Tysabri
natalizumab · Injection · Intravenous
Uses
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 [ see Warnings and Precautions ( 5.1 ) ].
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.
Dosage forms and strengths
Injection: 300 mg /15 mL (20 mg/mL) colorless and clear to slightly opalescent solution in a single-dose vial for dilution prior to infusion. Injection: 300 mg/15 mL (20 mg/mL) solution in a single-dose vial for dilution prior to infusion ( 3 )
Contraindications
4 CONTRAINDICATIONS TYSABRI is contraindicated in patients who have or have had progressive multifocal leukoencephalopathy (PML) [ see Warnings and Precautions ( 5.1 ) ]. TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI. 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 TYSABRI ( 4 , 5.3 )
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 TYSABRI if these infections occur and treat appropriately ( 5.3 ) Hepatotoxicity: Significant liver injury, including liver failure requiring transplant, has occurred. Discontinue TYSABRI in patients with evidence of liver injury ( 5.4 ) Hypersensitivity reactions: Serious hypersensitivity reactions (e.g., anaphylaxis) have occurred. Permanently discontinue TYSABRI if such a reaction occurs ( 5.5 ) Immunosuppression/Infections: TYSABRI may increase the risk for certain infections. Monitor patients for development of infections due to increased risk with use of TYSABRI ( 5.6 ) Hematological Abnormalities: TYSABRI may cause thrombocytopenia. Monitor patients for bleeding abnormalities. Discontinue TYSABRI in patients with thrombocytopenia. Neonatal thrombocytopenia and anemia have also occurred. Obtain a complete blood count in neonates exposed to TYSABRI 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 TYSABRI. Three factors that are known to increase the risk of PML in TYSABRI-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 TYSABRI. Table 1: Estimated United States Incidence of PML Stratified by Risk Factor Notes: The risk estimates are based on postmarketing data in the United States from approximately 100,000 TYSABRI 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%. Anti-JCV Antibody Negative TYSABRI 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 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 TYSABRI. 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 TYSABRI 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 TYSABRI 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.
Side effects
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 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.
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 ) ].
Use in specific populations
Pregnancy: Can cause fetal harm. ( 5.8 , 8.1 ) 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 TYSABRI 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 TYSABRI 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 TYSABRI 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. 8.2 Lactation Risk Summary Natalizumab has been detected in human milk. There are no data on the effects of this exposure on the breastfed infant or the effects of the drug on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TYSABRI and any potential adverse effects on the breastfed infant from TYSABRI or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients with multiple sclerosis or Crohn's disease below the age of 18 years have not been established. TYSABRI is not indicated for use in pediatric patients. 8.5 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. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
Pregnancy
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 TYSABRI 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 TYSABRI 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 TYSABRI 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.
Pediatric use
8.4 Pediatric Use Safety and effectiveness in pediatric patients with multiple sclerosis or Crohn's disease below the age of 18 years have not been established. TYSABRI is not indicated for use in pediatric patients.
Geriatric use
8.5 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. Other reported clinical experience has not identified differences in responses between the elderly and younger patients.
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.
Description
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 (natalizumab) injection is supplied as a sterile, colorless, and clear to slightly opalescent solution for intravenous infusion. Each 15 mL of solution contains 300 mg natalizumab; sodium chloride, USP (123 mg); sodium phosphate, monobasic, monohydrate, USP (17 mg); sodium phosphate, dibasic, heptahydrate, USP (7.24 mg); polysorbate 80, USP/NF (3 mg), in Water for Injection, USP at pH 6.1.
Mechanism of action
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 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. In Crohn's disease, the interaction of the α4β7 integrin with the endothelial receptor MAdCAM-1 has been implicated as an important contributor to the chronic inflammation that is a hallmark of the disease. MAdCAM-1 is mainly expressed on gut endothelial cells and plays a critical role in the homing of T lymphocytes to gut lymph tissue found in Peyer's patches. MAdCAM-1 expression has been found to be increased at active sites of inflammation in patients with CD, which suggests it may play a role in the recruitment of leukocytes to the mucosa and contribute to the inflammatory response characteristic of CD. The clinical effect of natalizumab in CD may therefore be secondary to blockade of the molecular interaction of the α4ß7-integrin receptor with MAdCAM-1 expressed on the venular endothelium at inflammatory foci. VCAM-1 expression has been found to be upregulated on colonic endothelial cells in a mouse model of IBD and appears to play a role in leukocyte recruitment to sites of inflammation. The role of VCAM-1 in CD, however, is not clear.
How supplied
(natalizumab) injection, a sterile, preservative-free, colorless and clear to slightly opalescent solution for dilution prior to intravenous infusion, is supplied as one 300 mg/15 mL (20 mg/mL) single-dose vial per carton (NDC 64406-008-01). TYSABRI is available only through registered infusion centers participating in the TOUCH ® Prescribing Program. To locate these infusion centers, contact Biogen at 1-800-456-2255. TYSABRI single-dose vials must be refrigerated between 2°C to 8°C (36°F to 46°F). Do not use beyond the expiration date stamped on the carton and vial label. DO NOT SHAKE OR FREEZE. Protect from light. Store diluted TYSABRI solution refrigerated at 2°C to 8°C (36°F to 46°F) [ see Dosage and Administration ( 2.3 ) ]
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide). General Counseling Information Counsel patients to understand the risks and benefits of TYSABRI before an initial prescription is written. The patient may be educated by either the enrolled prescriber or a healthcare provider under that prescriber's direction. INSTRUCT PATIENTS USING TYSABRI TO: Read the Medication Guide before starting TYSABRI and before each TYSABRI infusion. Promptly report any new or continuously worsening symptoms that persist over several days to their prescriber [ see Warnings and Precautions ( 5.1 ) ]. Inform all of their physicians that they are receiving TYSABRI. Plan to see their prescriber three months after the first infusion, six months after the first infusion, every six months thereafter, and for at least six months after discontinuing TYSABRI. Progressive Multifocal Leukoencephalopathy Inform patients that Progressive Multifocal Leukoencephalopathy (PML) has occurred in patients who received TYSABRI. Instruct the patient of the importance of contacting their doctor if they develop any symptoms suggestive of PML. Instruct the patient that typical 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. Instruct the patient that the progression of deficits usually leads to death or severe disability over weeks or months. Instruct patients to continue to look for new signs and symptoms suggestive of PML for approximately 6 months following discontinuation of TYSABRI [ see Warnings and Precautions ( 5.1 ) ]. TYSABRI TOUCH ® Prescribing Program Advise the patient that TYSABRI is only available through a restricted program called the TOUCH ® Prescribing Program. Inform the patient of the following requirements: Patients must read the Medication Guide and sign the Patient Enrollment Form. Advise patients that TYSABRI is available only from certified pharmacies and infusion centers participating in the program [ see Warnings and Precautions ( 5.2 ) ]. Herpes Infections Inform patients that TYSABRI increases the risk of developing encephalitis and meningitis, which could be fatal, and acute retinal necrosis, which could lead to blindness, caused by the family of herpes viruses (e.g., herpes simplex and varicella zoster viruses). Instruct patients to immediately report any possible symptoms of encephalitis and meningitis (such as fever, headache, and confusion) or acute retinal necrosis (such as decreased visual acuity, eye redness, or eye pain) [ see Warnings and Precautions ( 5.3 ) ]. Hepatotoxicity Inform patients that TYSABRI may cause liver injury. Instruct patients treated with TYSABRI to report promptly any symptoms that may indicate liver injury, including fatigue, anorexia, right upper abdominal discomfort, dark urine, or jaundice [ see Warnings and Precautions ( 5.4 ) ]. Hypersensitivity Reactions Instruct patients to report immediately if they experience symptoms consistent with a hypersensitivity reaction (e.g., urticaria with or without associated symptoms) during or following an infusion of TYSABRI [ see Warnings and Precautions ( 5.5 ) ]. Immunosuppression/Infections Inform patients that TYSABRI may lower the ability of their immune system to fight infections. Instruct the patient of the importance of contacting their doctor if they develop any symptoms of infection [ see Warnings and Precautions ( 5.6 ) ]. Hematological Abnormalities Inform patients that Tysabri may cause a low platelet count, which can cause severe bleeding that may be life-threatening. Instruct patients to report any symptoms that may indicate thrombocytopenia, such as easy bruising, prolonged bleeding from cuts, petechiae, abnormally heavy menstrual periods, or bleeding from the nose or gums that is new. Advise patients that TYSABRI may cause low platelet or red blood cell counts in neonates exposed to TYSABRI during pregnancy [see Warnings and Precuations ( 5.8 )] . Pregnancy Instruct patients that if they become pregnant or plan to become pregnant while taking TYSABRI they should inform their healthcare provider [see Use in Specific Populations ( 8.1 )] . I61061-31 TYSABRI (natalizumab) Manufactured by: Biogen Inc. Cambridge, MA 02142 USA US License No. 1697 © 2015-2025 Biogen Inc. All rights reserved. U.S. Patent Numbers: 5,840,299; 6,602,503
Label text from the FDA structured product label by Biogen Inc. (revised Mar 21, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Natalizumab in 1 product
Tysabri NDC products (1)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 64406-008 | Natalizumab 300 mg/15mL Injection | Biogen Inc. | BLA |
Frequently asked questions
What is Tysabri used for?
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…
What are the side effects of Tysabri?
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… See the full label for the complete list.
Who makes Tysabri?
Tysabri is listed by 1 labeler in the FDA NDC directory, including Biogen Inc..