Natalizumab

12.1 Mechanism of Action Natalizumab 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 , natalizumab 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 and Crohn's disease 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 an

1 INDICATIONS AND USAGE TYSABRI is an integrin receptor antagonist indicated for treatment of: Multiple Sclerosis (MS) TYSABRI is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. TYSABRI increases the risk of PML [See Warnings and Precautions ( 5.1 ) ]. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk. ( 1.1 ) Crohn's Disease (CD) TYSABRI is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. ( 1.2 ) Important Limitations: In CD, TYSABRI should not be used in combination with immunosuppressants or inhibitors of TNF-α. ( 1.2 ) 1.1 Multiple Sclerosis (MS) TYSABRI is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. TYSABRI increases the risk of PML [ see Warnings and Precautions ( 5.1 ) ]. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk. 1.2 Crohn's Disease (CD) TYSABRI is indicated for inducing and maintaining clinical response and remission in adult patients with moderately to severely active Crohn's disease with evidence of inflammation who have had an inadequate response to, or are unable to tolerate, conventional CD therapies and inhibitors of TNF-α. TYSABRI should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α [ s

2 DOSAGE AND ADMINISTRATION 300 mg infused intravenously over one hour, every four weeks. Do not give as an intravenous push or bolus ( 2.1 , 2.2 ) TYSABRI solution must be administered within 48 hours of preparation ( 2.3 ) Observe patients during all infusions. Post-infusion, for the first 12 infusions, observe patients for one hour after the infusion is complete. For patients who have received 12 infusions without evidence of a hypersensitivity reaction, observe patients post-infusion for the 13th and subsequent infusions according to clinical judgment. ( 2.4 ) In CD, discontinue in patients that have not experienced therapeutic benefit by 12 weeks of induction therapy, and in patients that cannot discontinue chronic concomitant steroids within six months of starting therapy ( 2.2 ) 2.1 Multiple Sclerosis (MS) Only prescribers registered in the MS TOUCH ® Prescribing Program may prescribe TYSABRI for multiple sclerosis [ see Warnings and Precautions ( 5.2 ) ]. The recommended dose of TYSABRI for multiple sclerosis is 300 mg intravenous infusion over one hour every four weeks. 2.2 Crohn's Disease (CD) Only prescribers registered in the CD TOUCH ® Prescribing Program may prescribe TYSABRI for Crohn's disease [ see Warnings and Precautions ( 5.2 ) ]. The recommended dose of TYSABRI for Crohn's disease is 300 mg intravenous infusion over one hour every four weeks. TYSABRI should not be used with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or concomitant inhibitors of TNF-α. Aminosalicylates may be continued during treatment with TYSABRI. If the patient with Crohn's disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue TYSABRI. For patients with Crohn's disease who start TYSABRI while on chronic oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of TYSABRI has occurred; if the patient with Crohn's disease cannot be tapered off of oral corticosteroids within six months of starting TYSABRI, discontinue TYSABRI. Other than the initial six-month taper, prescribers should consider discontinuing TYSABRI for patients who require additional steroid use that exceeds three months in a calendar year to control their Crohn's disease. 2.3 Dilution Instructions Use aseptic technique when preparing TYSABRI solution for intravenous infusion. Each vial is intended for single use only. Discard any unused portion. TYSABRI is a colorless, clear to slightly opalescent solution. Inspect the TYSABRI vial for particulate material and discoloration 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. To prepare the diluted solution, withdraw 15 mL of TYSABRI from the vial using a sterile needle and syringe. Inject TYSABRI into 100 mL of 0.9% Sodium Chloride Injection, USP. No other intravenous diluents may be used to prepare the TYSABRI diluted solution. Gently invert the TYSABRI diluted solution to mix completely. Do not shake. Inspect the solution visually for particulate material prior to administration. The final dosage diluted solution has a concentration of 2.6 mg/mL. Following dilution, infuse TYSABRI solution immediately, or refrigerate the diluted solution at 2°C to 8°C, and use within 48 hours. If stored at 2°C to 8°C, allow the diluted solution to warm to room temperature prior to infusion. DO NOT FREEZE. 2.4 Administration Instructions Infuse TYSABRI 300 mg in 100 mL 0.9% Sodium Chloride Injection, USP, over approximately one hour (infusion rate approximately 5 mg per minute). Do not administer TYSABRI as an intravenous push or bolus injection. After the infusion is complete, flush with 0.9% Sodium Chloride Injection, USP. Observe patients during all infusions. Promptly discontinue the infusion upon the first observation of any signs or symptoms consistent with a hypersensitivity-type reaction [ see Warnings and Precautions ( 5.5 ) ]. Post-infusion, for the first 12 infusions, observe patients for one hour after the infusion is complete. For patients who have received 12 infusions without evidence of a hypersensitivity reaction, observe patients post-infusion for the 13th and subsequent infusions according to clinical judgment. 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.

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Progressive Multifocal Leukoencephalopathy (PML) [see Warnings and Precautions ( 5.1 )] Herpes Infections [see Warnings and Precautions ( 5.3 )] Hepatotoxicity [see Warnings and Precautions ( 5.4 )] Hypersensitivity/Antibody Formation [see Warnings and Precautions ( 5.5 )] Immunosuppression/Infections [see Warnings and Precautions ( 5.6 )] Hematological Abnormalities [see Warnings and Precautions ( 5.8 )] Most common adverse reactions (incidence ≥ 10%): MS - headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash ( 6.1 ) CD - headache, upper respiratory tract infections, nausea, and fatigue ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Biogen at 1-800-456-2255 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse reactions (incidence ≥ 10%) were headache and fatigue in both the multiple sclerosis (MS) and Crohn's disease (CD) studies. Other common adverse reactions (incidence ≥ 10%) in the MS population were arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremity, abdominal discomfort, diarrhea NOS, and rash. Other common adverse reactions (incidence ≥ 10%) in the CD population were upper respiratory tract infections and nausea. The most frequently reported adverse reactions resulting in clinical intervention (i.e., discontinuation of TYSABRI) in the MS studies were urticaria (1%) and other hypersensitivity reactions (1%), and in the CD studies (Studies CD1 and CD2) were the exacerbation of Crohn's disease (4.2%) and acute hypersensitivity reactions (1.5%) [ see Warnings and Precautions ( 5.5 ) ]. A total of 1617 multiple sclerosis patients in controlled studies received TYSABRI, with a median duration of exposure of 28 months. A total of 1563 patients received TYSABRI in all CD studies for a median exposure of 5 months; of these patients, 33% (n=518) received at least one year of treatment and 19% (n=297) received at least two years of treatment. Multiple Sclerosis Clinical Studies The most common serious adverse reactions in Study MS1 [ see Clinical Studies ( 14.1 ) ] with TYSABRI 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 MS2, serious adverse reactions of appendicitis were also more common in patients who received TYSABRI (0.8% versus 0.2% in placebo). Table 2 enumerates adverse reactions and selected laboratory abnormalities that occurred in Study MS1 at an incidence of at least 1 percentage point higher in TYSABRI-treated patients than was observed in placebo-treated patients. Table 2: Adverse Reactions in Study MS1 (Monotherapy Study) Adverse Reactions (Preferred Term) TYSABRI n=627 % Placebo n=312 % *Percentage based on female patients only. ** Acute versus other hypersensitivity reactions are defined as occurring within 2 hours post-infusion versus more than 2 hours. General Headache 38 33 Fatigue 27 21 Arthralgia 19 14 Chest discomfort 5 3 Other hypersensitivity reactions** 5 2 Acute hypersensitivity reactions** 4 <1 Seasonal allergy 3 2 Rigors 3 <1 Weight increased 2 <1 Weight decreased 2 <1 Infection Urinary tract infection 21 17 Lower respiratory tract infection 17 16 Gastroenteritis 11 9 Vaginitis* 10 6 Tooth infections 9 7 Herpes 8 7 Tonsillitis 7 5 Psychiatric Depression 19 16 Musculoskeletal/Connective Tissue Disorders Pain in extremity Muscle cramp Joint swelling 16 5 2 14 3 1 Gastrointestinal Abdominal discomfort Diarrhea NOS Abnormal liver function test 11 10 5 10 9 4 Skin Rash Dermatitis Pruritus Night sweats 12 7 4 1 9 4 2 0 Menstrual Disorders* Irregular menstruation Dysmenorrhea Amenorrhea Ovarian cyst 5 3 2 2 4 <1 1 <1 Neurologic Disorders Vertigo Somnolence 6 2 5 <1 Renal and Urinary Disorders Urinary urgency/frequency Urinary incontinence 9 4 7 3 Injury Limb injury NOS Skin laceration Thermal burn 3 2 1 2 <1 <1 In Study MS2, peripheral edema was more common in patients who received TYSABRI (5% versus 1% in placebo). Crohn's Disease Clinical Studies The following serious adverse reactions in the induction Studies CD1 and CD2 [ see Clinical Studies ( 14.2 ) ] were reported more commonly with TYSABRI than placeb

7 DRUG INTERACTIONS Because of the potential for increased risk of PML and other infections, Crohn's disease patients receiving TYSABRI should not be treated with concomitant immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α, and corticosteroids should be tapered in those patients with Crohn's disease who are on chronic corticosteroids when they start TYSABRI therapy [ see Indications and Usage ( 1.2 ), Warnings and Precautions ( 5.1 , 5.6 ) ]. Ordinarily, MS patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with TYSABRI [ see Indications and Usage ( 1.1 ), Warnings and Precautions ( 5.1 , 5.6 ) ].