
`
`Infection
`Urinary tract infection
`Lower respiratory tract infection
`Gastroenteritis
`Vaginitis*
`Tonsillitis
`
`Psychiatric
`Depression
`
`Gastrointestinal
`Abdominal discomfort
`Abnormal liver function test
`
`Skin
`Rash
`Dermatitis
`Pruritus
`
`Menstrual disorders*
`Irregular menstruation/dysmenorrhea
`Amenorrhea
`
`Neurologic
`Tremor
`
`*percentage based on female n
`
`
`
`
`
`
`
`
`
`TYSABRI®
`n=627
`Percentage
`
`35%
`24%
`15%
`7%
`7%
`4%
`3%
`3%
`2%
`
`
`18%
`15%
`9%
`8%
`5%
`
`
`17%
`
`
`10%
`5%
`
`
`9%
`5%
`4%
`
`
`7%
`2%
`
`
`3%
`
`Control
`n=312
`Percentage
`
`30%
`18%
`11%
`3%
`5%
`2%
`1%
`1%
`1%
`
`
`15%
`14%
` 5%
` 5%
`3%
`
`
`14%
`
`
`9%
`3%
`
`
`7%
`4%
`2%
`
`
`2%
`0%
`
`
`2%
`
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`Infections
`
`In Studies 1 and 2, the rate of infection was approximately 1 per patient-year in both
`TYSABRI®-treated patients and placebo-treated patients. The infections were predominately
`upper respiratory tract infections, influenza, and urinary tract infections. Most patients did not
`interrupt treatment with TYSABRI® during the infection. In Study 1, the incidence of serious
`infection was 2.1% in TYSABRI®-treated patients versus 1.3% in placebo-treated patients. No
`difference was seen between treatment groups in Study 2.
`
`Infusion-related Reactions (see WARNINGS, Hypersensitivity)
`
`An infusion-related reaction was defined in clinical trials as any adverse event occurring within
`2 hours of the start of an infusion. Approximately 22% of TYSABRI®-treated multiple sclerosis
`patients experienced an infusion-related reaction, compared to 17% of placebo-treated patients.
`Events more common in the TYSABRI®-treated patients included headache, dizziness, fatigue,
`hypersensitivity reactions, urticaria, pruritus, and rigors. Acute urticaria was observed in
`approximately 2% of patients. Other hypersensitivity reactions were observed in 1% of patients
`receiving TYSABRI®. 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® were more likely to have an
`infusion-related reaction than those who were antibody-negative (see ADVERSE REACTIONS,
`Immunogenicity).
`
`Immunogenicity
`
`Patients in Study 1 and Study 2 were tested for antibodies to natalizumab every 12 weeks. The
`assays used in these studies were unable to detect low to moderate levels of antibodies to natalizumab.
`Antibodies were detected in approximately 10% of multiple sclerosis patients receiving TYSABRI®
`at least once during treatment with persistent antibody-positivity in 6% of patients.
`Approximately 90% of patients who became persistently antibody-positive by this assay had
`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. Across studies, the week 12 pre-infusion mean natalizumab serum
`concentrations in antibody-negative patients were approximately 17 mcg/mL compared to <1
`mcg/mL in antibody-positive patients. Persistent antibody-positivity to natalizumab was
`associated with a substantial decrease in the effectiveness of TYSABRI®. In Study 1, the
`annualized relapse rate of persistently antibody-positive TYSABRI®-treated patients (0.75) was
`similar to the annualized relapse rate in subjects who received placebo (0.74). A similar
`phenomenon was also observed in Study 2.
`
`Infusion-related reactions most often associated with persistent antibody-positivity included
`hypersensitivity reactions, urticaria, rigors, nausea, vomiting, and flushing. Additional adverse
`events more common in persistently antibody-positive patients included myalgia, hypertension,
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`dyspnea, anxiety, and tachycardia.
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`The long-term immunogenicity of TYSABRI® and the effects of low to moderate levels of
`antibody to natalizumab are unknown (see 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® with the incidence of antibodies to other products may be misleading.
`
`OVERDOSAGE
`
`Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of
`TYSABRI® that can be safely administered has not been determined.
`
`DOSAGE AND ADMINISTRATION
`
`The recommended dose of TYSABRI® is 300 mg IV infusion every four weeks. Dilute
`TYSABRI® concentrate 300 mg/15 mL in 100 mL 0.9% Sodium Chloride Injection, USP, and infuse
`over approximately one hour. Do not administer TYSABRI® 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).
`
`Preparation Instructions
`
`Use aseptic technique when preparing TYSABRI® solution for IV infusion. Each vial is
`intended for single use only.
`
`TYSABRI® is a colorless, clear to slightly opalescent concentrate. Inspect the TYSABRI® 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® beyond
`the expiration date stamped on the carton or vial.
`
`To prepare the solution, withdraw 15 mL of TYSABRI® 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® solution.
`
`Gently invert the TYSABRI® solution to mix completely. Do not shake. Inspect the solution
`visually for particulate material prior to administration.
`
`Following dilution, infuse TYSABRI® solution immediately, or refrigerate solution at 2-8°C, and use
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`within 8 hours. If stored at 2-8°C, allow the solution to warm to room temperature prior to infusion.
`DO NOT FREEZE.
`
`Administration Instructions
`
`Infuse TYSABRI® 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®.
`
`HOW SUPPLIED
`
`TYSABRI® 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
`
`Storage
`
`TYSABRI® 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® solution for infusion at 2-8°C (36°-46°F).
`TYSABRI® solution for infusion must be administered within 8 hours of preparation.
`
`I61061-1 Issue date [November/2004]
`
`TYSABRI® (natalizumab)
`
`Manufactured by:
`Biogen Idec Inc.
`14 Cambridge Center
`Cambridge, MA 02142 USA
`1-888-489-7227
`
`Distributed by:
`Elan Pharmaceuticals, Inc.
`San Diego, CA 92121
`
` ©
`
` 2004 Biogen Idec Inc. All rights reserved.
`
`
`TYSABRI® is a trademark of Elan
`AVONEX® is a trademark of Biogen Idec
`
`
`U.S. Patent Numbers: 5,840,299, 6,033,665, 6,602,503, 5,168,062, 5,385,839, 5,730,978
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