TYRUKO

1 INDICATIONS AND USAGE TYRUKO is an integrin receptor antagonist indicated for treatment of: Multiple Sclerosis (MS) TYRUKO 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. Natalizumab products increase the risk of PML [see Warnings and Precautions ( 5.1 )] . When initiating and continuing treatment with TYRUKO, physicians should consider whether the expected benefit of TYRUKO is sufficient to offset this risk. ( 1.1 ) Crohn's Disease (CD) • TYRUKO 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, TYRUKO should not be used in combination with immunosuppressants or inhibitors of TNF-α. ( 1.2 ) 1.1 Multiple Sclerosis (MS) TYRUKO 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. Natalizumab products increase the risk of PML [see Warnings and Precautions ( 5.1 )] . When initiating and continuing treatment with TYRUKO, physicians should consider whether the expected benefit of TYRUKO is sufficient to offset this risk. 1.2 Crohn's Disease (CD) TYRUKO 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. TYRUKO should not be used in combination with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, or methotrexate) or inhibitors of TNF-α [see Warnings and Precautions ( 5.1 )] .

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 ) • TYRUKO solution must be administered within 4 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 TYRUKO REMS Program may prescribe TYRUKO for multiple sclerosis [see Warnings and Precautions ( 5.2 )] . The recommended dose of TYRUKO 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 TYRUKO REMS Program may prescribe TYRUKO for Crohn’s disease [see Warnings and Precautions ( 5.2 )] . The recommended dose of TYRUKO for Crohn’s disease is 300 mg intravenous infusion over one hour every four weeks. TYRUKO 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 TYRUKO. If the patient with Crohn’s disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue TYRUKO. For patients with Crohn’s disease who start TYRUKO while on chronic oral corticosteroids, commence steroid tapering as soon as a therapeutic benefit of TYRUKO has occurred; if the patient with Crohn’s disease cannot be tapered off of oral corticosteroids within six months of starting TYRUKO, discontinue TYRUKO. Other than the initial six-month taper, prescribers should consider discontinuing TYRUKO 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 1. Use aseptic technique when preparing TYRUKO solution for intravenous infusion. Each vial is intended for single use only. Discard any unused portion. 2. TYRUKO is a colorless and clear to slightly opalescent solution. Inspect the TYRUKO 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. 3. To prepare the diluted solution, withdraw 15 mL of TYRUKO from the vial using a sterile needle and syringe. Inject TYRUKO into 100 mL of 0.9% Sodium Chloride Injection, USP. No other intravenous diluents may be used to prepare the TYRUKO diluted solution. 4. Gently invert the TYRUKO diluted solution to mix completely. Do not shake. Inspect the solution visually for particulate material prior to administration. 5. The final dosage diluted solution has a concentration of 2.6 mg/mL. 6. Following dilution, infuse TYRUKO solution immediately, or refrigerate the diluted solution at 2°C to 8°C, and use within 4 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 TYRUKO 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 TYRUKO 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 )]…

5 WARNINGS AND PRECAUTIONS • Herpes infections: Life-threatening and fatal cases have occurred with herpes encephalitis and meningitis infections. Blindness has occurred in patients developing acute retinal necrosis. Discontinue TYRUKO if these infections occur and treat appropriately. ( 5.3 ) • Hepatotoxicity: Significant liver injury, including liver failure requiring transplant, has occurred. Discontinue TYRUKO in patients with evidence of liver injury. ( 5.4 ) • Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have occurred. Permanently discontinue TYRUKO if such a reaction occurs. ( 5.5 ) • Immunosuppression/Infections: Natalizumab products may increase the risk for certain infections. Monitor patients for development of infections due to increased risk with use of TYRUKO. ( 5.6 ) • Hematological abnormalities: Natalizumab products may cause thrombocytopenia. Monitor patients for bleeding abnormalities. Discontinue TYRUKO in patients with thrombocytopenia. Neonatal thrombocytopenia and anemia have also occurred. Obtain a complete blood count in neonates exposed to TYRUKO in utero. ( 5.8 ) 5.1 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by the JC virus (JCV) that typically only occurs in patients who are immunocompromised, and that usually leads to death or severe disability, has occurred in patients who have received natalizumab products. Three factors that are known to increase the risk of PML in natalizumab-treated patients have been identified: • The presence of anti-JCV antibodies. Patients who are anti-JCV antibody positive have a higher risk for developing PML. • Longer treatment duration, especially beyond 2 years. • Prior treatment with an immunosuppressant (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil). These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYRUKO. Table 1: Estimated United States Incidence of PML Stratified by Risk Factor Anti-JCV Antibody Negative Natalizumab Exposure Anti-JCV Antibody Positive No Prior Immunosuppressant Use Prior Immunosuppressant Use 1/10,000 1-24 months <1/1,000 1/1,000 25-48 months 2/1,000 6/1,000 49-72 months 4/1,000 7/1,000 73-96 months 2/1,000 6/1,000 Notes: The risk estimates are based on postmarketing data in the United States from approximately 100,000 natalizumab exposed patients. The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA) that has been analytically and clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific antibodies with an analytical false negative rate of 3%. Retrospective analyses of postmarketing data from various sources, including observational studies and spontaneous reports obtained worldwide, suggest that the risk of developing PML may be associated with relative levels of serum anti-JCV antibody compared to a calibrator as measured by ELISA (often described as an anti-JCV antibody index value). Ordinarily, patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not be treated with TYRUKO. Infection by the JC virus is required for the development of PML. Anti-JCV antibody testing should not be used to diagnose PML. Anti-JCV antibody negative status indicates that antibodies to the JC virus have not been detected. Patients who are anti-JCV antibody negative have a lower risk of PML than those who are positive. Patients who are anti-JCV antibody negative are still at risk for the development of PML due to the potential for a new JCV infection or a false negative test result. The reported rate of seroconversion in patients with MS (changing from anti-JCV antibody negative to positive and remaining pos…

4 CONTRAINDICATIONS • TYRUKO is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) [see Warnings and Precautions ( 5.1 )] . • TYRUKO is contraindicated in patients who have had a hypersensitivity reaction to natalizumab products or any of the ingredients in TYRUKO. Observed reactions range from urticaria to anaphylaxis [see Warnings and Precautions ( 5.5 )] . • Patients who have or have had PML ( 4 ) • Patients who have had a hypersensitivity reaction to natalizumab products ( 4 , 5.3 )

7 DRUG INTERACTIONS Because of the potential for increased risk of PML and other infections, Crohn’s disease patients receiving natalizumab products 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 TYRUKO therapy [see Indications and Usage ( 1.2 ) and Warnings and Precautions ( 5.1 , 5.6 )] . Ordinarily, MS patients receiving chronic immunosuppressant or immunomodulatory therapy should not be treated with TYRUKO [see Indications and Usage ( 1.1 ) and Warnings and Precautions ( 5.1 , 5.6 )] .

8.1 Pregnancy Risk Summary There are no adequate data on the risk of major birth defects, miscarriage, or other adverse maternal outcomes associated with the use of natalizumab products in pregnant women. Adverse fetal outcomes of neonatal thrombocytopenia and anemia have been reported (see Clinical Considerations ) . In animal studies, administration of natalizumab during pregnancy produced fetal immunologic and hematologic effects in monkeys at doses similar to the human dose and reduced offspring survival in guinea pigs at doses greater than the human dose. These doses were not maternally toxic but produced the expected pharmacological effects in maternal animals ( see Data ). In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Fetal/Neonatal Adverse Reactions Cases of neonatal thrombocytopenia and anemia in infants born to women exposed to natalizumab products during pregnancy were reported in the post-marketing setting [see Warnings and Precautions ( 5.8 )] . Therefore, a CBC should be obtained in neonates who were exposed to TYRUKO in utero. Data Animal Data In developmental toxicity studies conducted in guinea pigs and monkeys, at natalizumab doses up to 30 mg/kg (7 times the recommended human dose based on body weight [mg/kg]), transplacental transfer and in utero exposure of the embryo/fetus was demonstrated in both species. In a study in which pregnant guinea pigs were administered natalizumab (0, 3, 10, or 30 mg/kg) by intravenous (IV) infusion on alternate days throughout organogenesis (gestation days [GD] 4‑30), no effects on embryofetal development were observed. When pregnant monkeys were administered natalizumab (0, 3, 10, or 30 mg/kg) by IV infusion on alternative days throughout organogenesis (GDs 20-70), serum levels in fetuses at delivery were approximately 35% of maternal serum natalizumab levels. There were no effects on embryofetal development; however, natalizumab-related immunological and hematologic changes were observed in the fetuses at the two highest doses. These changes included decreases in lymphocytes (CD3+ and CD20+), changes in lymphocyte subpopulation percentages, 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 a study in which monkeys were exposed to natalizumab during pregnancy (IV infusion of 30 mg/kg) on alternate days from GD20 to GD70 or GD20 to term, abortions were increased approximately 2-fold compared to controls. In offspring born to mothers administered natalizumab on alternate days from GD20 until delivery, hematologic effects (decreased lymphocyte and platelet counts) were also observed. These effects were reversed upon clearance of natalizumab. There was no evidence of anemia in these offspring. Offspring exposed in utero and during lactation had a normal immune response to challenge with a T-cell dependent antigen. In a study in which pregnant guinea pigs were exposed to natalizumab (30 mg/kg IV) on alternate dates during GDs 30-64, a reduction in pup survival was observed.

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 Sandoz Inc. at 1-800-525-8747 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 natalizumab) 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 natalizumab, with a median duration of exposure of 28 months. A total of 1563 patients received natalizumab 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 natalizumab 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 natalizumab (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 natalizumab-treated patients than was observed in placebo-treated patients. Table 2: Adverse Reactions in Study MS1 (Monotherapy Study) Adverse Reactions (Preferred Term) Natalizumab (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 Infecti…