Introduction
Tysabri (natalizumab) is a monoclonal antibody medication used primarily for the treatment of multiple sclerosis and Crohn's disease. It was first approved by the FDA in 2004 and represents a significant advancement in the management of these autoimmune conditions. Tysabri works by modulating the immune system's activity to reduce inflammatory processes that damage the central nervous system in MS and the gastrointestinal tract in Crohn's disease.
Mechanism of Action
Tysabri exerts its therapeutic effects through selective adhesion molecule inhibition. It targets α4-integrin, a protein expressed on the surface of leukocytes. By binding to α4-integrin, natalizumab blocks the interaction between α4β1-integrin (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1), which is necessary for leukocyte migration across the endothelium into inflamed parenchymal tissue. This mechanism prevents immune cells from crossing the blood-brain barrier in multiple sclerosis and the intestinal mucosa in Crohn's disease, thereby reducing inflammation and tissue damage.
Indications
- Treatment of relapsing forms of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease
- Moderately to severely active Crohn's disease in adults who have had inadequate response to or are unable to tolerate conventional Crohn's disease therapies and TNF-α antagonists
Dosage and Administration
Standard dosing: 300 mg intravenous infusion every 4 weeks Infusion duration: Approximately 1 hour Preparation: Dilute 300 mg (15 mL) in 100 mL of 0.9% Sodium Chloride Injection, USP Special populations:- Renal impairment: No dosage adjustment necessary
- Hepatic impairment: Not studied; use with caution
- Elderly: No specific dosage recommendation
- Pediatrics: Safety and effectiveness not established
Pharmacokinetics
Absorption: Administered intravenously with 100% bioavailability Distribution: Steady-state volume of distribution approximately 5.7 L Metabolism: Presumed to be degraded by proteolytic enzymes throughout the body Elimination: Half-life approximately 11 days; clearance 16 mL/hour Special populations: Body weight and gender do not significantly affect pharmacokineticsContraindications
- History of or current progressive multifocal leukoencephalopathy (PML)
- Patients who have or have had John Cunningham virus (JCV) infection (unless benefits outweigh risks)
- Hypersensitivity to natalizumab or any component of the formulation
- Combination therapy with immunosuppressants or immunomodulators
Warnings and Precautions
Boxed Warning: Increased risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain that typically leads to death or severe disability- PML risk factors include: duration of therapy, prior immunosuppressant use, and John Cunningham virus (JCV) antibody status
- Requires mandatory enrollment in the TOUCH Prescribing Program
- Hepatotoxicity: Clinically significant liver injury has been reported
- Hypersensitivity reactions: Including anaphylaxis
- Immunosuppression: Increased susceptibility to infections
- Thrombocytopenia: Has been reported
Drug Interactions
- Concomitant use with other immunosuppressive agents increases PML risk
- Live vaccines: Avoid concurrent administration
- TNF-α inhibitors: Increased risk of serious infections
- Antineoplastic agents: Potential additive immunosuppression
- Corticosteroids: May increase infection risk
Adverse Effects
Most common (>10%): Headache, fatigue, arthralgia, urinary tract infection, lower respiratory tract infection, gastroenteritis, vaginitis, depression, pain in extremities, abdominal discomfort, diarrhea, nausea Serious adverse effects:- Progressive multifocal leukoencephalopathy (PML)
- Hepatotoxicity
- Hypersensitivity reactions
- Infections (including opportunistic infections)
- Thrombocytopenia
- Immunosuppression
Monitoring Parameters
Prior to initiation:- JCV antibody testing
- MRI brain scan
- Complete blood count
- Liver function tests
- Pregnancy test if applicable
- Neurological assessment every 3-6 months
- Regular monitoring for signs of PML (cognitive, motor, visual changes)
- CBC and LFTs periodically
- Vigilance for infectious complications
- Regular JCV antibody status reassessment (every 6 months)
- Observe for 1 hour after infusion for hypersensitivity reactions
Patient Education
- Understand the risks and benefits of therapy, particularly PML risk
- Recognize and report immediately any new or worsening neurological symptoms
- Report signs of infection, liver problems, or allergic reactions
- Understand the importance of regular monitoring and follow-up appointments
- Inform all healthcare providers about Tysabri therapy
- Avoid live vaccines during treatment
- Practice effective contraception during treatment
- Participate in the TOUCH Prescribing Program as required
References
1. FDA Prescribing Information: Tysabri (natalizumab) [2023] 2. Polman CH, et al. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910. 3. Bloomgren G, et al. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870-1880. 4. Targan SR, et al. Natalizumab for the treatment of active Crohn's disease: results of the ENCORE Trial. Gastroenterology. 2007;132(5):1672-1683. 5. National Multiple Sclerosis Society. Natalizumab (Tysabri) Medication Guide. 2023. 6. Schwab N, et al. Therapy with natalizumab is associated with high JCV seroconversion and rising JCV index values. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e195. 7. Fine AJ, et al. Updated safety and effectiveness of natalizumab in clinical practice: 10 years of postmarketing data. Neurol Clin Pract. 2020;10(3):225-234.