TYSABRI
Clinical safety rating: caution
Comprehensive clinical and safety monograph for TYSABRI (TYSABRI).
Natalizumab is a recombinant humanized monoclonal antibody that binds to α4β1 and α4β7 integrins, blocking their interaction with vascular cell adhesion molecule-1 (VCAM-1) and mucosal addressin cell adhesion molecule-1 (MadCAM-1), thereby preventing lymphocyte migration across the blood-brain barrier and into inflamed parenchyma.
| Metabolism | Natalizumab is a monoclonal antibody; it is primarily catabolized by proteolytic degradation into small peptides and amino acids. No specific metabolic enzymes are involved; clearance occurs via reticuloendothelial system. |
| Excretion | Primarily via reticuloendothelial system catabolism; renal elimination accounts for <1%, biliary/fecal <1% as intact drug. |
| Half-life | Terminal half-life approximately 11 days (range 6–28 days); supports monthly IV dosing. |
| Protein binding | ~90% bound, primarily to albumin. |
| Volume of Distribution | 5.7 L (not weight-adjusted, ~0.08 L/kg for 70 kg human); reflects limited extravascular distribution consistent with a large monoclonal antibody. |
| Bioavailability | IV: 100% by definition; not administered via other routes. |
| Onset of Action | IV administration: Clinical effect on MRI lesions seen as early as 4 weeks; maximal pharmacodynamic effect (α4-integrin saturation) achieved within 24 hours. |
| Duration of Action | Pharmacodynamic effect (α4-integrin blockade) persists for ≥4 weeks post-dose; clinical durability supports monthly dosing; rebound disease activity may occur after discontinuation. |
| Action Class | Alpha-4 integrin inhibitor |
300 mg intravenously infused over 1 hour every 4 weeks.
| Dosage form | VIAL |
| Renal impairment | No dose adjustment required for renal impairment. Not studied in severe renal impairment. |
| Liver impairment | No dose adjustment required for mild to moderate hepatic impairment. Not studied in severe hepatic impairment. |
| Pediatric use | Not approved for use in pediatric patients. |
| Geriatric use | No specific dose adjustment, but caution due to potential increased immunosuppression. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for TYSABRI (TYSABRI).
| Breastfeeding | It is not known whether natalizumab is excreted in human milk. However, many monoclonal antibodies are excreted in breast milk in small amounts. The manufacturer recommends that caution be exercised when administered to a nursing woman. No M/P ratio is available. |
| Teratogenic Risk | TYSABRI (natalizumab) is an IgG4 monoclonal antibody. As such, it does not cross the placenta in significant amounts during the first trimester, but crosses increasingly during the second and third trimesters. There are no adequate and well-controlled studies in pregnant women. In animal studies, no teratogenic effects were observed at doses up to 30 mg/kg intravenously. However, there is a theoretical risk of fetal immune system effects due to blockade of α4-integrin. The drug should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. |
■ FDA Black Box Warning
Progressive multifocal leukoencephalopathy (PML) can occur with TYSABRI, usually in patients with longer treatment duration, prior immunosuppressant use, or presence of anti-JCV antibodies; PML is an opportunistic viral infection of the brain that usually leads to death or severe disability. Because of the risk of PML, TYSABRI is available only through a restricted distribution program called the TOUCH Prescribing Program.
| Serious Effects |
["Hypersensitivity to natalizumab or any component","Patients with known PML","Patients with active infections except those on therapy for Crohn's disease who have active infection"]
| Precautions | ["Progressive multifocal leukoencephalopathy (PML)","Herpes infections (e.g., encephalitis, meningitis)","Hypersensitivity reactions (including anaphylaxis)","Hepatotoxicity (including liver failure)","Immunosuppression/infections","Immunogenicity (development of anti-natalizumab antibodies)"] |
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| Fetal Monitoring | Maternal monitoring: complete blood count (CBC), liver function tests (LFTs), and signs of progressive multifocal leukoencephalopathy (PML). Fetal monitoring: standard prenatal care including ultrasound to assess fetal growth and development. No specific additional fetal monitoring is recommended, but consider monitoring for potential effects on fetal immune system. |
| Fertility Effects | No specific studies on fertility effects in humans are available. In animal studies, natalizumab did not impair fertility in male or female rats at doses up to 30 mg/kg intravenously. However, due to its mechanism of action (α4-integrin blockade), there is a theoretical potential for effects on reproductive tissues, though no clear evidence of harm. |