Natalizumab (1 brand name, 1 dosage form, 1 route)
Available dosage forms: VIAL.
Routes of administration: SINGLE-USE.
Brand Names
- TYSABRI
Boxed Warning
Natalizumab products increase the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include the presence of anti-JCV antibodies, duration of therapy, and prior use of immunosuppressants. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYRUKO [see Warnings and Precautions (5.1)]. - Healthcare professionals should monitor patients on TYRUKO for any new sign or symptom that may be suggestive of PML. TYRUKO dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation that includes a gadolinium-enhanced magnetic resonance imaging (MRI) scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended [see Contraindications (4), Warnings and Precautions (5.1)]. - Because of the risk of PML, TYRUKO is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TYRUKO REMS Program [see Warnings and Precautions (5.2)].
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)].
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)]
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)].
Mechanism of Action
Natalizumab products bind 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 products 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 natalizumab products exert their 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 products 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
Overdosage
Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount of natalizumab products that can be safely administered has not been determined.