NATALIZUMAB: 64,315 Adverse Event Reports & Safety Profile

Natalizumab-sztn is a recombinant humanized IgG4ĸ monoclonal antibody produced in a Chinese hamster ovary (CHO) mammalian cell expression system. Natalizumab-sztn contains human framework regions and the complementarity-determining regions of an antibody that binds to α4-integrin. The molecular weight of natalizumab-sztn is 149 kilodaltons. TYRUKO (natalizumab-sztn) injection is supplied as a sterile, preservative-free, colorless, and clear to slightly opalescent solution for intravenous infusion.

Each

15 mL of solution contains 300 mg natalizumab-sztn; histidine (6.36 mg); L-histidine hydrochloride monohydrate (22.86 mg); polysorbate 80, USP/NF (3 mg); sodium chloride, USP (131.49 mg); and Water for Injection, USP at pH 5.7.

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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . 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&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> .

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&apos;s Disease (CD) Only prescribers registered in the CD TOUCH ® Prescribing Program may prescribe TYSABRI for Crohn&apos;s disease [ see Warnings and Precautions ( 5.2 ) ]. The recommended dose of TYSABRI for Crohn&apos;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&apos;s disease has not experienced therapeutic benefit by 12 weeks of induction therapy, discontinue TYSABRI. For patients with Crohn&apos;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&apos;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&apos;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.

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 )

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&apos;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&apos;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 placebo and occurred at an incidence of at least 0.3%: intestinal obstruction or stenosis (2% vs. 1% in placebo), acute hypersensitivity reactions (0.5% vs. 0%), abdominal adhesions (0.3% vs. 0%), and cholelithiasis (0.3% vs. 0%). Similar serious adverse reactions were seen in the maintenance Study CD3.

Table

3 enumerates adverse reactions that occurred in Studies CD1 and CD2 (median exposure of 2.8 months).

Table

4 enumerates adverse reactions that occurred in Study CD3 (median exposure of 11.0 months).

Table

3: Adverse Reactions in Studies CD1 and CD2 (Induction Studies)

Adverse

Reactions* TYSABRI n=983 % Placebo n=431 % * Occurred at an incidence of at least 1% higher in TYSABRI-treated patients than placebo-treated patients. ** Percentage based on female patients only.

General Headache Fatigue Arthralgia

Influenza-like illness Acute hypersensitivity reactions Tremor 32 10 8 5 2 1 23 8 6 4 <1 <1 Infection Upper respiratory tract infection Vaginal infections ** Viral infection Urinary tract infection 22 4 3 3 16 2 2 1 Respiratory Pharyngolaryngeal pain Cough 6 3 4 <1 Gastrointestinal Nausea Dyspepsia Constipation Flatulence Aphthous stomatitis 17 5 4 3 2 15 3 2 2 <1 Skin Rash Dry skin 6 1 4 0 Menstrual Disorder Dysmenorrhea ** 2 <1 Table 4: Adverse Reactions in Study CD3 (Maintenance Study)

Adverse

Reactions* TYSABRI n=214 % Placebo n=214 % * Occurred at an incidence of at least 2% higher in TYSABRI-treated patients than placebo-treated patients. ** Percentage based on female patients only.

General Headache

Influenza-like illness Peripheral edema Toothache 37 11 6 4 31 6 3 <1 Infection Influenza Sinusitis Vaginal infections ** Viral infection 12 8 8 7 5 4 <1 3 Respiratory Cough 7 5 Gastrointestinal Lower abdominal pain 4 2 Musculoskeletal and Connective Tissue Back pain 12 8 Menstrual Disorder Dysmenorrhea ** 6 3 Infections Progressive Multifocal Leukoencephalopathy (PML) occurred in three patients who received TYSABRI in clinical trials [ see Warnings and Precautions ( 5.1 ) ]. Two cases of PML were observed in the 1869 patients with multiple sclerosis who were treated for a median of 120 weeks. These two patients had received TYSABRI in addition to interferon beta-1a [ see Warnings and Precautions ( 5.1 ) ]. The third case occurred after eight doses in one of the 1043 patients with Crohn's disease who were evaluated for PML. In the postmarketing setting, additional cases of PML have been reported in TYSABRI-treated multiple sclerosis and Crohn's disease patients who were not receiving concomitant immunomodulatory therapy.

In

Studies MS1 and MS2 [ see Clinical Studies ( 14.1 ) ], the rate of any type of infection was approximately 1.5 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.

In

Study MS1, the incidence of serious infection was approximately 3% in TYSABRI-treated patients and placebo-treated patients. Most patients did not interrupt treatment with TYSABRI during infections. The only opportunistic infection in the multiple sclerosis clinical trials was a case of cryptosporidial gastroenteritis with a prolonged course.

In

Studies CD1 and CD2 [ see Clinical Studies ( 14.2 ) ], the rate of any type of infection was 1.7 per patient-year in TYSABRI-treated patients and 1.4 per patient-year in placebo-treated patients.

In

Study CD3, the incidence of any type of infection was 1.7 per patient-year in TYSABRI-treated patients and was similar in placebo-treated patients. The most common infections were nasopharyngitis, upper respiratory tract infection, and influenza. The majority of patients did not interrupt TYSABRI therapy during infections, and recovery occurred with appropriate treatment. Concurrent use of TYSABRI in CD clinical trials with chronic steroids and/or methotrexate, 6-MP, and azathioprine did not result in an increase in overall infections compared to TYSABRI alone; however, the concomitant use of such agents could lead to an increased risk of serious infections.

In

Studies CD1 and CD2, the incidence of serious infection was approximately 2.1% in both TYSABRI-treated patients and placebo-treated patients.

In

Study CD3, the incidence of serious infection was approximately 3.3% in TYSABRI-treated patients and approximately 2.8% in placebo-treated patients. In clinical studies for CD, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of TYSABRI-treated patients; some of these patients were receiving concurrent immunosuppressants [ see Warnings and Precautions ( 5.6 ) ]. Two serious non-bacterial meningitides occurred in TYSABRI-treated patients compared to none in placebo-treated patients. Infusion-related Reactions An infusion-related reaction was defined in clinical trials as any adverse event occurring within two hours of the start of an infusion. In MS clinical trials, approximately 24% of TYSABRI-treated multiple sclerosis patients experienced an infusion-related reaction, compared to 18% of placebo-treated patients. In the controlled CD clinical trials, infusion-related reactions occurred in approximately 11% of patients treated with TYSABRI compared to 7% of placebo-treated patients. Reactions more common in the TYSABRI-treated MS patients compared to the placebo-treated MS 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. Serious systemic hypersensitivity infusion reactions occurred in <1% of patients [ see Warnings and Precautions ( 5.5 ) ]. All patients recovered with treatment and/or discontinuation of the infusion. Infusion-related reactions that were more common in CD patients receiving TYSABRI than those receiving placebo included headache, nausea, urticaria, pruritus, and flushing. Serious infusion reactions occurred in Studies CD1, CD2, and CD3 at an incidence of <1% in TYSABRI-treated patients. MS and CD patients who became persistently positive for antibodies to TYSABRI were more likely to have an infusion-related reaction than those who were antibody-negative.

6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to natalizumab in the studies described below with the incidence of antibodies in other studies or to other products may be misleading. Patients in Study MS1 [ see Clinical Studies ( 14.1 ) ] 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 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 MS1, the Week 12 pre-infusion mean natalizumab serum concentration in antibody-negative patients was 15 mcg/mL compared to 1.3 mcg/mL in antibody-positive patients. Persistent antibody-positivity resulted in a substantial decrease in the effectiveness of TYSABRI. The risk of increased disability and the annualized relapse rate were similar in persistently antibody-positive TYSABRI-treated patients and patients who received placebo. A similar phenomenon was also observed in Study MS2. Infusion-related reactions that were most often associated with persistent antibody-positivity included urticaria, rigors, nausea, vomiting, headache, flushing, dizziness, pruritus, tremor, feeling cold, and pyrexia. Additional adverse reactions more common in persistently antibody-positive patients included myalgia, hypertension, dyspnea, anxiety, and tachycardia. Patients in CD studies [ see Clinical Studies ( 14.2 ) ] were first tested for antibodies at Week 12, and in a substantial proportion of patients, this was the only test performed given the 12-week duration of placebo-controlled studies.

Approximately

10% of patients were found to have anti-natalizumab antibodies on at least one occasion. Five percent (5%) of patients had positive antibodies on more than one occasion. Persistent antibodies resulted in reduced efficacy and an increase in infusion-related reactions with symptoms that include urticaria, pruritus, nausea, flushing, and dyspnea. The long-term immunogenicity of TYSABRI and the effects of low to moderate levels of antibody to natalizumab are unknown [ see Warnings and Precautions ( 5.5 ), Adverse Reactions ( 6.1 ) ].

6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of TYSABRI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood disorders: hemolytic anemia, thrombocytopenia (including immune thrombocytopenic purpura).

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 positive in subsequent testing) is 3 to 8 percent annually. In addition, some patients’ serostatus may change intermittently. Therefore, patients with a negative anti-JCV antibody test result should be retested periodically. For purposes of risk assessment, a patient with a positive anti-JCV antibody test at any time is considered anti-JCV antibody positive regardless of the results of any prior or subsequent anti-JCV antibody testing. When assessed, anti-JCV antibody status should be determined using an analytically and clinically validated immunoassay. After plasma exchange (PLEX), wait at least two weeks to test for anti-JCV antibodies to avoid false negative test results caused by the removal of serum antibodies. After infusion of intravenous immunoglobulin (IVIg), wait at least 6 months (5 half-lives) for the IVIg to clear in order to avoid false positive anti-JCV antibody test results. Healthcare professionals should monitor patients on TYRUKO for any new sign or symptom suggestive of PML. Symptoms associated with PML are diverse, progress over days to weeks, and include progressive weakness on one side of the body or clumsiness of limbs, disturbance of vision, and changes in thinking, memory, and orientation leading to confusion and personality changes. The progression of deficits usually leads to death or severe disability over weeks or months. Withhold TYRUKO dosing immediately and perform an appropriate diagnostic evaluation at the first sign or symptom suggestive of PML. MRI findings may be apparent before clinical signs or symptoms. Cases of PML, diagnosed based on MRI findings and the detection of JCV DNA in the cerebrospinal fluid in the absence of clinical signs or symptoms specific to PML, have been reported. Many of these patients subsequently became symptomatic with PML. Therefore, monitoring with MRI for signs that may be consistent with PML may be useful, and any suspicious findings should lead to further investigation to allow for an early diagnosis of PML, if present. Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following natalizumab products discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis. It is not known whether these differences are due to early detection and discontinuation of natalizumab products or due to differences in disease in these patients. There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs. PML has been reported following discontinuation of natalizumab products in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for at least six months following discontinuation of TYRUKO. Because of the risk of PML, TYRUKO is available only under a restricted distribution program, the TYRUKO REMS Program. In multiple sclerosis patients, an MRI scan should be obtained prior to initiating therapy with TYRUKO. This MRI may be helpful in differentiating subsequent multiple sclerosis symptoms from PML.

In

Crohn’s disease patients, a baseline brain MRI may also be helpful to distinguish pre-existent lesions from newly developed lesions, but brain lesions at baseline that could cause diagnostic difficulty while on natalizumab product therapy are uncommon. For diagnosis of PML, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended. If the initial evaluations for PML are negative but clinical suspicion for PML remains, continue to withhold TYRUKO dosing, and repeat the evaluations. There are no known interventions that can adequately treat PML if it occurs. Three sessions of PLEX over 5 to 8 days were shown to accelerate natalizumab clearance in a study of 12 patients with MS who did not have PML, although in the majority of patients, alpha-4 integrin receptor binding remained high. Adverse events which may occur during PLEX include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not been prospectively studied in natalizumab-treated patients with PML, it has been used in such patients in the postmarketing setting to remove natalizumab more quickly from the circulation. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML. JC virus infection of granule cell neurons in the cerebellum (i.e., JC virus granule cell neuronopathy [JCV GCN]) has been reported in patients treated with natalizumab products. JCV GCN can occur with or without concomitant PML. JCV GCN can cause cerebellar dysfunction (e.g., ataxia, incoordination, apraxia, visual disorders), and neuroimaging can show cerebellar atrophy. For diagnosis of JCV GCN, an evaluation that includes a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA, is recommended. JCV GCN should be managed similarly to PML. Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of natalizumab product-treated patients who developed PML and subsequently discontinued natalizumab products. In almost all cases, IRIS occurred after PLEX was used to eliminate circulating natalizumab products. It presents as a clinical decline in the patient’s condition after natalizumab product removal (and in some cases after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. Natalizumab products have not been associated with IRIS in patients discontinuing treatment with natalizumab products for reasons unrelated to PML. In natalizumab product-treated patients with PML, IRIS has been reported within days to several weeks after PLEX. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.

5.2 TYRUKO REMS Program TYRUKO is available only through a restricted program under a REMS called the TYRUKO REMS Program because of the risk of PML <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 )]</span> . For prescribers and patients, the TYRUKO REMS Program has two components: MS TYRUKO REMS (for patients with multiple sclerosis) and CD TYRUKO REMS (for patients with Crohn’s disease). Selected requirements of the TYRUKO REMS Program include the following:

• Prescribers must be certified and comply with the following:
• Review the TYRUKO REMS Program prescriber educational materials, including the full prescribing information.
• Review, complete, and sign the Prescriber Enrollment Form.
• Educate patients on the benefits and risks of treatment with TYRUKO, ensure that patients receive the Medication Guide, and encourage them to ask questions.
• Review, complete, and sign the Patient Enrollment Form for each patient.
• Evaluate patients three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing TYRUKO.
• Determine every six months whether patients should continue on treatment and, if so, authorize treatment for another six months.
• Submit to Sandoz Inc. the “TYRUKO Patient Status Report and Reauthorization Questionnaire” six months after initiating treatment and every six months thereafter.
• Complete an “Initial Discontinuation Questionnaire” when TYRUKO is discontinued, and a “6-Month Discontinuation Questionnaire” following discontinuation of TYRUKO.
• Report cases of PML, hospitalizations due to opportunistic infections, and deaths to Sandoz Inc. at 1-800-525-8747 as soon as possible.
• Patients must be enrolled in the TYRUKO REMS Program, read the Medication Guide, understand the risks associated with TYRUKO, and complete and sign the Patient Enrollment Form.
• Pharmacies and infusion centers must be specially certified to dispense or infuse TYRUKO.

5.3 Herpes Infections Herpes Encephalitis and Meningitis Natalizumab products increase the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving natalizumab products. Laboratory confirmation in those cases was based on positive PCR for viral DNA in the cerebrospinal fluid. The duration of treatment with natalizumab products prior to onset ranged from a few months to several years. Monitor patients receiving TYRUKO for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYRUKO should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered.

Acute Retinal Necrosis

Acute retinal necrosis (ARN) is a fulminant viral infection of the retina caused by the family of herpes viruses (e.g., varicella zoster, herpes simplex virus). A higher risk of ARN has been observed in patients being administered natalizumab products. Patients presenting with eye symptoms, including decreased visual acuity, redness, or eye pain, should be referred for retinal screening for ARN. Some ARN cases occurred in patients with central nervous system (CNS) herpes infections (e.g., herpes meningitis or encephalitis). Serious cases of ARN led to blindness of one or both eyes in some patients. Following clinical diagnosis of ARN, consider discontinuation of TYRUKO. The treatment reported in ARN cases included anti-viral therapy and, in some cases, surgery.

5.4 Hepatotoxicity Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with natalizumab products in the postmarketing setting. Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses. In some patients, liver injury recurred upon rechallenge, providing evidence that natalizumab products caused the injury. The combination of transaminase elevations and elevated bilirubin without evidence of obstruction is generally recognized as an important predictor of severe liver injury that may lead to death or the need for a liver transplant in some patients. TYRUKO should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).

5.5 Hypersensitivity/Antibody Formation Hypersensitivity reactions have occurred in patients receiving natalizumab products, including serious systemic reactions (e.g., anaphylaxis), which occurred at an incidence of &lt;1%. These reactions usually occur within two 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 natalizumab products. If a hypersensitivity reaction occurs, discontinue administration of TYRUKO, and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYRUKO. Hypersensitivity reactions were more frequent in patients with antibodies to natalizumab compared to patients who did not develop antibodies to natalizumab in both MS and CD studies. Therefore, the possibility of antibodies to TYRUKO should be considered in patients who have hypersensitivity reactions <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . Antibody testing: 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 six months) may be transient and may disappear with continued dosing. It is recommended that testing be repeated three months after an initial positive result to confirm that antibodies are persistent. Prescribers should consider the overall benefits and risks of TYRUKO in a patient with persistent antibodies. Patients who receive natalizumab products for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-drug antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment. Given that patients with persistent antibodies to natalizumab products experience reduced efficacy, and that hypersensitivity reactions are more common in such patients, consideration should be given to testing for the presence of antibodies in patients who wish to recommence therapy following a dose interruption. Following a period of dose interruption, patients testing negative for antibodies prior to re-dosing have a risk of antibody development with re-treatment that is similar to natalizumab product naïve patients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> .

5.6 Immunosuppression/Infections The immune system effects of natalizumab products may increase the risk for infections.

In

Study MS1 [see Clinical Studies ( 14.1 )] , 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 natalizumab-treated patients than in placebo-treated patients [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] . One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received natalizumab in Study MS1.

In

Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in natalizumab-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids. In a long-term safety study of patients treated with natalizumab for multiple sclerosis, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in <1% of natalizumab-treated patients. In CD clinical studies, opportunistic infections (pneumocystis carinii pneumonia, pulmonary mycobacterium avium intracellulare, bronchopulmonary aspergillosis, and burkholderia cepacia) have been observed in <1% of natalizumab-treated patients; some of these patients were receiving concurrent immunosuppressants [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] .

In

Studies CD1 and CD2, an increase in infections was seen in patients concurrently receiving corticosteroids. However, the increase in infections was similar in placebo-treated and natalizumab-treated patients who received steroids. 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 natalizumab alone [see Warnings and Precautions ( 5.1 ) and Adverse Reactions ( 6.1 )] . The safety and efficacy of natalizumab products in combination with antineoplastic, immunosuppressant, or immunomodulating agents have not been established. Patients receiving chronic immunosuppressant or immunomodulatory therapy or who have systemic medical conditions resulting in significantly compromised immune system function should not ordinarily be treated with natalizumab products. The risk of PML is also increased in patients who have been treated with an immunosuppressant prior to receiving natalizumab products [see Warnings and Precautions ( 5.1 )] . For patients with Crohn's disease who start TYRUKO while on chronic corticosteroids, commence steroid withdrawal as soon as a therapeutic benefit has occurred. If the patient cannot discontinue systemic corticosteroids within six months, discontinue TYRUKO.

5.7 Laboratory Test Abnormalities In clinical trials, natalizumab was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during natalizumab exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. Natalizumab induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dL) that are frequently transient.

5.8 Hematological Abnormalities Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of natalizumab products in the postmarketing setting. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, TYRUKO should be discontinued. Cases of neonatal thrombocytopenia and anemia have been reported in newborns with in utero exposure to natalizumab products <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.1 )]</span>. A CBC should be obtained in neonates with in utero exposure to TYRUKO.

5.9 Immunizations No data are available on the effects of vaccination in patients receiving natalizumab products. No data are available on the secondary transmission of infection by live vaccines in patients receiving natalizumab products.

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 )] .