Natalizumab
Natalizumab increases the risk of progressive multifocal leukoencephalopathy (PML), an opportunistic viral infection of the brain caused by JC virus that usually leads to death or severe disability.
Three risk factors that increase PML risk in natalizumab-treated patients have been identified:
- Presence of anti-JCV antibodies (anti-JCV antibody-positive patients have higher risk)
- Longer treatment duration, especially beyond 2 years
- Prior treatment with immunosuppressants (e.g., mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil)
Healthcare professionals must monitor patients for any new sign or symptom suggestive of PML and withhold natalizumab immediately at the first sign or symptom suggestive of PML. For diagnosis, gadolinium-enhanced MRI of the brain and, when indicated, CSF analysis for JC viral DNA are recommended.
Because of the risk of PML, natalizumab is available only through a restricted distribution program — the TOUCH® Prescribing Program (REMS) — for both Tysabri and the Tyruko REMS Program for the biosimilar.
Quick Facts
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Relapsing forms of multiple sclerosis — including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease | Adults | Monotherapy only | FDA Approved |
| Moderately to severely active Crohn’s disease with evidence of inflammation, in patients with inadequate response to or intolerance of conventional CD therapies AND TNF-α inhibitors — for inducing and maintaining clinical response and remission | Adults | Monotherapy (no immunosuppressants or TNF-α inhibitors permitted; aminosalicylates may be continued) | FDA Approved |
Natalizumab is a recombinant humanized IgG4κ monoclonal antibody and was the first selective adhesion-molecule inhibitor introduced into clinical practice. The FDA initially approved natalizumab in November 2004 for relapsing MS. After two patients with MS and one with Crohn’s disease developed PML in pre-marketing/early post-marketing studies, the manufacturer voluntarily withdrew the drug in February 2005. Following implementation of a restricted distribution program (TOUCH®) and updated risk-benefit analyses, FDA reinstated approval in June 2006 for relapsing MS, with approval for moderately-to-severely active Crohn’s disease following in January 2008.
Approval for relapsing MS rests on the AFFIRM (Study MS1, n=942) and SENTINEL (Study MS2, n=1171) trials, both published in the New England Journal of Medicine in 2006. Approval for Crohn’s disease rests on the ENACT-1, ENACT-2, and ENCORE trials, where benefit was most robust in patients with elevated C-reactive protein (CRP) at baseline. The pediatric population is not included in either approval.
Within the AAN treatment hierarchy and the ECTRIMS/EAN guideline, natalizumab is positioned as a high-efficacy MS disease-modifying therapy, typically reserved for patients with breakthrough disease activity on platform therapies or with markedly active disease at presentation, where the magnitude of expected benefit justifies the PML and other risks. Within the ACG Crohn’s disease guideline, natalizumab is reserved for moderately-to-severely active disease unresponsive to or intolerant of conventional therapy and TNF-α inhibitors, with vedolizumab and ustekinumab generally preferred when feasible because of their more favourable safety profiles.
In Crohn’s disease, natalizumab must NOT be combined with immunosuppressants (e.g., 6-mercaptopurine, azathioprine, cyclosporine, methotrexate) or TNF-α inhibitors. Aminosalicylates may be continued. In MS, natalizumab is administered as monotherapy; chronic immunosuppressant or immunomodulatory therapy should not ordinarily be co-administered. The 2005 SENTINEL combination experience with intramuscular interferon beta-1a is no longer a recommended treatment paradigm because PML occurred in this combination cohort.
Dosing
Natalizumab is administered as a fixed-dose intravenous infusion every 4 weeks for both approved indications. Dosing is independent of body weight. Natalizumab must be diluted in 0.9% sodium chloride before administration, infused over approximately one hour, and never given as an intravenous push or bolus. Only prescribers, infusion centres, and pharmacies registered in the TOUCH® Prescribing Program (or the Tyruko REMS for the biosimilar) may prescribe, dispense, or administer natalizumab.
Standard Dosing
| Indication | Recommended Dose | Indication-Specific Stopping Rules |
|---|---|---|
| Multiple sclerosis (relapsing forms) | 300 mg IV infusion over ~1 hour every 4 weeks | Continue indefinitely while benefit-risk is favourable; reassess every 6 months per TOUCH® Program; consider alternative therapy if anti-JCV antibody status converts to positive and especially if treatment exceeds 2 years Maximum dose: 300 mg per infusion; safety of higher doses not established |
| Crohn’s disease (moderate-to-severe, inadequate response to/intolerance of conventional CD therapy and TNF-α inhibitors) | 300 mg IV infusion over ~1 hour every 4 weeks | Discontinue if no therapeutic benefit by 12 weeks of induction. For patients on chronic oral corticosteroids: begin steroid taper as soon as benefit occurs; if steroids cannot be discontinued within 6 months, discontinue natalizumab. Consider discontinuation if steroid use exceeds 3 months in a calendar year (beyond the initial 6-month taper) |
Dilution and Preparation
- Solution: Withdraw the entire 15 mL (300 mg) from the single-use vial; inject into 100 mL of 0.9% sodium chloride injection — no other diluents may be used. Final concentration is 2.6 mg/mL.
- Mixing: Gently invert to mix; do not shake. Inspect for particulates and discoloration; do not use if abnormal.
- Storage: Refrigerate vial at 2–8 °C; do not freeze; protect from light. After dilution, infuse immediately, or refrigerate at 2–8 °C and use within 48 hours; allow to warm to room temperature before infusion.
- Filtration: Use of in-line filters has not been evaluated. Do not co-administer other medications through the same line or mix with natalizumab.
Administration and Post-Infusion Observation
| Phase | Action |
|---|---|
| Pre-infusion | Confirm TOUCH® enrollment is current; complete infusion screening questionnaire (review for any new neurological symptoms, recent infections, or PML signs); confirm continued benefit-risk per TOUCH® reauthorization (every 6 months) |
| Infusion | Infuse over approximately 1 hour (rate ~5 mg/min); observe throughout. Promptly discontinue and treat at the first sign or symptom of a hypersensitivity-type reaction |
| Post-infusion (infusions 1 through 12) | Observe patient for 1 hour after infusion |
| Post-infusion (infusions 13 and beyond) | For patients who have completed 12 infusions without a hypersensitivity reaction, post-infusion observation may follow clinical judgment |
| End of infusion | Flush the line with 0.9% sodium chloride injection |
Special Populations
| Population | Recommendation | Rationale |
|---|---|---|
| Renal impairment (any severity) | No formal adjustment | Pharmacokinetics not formally studied; renal elimination not a major route for IgG monoclonal antibodies |
| Hepatic impairment | No formal adjustment; discontinue if signs of significant liver injury | Pharmacokinetics not formally studied; clinically significant liver injury, including liver failure requiring transplant, has been reported postmarketing |
| Geriatric (≥65 years) | Use with caution; clinical experience limited | Insufficient enrolled in trials to determine differences in response or safety |
| Pediatric <18 years | Not indicated | Safety and effectiveness not established in MS or Crohn’s disease |
| Pregnancy | Use only if clearly indicated; obtain CBC in neonates exposed in utero | May cause fetal harm; neonatal thrombocytopenia and anemia have been reported postmarketing |
| Patients with persistent anti-natalizumab antibodies | Reassess benefit-risk; clearance increases ~3-fold; efficacy substantially reduced | Retest 3 months after first positive test to confirm persistence; prior antibody-negative patients re-treated after a long interruption have a higher rate of antibody development |
Patients who receive only 1–2 infusions followed by an extended interruption are at higher risk of developing anti-natalizumab antibodies and hypersensitivity reactions on re-exposure than patients on regularly scheduled therapy. Before re-starting natalizumab after a dose interruption, consider testing for anti-natalizumab antibodies. In addition, because of the risk of severe rebound MS activity within 12 weeks of discontinuation (and reports up to 24 weeks), planning for any treatment break or switch should involve the MS specialist and ideally a bridging strategy.
Pharmacology
Mechanism of Action
Natalizumab is a recombinant humanized IgG4κ monoclonal antibody (149 kDa) that binds the α4 subunit of α4β1 and α4β7 integrins expressed on the surface of all leukocytes except neutrophils. By binding α4-integrin, natalizumab inhibits the α4-mediated adhesion of leukocytes to their counter-receptors — vascular cell adhesion molecule-1 (VCAM-1) on activated vascular endothelium and mucosal addressin cell adhesion molecule-1 (MAdCAM-1) on gastrointestinal endothelium. Disruption of these adhesion interactions prevents leukocyte transmigration across the endothelium into inflamed parenchymal tissue, including the central nervous system in multiple sclerosis and the gut wall in Crohn’s disease.
In multiple sclerosis, the therapeutic effect is thought to derive from blockade of the α4β1-integrin / VCAM-1 interaction (and possibly α4β1 binding to CS-1 fibronectin and osteopontin) at the blood-brain barrier, thereby reducing trafficking of activated lymphocytes into CNS lesions. In Crohn’s disease, the α4β7 / MAdCAM-1 interaction is implicated in homing of T lymphocytes to gut-associated lymphoid tissue and to actively inflamed mucosa. The same mechanism that produces therapeutic benefit — restriction of immune-cell trafficking — also reduces immune surveillance of the CNS, which underlies the increased risk of PML and JCV granule cell neuronopathy in treated patients.
Pharmacodynamically, natalizumab administration produces a measurable increase in circulating leukocyte counts (lymphocytes, monocytes, basophils, eosinophils) because of inhibited transmigration out of the vascular space; absolute neutrophil counts are not affected. Mild decreases in hemoglobin (mean 0.6 g/dL) are observed and are usually transient. These laboratory changes generally normalize within ~16 weeks of the last dose.
ADME Profile (300 mg IV every 4 weeks)
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Bioavailability 100% (intravenous administration) | No oral or absorption-related variability; full dose delivered to systemic circulation |
| Distribution | Vd 5.7 ± 1.9 L (MS) and 5.2 ± 2.8 L (CD); confined largely to the vascular space, typical for an IgG monoclonal antibody | Limited tissue distribution; does not penetrate the CNS appreciably under normal conditions |
| Metabolism | Catabolised by reticuloendothelial proteolysis to amino acids — typical IgG monoclonal antibody clearance pathway. No CYP-mediated metabolism | No clinically significant CYP-mediated drug interactions; pharmacokinetic interactions are limited to immunogenicity-mediated effects |
| Steady State | Reached after ~24 weeks (MS) or 16–24 weeks (CD) of every-4-week dosing | Mean steady-state Cmax 110 ± 52 mcg/mL (MS) or 101 ± 34 mcg/mL (CD); trough 23–29 mcg/mL (MS) or 10 ± 9 mcg/mL (CD) |
| Elimination | Mean half-life 11 ± 4 days (MS) or 10 ± 7 days (CD); clearance 16 ± 5 mL/h (MS) or 22 ± 22 mL/h (CD) | Pharmacodynamic effects (and α4-integrin receptor occupancy) persist well beyond drug elimination; PML monitoring should continue for at least 6 months after discontinuation |
| Effect of immunogenicity | Persistent anti-natalizumab antibodies increase clearance ~3-fold and substantially reduce efficacy; hypersensitivity reactions are also more common in antibody-positive patients | Test for antibodies if hypersensitivity reactions occur, or before re-initiation after long interruptions; reduced efficacy in persistently antibody-positive patients warrants reconsidering therapy |
| Effect of plasma exchange (PLEX) | Three sessions of PLEX over 5–8 days accelerate natalizumab clearance, although α4-integrin receptor binding remains high in many patients | PLEX has been used postmarketing to remove natalizumab in patients with PML, but does not treat PML itself; IRIS frequently follows PLEX-mediated drug removal |
Population pharmacokinetic analyses (n=2195 in MS; n=1156 in CD) found that natalizumab clearance increases with body weight in a less-than-proportional manner — a 43% increase in body weight corresponds to a 32% increase in clearance — but this does not warrant weight-based dosing in clinical practice. Age, gender, race, and concomitant medications (including methotrexate, immunosuppressants, infliximab, and steroids in CD) had no clinically significant effects on natalizumab pharmacokinetics. Serum natalizumab concentrations are inversely related to anti-natalizumab antibody titres and may be substantially reduced (to ~1–2 mcg/mL pre-infusion) in persistently antibody-positive patients.
Side Effects
Adverse-reaction data below are drawn from the registrational MS and Crohn’s disease trials. For MS, frequencies are from Study MS1 (AFFIRM, n=627 natalizumab vs n=312 placebo; median 28 months exposure). For Crohn’s disease, frequencies are from the induction Studies CD1 and CD2 (combined n=983 natalizumab vs n=431 placebo; median 2.8 months exposure) and the maintenance Study CD3 (n=214 vs n=214; median 11 months exposure). Acute hypersensitivity reactions are defined as occurring within 2 hours of infusion start; all other reactions described as “infusion-related” occurred within 2 hours.
| Adverse Effect | Incidence (Natalizumab vs Placebo) | Clinical Note |
|---|---|---|
| Headache | 38% vs 33% | Most common adverse reaction in both indications |
| Fatigue | 27% vs 21% | — |
| Urinary tract infection | 21% vs 17% | Standard management; may rarely require interruption |
| Arthralgia | 19% vs 14% | — |
| Depression | 19% vs 16% | Suicidal ideation/attempt 0.6% vs 0.3% in MS Study MS1; counsel patients and screen periodically |
| Lower respiratory tract infection | 17% vs 16% | Investigate for pneumonia in symptomatic patients |
| Pain in extremity | 16% vs 14% | — |
| Rash | 12% vs 9% | Distinguish from acute hypersensitivity reaction (occurs within 2 hours of infusion) |
| Gastroenteritis | 11% vs 9% | Investigate persistent diarrhea, particularly for opportunistic pathogens (e.g., cryptosporidium) |
| Abdominal discomfort | 11% vs 10% | — |
| Diarrhea NOS | 10% vs 9% | Standard supportive care; investigate persistent symptoms |
| Vaginitis (women) | 10% vs 6% | — |
| Adverse Effect | Incidence (Natalizumab vs Placebo) | Clinical Note |
|---|---|---|
| Headache (induction) | 32% vs 23% | — |
| Headache (maintenance) | 37% vs 31% | — |
| Upper respiratory tract infection (induction) | 22% vs 16% | Most common infection in CD trials |
| Influenza (maintenance) | 12% vs 5% | Annual inactivated influenza vaccination recommended |
| Lower abdominal pain (maintenance) | 12% vs 8% | Distinguish from CD flare |
| Nausea (induction) | 17% vs 15% | — |
| Adverse Effect | Incidence (Natalizumab vs Placebo) | Clinical Note |
|---|---|---|
| Tooth infections (MS) | 9% vs 7% | Maintain dental hygiene; address before initiation |
| Herpes infections (MS) | 8% vs 7% | Postmarketing reports of disseminated HSV/VZV including encephalitis, meningitis, and acute retinal necrosis |
| Tonsillitis (MS) | 7% vs 5% | — |
| Vertigo (MS) | 6% vs 5% | Investigate persistent vertigo for JCV granule cell neuronopathy or other CNS process |
| Chest discomfort (MS) | 5% vs 3% | — |
| Other hypersensitivity reactions (MS) (occurring >2 hours post-infusion) | 5% vs 2% | — |
| Acute hypersensitivity reactions (MS) (within 2 hours) | 4% vs <1% | Discontinue infusion at first sign; do not re-treat after a hypersensitivity reaction (contraindication) |
| Abnormal liver function tests (MS) | 5% vs 4% | Postmarketing reports of acute liver failure requiring transplant; monitor signs/symptoms |
| Peripheral edema (CD maintenance Study CD3) | 6% vs 3% | — |
| Sinusitis (CD maintenance) | 8% vs 4% | — |
| Cholelithiasis (MS Study MS1, serious AE) | 1% vs 0.3% | — |
| Cough (induction) | 3% vs <1% | — |
| Influenza-like illness (induction) | 5% vs 4% | — |
| Tremor (induction) | 1% vs <1% | — |
| Vaginal infections (CD induction, women) | 4% vs 2% | — |
| Acute hypersensitivity reactions (CD) | 2% vs <1% (induction) | — |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Progressive multifocal leukoencephalopathy (PML) | Stratified by anti-JCV antibody status, treatment duration, and prior immunosuppressant use (see PML Risk Stratification table); 3 cases occurred in pre-marketing trials (2 MS on add-on to interferon, 1 CD on prior immunosuppressants) | Most cases occur after >1 year (especially after 2+ years) of therapy | Withhold natalizumab immediately at first sign or symptom suggestive of PML; obtain gadolinium-enhanced MRI of the brain; if indicated, CSF JC viral DNA PCR. Continue PML monitoring for ≥6 months after discontinuation. PLEX has been used to accelerate clearance but does not treat PML; IRIS often follows PLEX |
| JCV granule cell neuronopathy (JCV GCN) | Postmarketing — frequency not established; can occur with or without concomitant PML | Variable | Suspect in patients with cerebellar dysfunction (ataxia, incoordination, apraxia, visual disorders); diagnostic workup as for PML; manage similarly |
| Herpes encephalitis and meningitis (HSV, VZV) | Postmarketing — life-threatening and fatal cases reported | Months to years on therapy | Discontinue natalizumab; initiate appropriate antiviral therapy; CSF PCR for HSV/VZV DNA confirms diagnosis |
| Acute retinal necrosis (ARN, herpes-mediated) | Postmarketing — increased risk; serious cases led to blindness in one or both eyes | Variable; some cases with concurrent CNS herpes infection | Refer urgently for retinal screening in any patient with decreased visual acuity, redness, or eye pain; consider discontinuation; antiviral therapy ± surgery |
| Clinically significant liver injury (including acute liver failure requiring transplant) | Postmarketing — onset as early as 6 days after first dose; also reported after multiple doses; recurrence on rechallenge documented | Days to years | Discontinue in jaundice or other evidence of significant liver injury (transaminase + bilirubin elevations without obstruction) |
| Acute hypersensitivity reactions and anaphylaxis | Acute hypersensitivity 4% vs <1% in MS; serious systemic reactions (anaphylaxis) <1% | Usually within 2 hours of start of infusion | Discontinue infusion immediately; treat as anaphylaxis if appropriate; permanently discontinue natalizumab — re-treatment is contraindicated. Hypersensitivity is more frequent in patients with anti-natalizumab antibodies |
| Serious infections including opportunistic infections | Serious infection rate ~3% in MS Study MS1 vs ~3% placebo; ~2.1% in CD induction (vs 2.1% placebo); 3.3% vs 2.8% in CD maintenance. Opportunistic infections in <1% of treated patients (mycobacterium avium, aspergillus, cryptococcus, cryptosporidium, Pneumocystis, Burkholderia) | Throughout therapy | Investigate and treat promptly; consider holding therapy during serious infection. Concomitant corticosteroids in CD do not increase infection rate over placebo + steroids, but combination with immunosuppressants or TNF-α inhibitors increases infection (and PML) risk |
| Thrombocytopenia (including immune thrombocytopenic purpura) | Postmarketing — frequency not established; section 5.8 emphasized in 3/2025 update | Variable | Discontinue natalizumab in suspected thrombocytopenia; investigate for ITP and treat; counsel patients on bleeding/petechiae symptoms |
| Neonatal thrombocytopenia and anemia (in utero exposure) | Postmarketing — added to W&P 5.8 in 3/2025 | At birth in exposed infants | Obtain CBC in any neonate exposed to natalizumab in utero; manage hematologic abnormalities supportively |
| Severe disability rebound after stopping natalizumab | Postmarketing — recurrence of disease activity above pre-treatment levels reported, particularly in MS | Within 12 weeks of stopping; reports up to 24 weeks | Plan transitions in advance with the MS specialist; consider bridging therapy; close clinical and MRI surveillance for at least 6 months after discontinuation |
| Immune reconstitution inflammatory syndrome (IRIS) | In majority of TYSABRI-treated patients with PML who subsequently discontinue, especially after PLEX | Days to weeks after PLEX or natalizumab discontinuation in PML | Monitor closely after PLEX/discontinuation in PML; corticosteroids may be needed for IRIS |
| Pneumonia (MS) | 0.6% vs 0% in MS Study MS1 | Throughout therapy | Investigate persistent respiratory symptoms; treat appropriately and consider hold |
| Hemolytic anemia | Postmarketing — frequency not established | Variable | Monitor for anemia; investigate and discontinue if hemolysis confirmed |
| Cholelithiasis | Serious AE: 1.0% vs 0.3% in MS Study MS1; 0.3% vs 0% in CD induction | Variable | Standard surgical management |
PML Risk Stratification (US Postmarketing Estimates, ~100,000 Treated Patients)
The risk of natalizumab-associated PML is stratified by three factors per the prescribing information: anti-JCV antibody status, duration of therapy, and prior immunosuppressant use. The table below reflects current US incidence estimates per the 3/2025 PI.
| Anti-JCV Antibody Status & Treatment Duration | No Prior Immunosuppressant Use | Prior Immunosuppressant Use |
|---|---|---|
| Anti-JCV antibody negative (any duration) | < 1 in 10,000 (regardless of duration or prior IS use) | |
| Anti-JCV antibody positive · 1–24 months | < 1 in 1,000 | 1 in 1,000 |
| Anti-JCV antibody positive · 25–48 months | 2 in 1,000 | 6 in 1,000 |
| Anti-JCV antibody positive · 49–72 months | 4 in 1,000 | 7 in 1,000 |
| Anti-JCV antibody positive · 73–96 months | 2 in 1,000 | 6 in 1,000 |
Anti-JCV antibody seroconversion in MS patients on natalizumab is estimated at 3–8% per year. The PI also notes that postmarketing data suggest the risk of PML may correlate with the relative anti-JCV antibody index value (a quantitative measure of antibody titre). Patients negative for anti-JCV antibodies should be retested periodically. After plasma exchange, wait at least 2 weeks before testing for anti-JCV antibodies (to avoid false negatives from removed serum antibodies). After IVIG, wait at least 6 months (5 half-lives) before testing (to avoid false positives from passive transfer of antibodies).
Symptoms of PML develop 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. PML symptoms can resemble an MS relapse, but they are typically more progressive and do not respond to corticosteroids. Withhold natalizumab immediately at the first sign or symptom suggestive of PML and obtain gadolinium-enhanced MRI of the brain. MRI may show characteristic findings before clinical symptoms become apparent — consider MRI surveillance in patients at higher risk.
Drug Interactions
Natalizumab is an IgG monoclonal antibody and does not interact with co-medications via cytochrome P450 metabolism. The clinically meaningful interactions are pharmacodynamic — primarily additive immunosuppression with other immune-modulating agents (markedly increasing PML and serious-infection risk) and pharmacokinetic effects from immunogenicity (anti-natalizumab antibodies increase clearance ~3-fold). The combination experience with intramuscular interferon beta-1a in the SENTINEL trial generated PML cases and has shaped the prohibition on combination therapy.
Monitoring
The TOUCH® Prescribing Program (and the Tyruko REMS Program for the biosimilar) defines the minimum monitoring framework: prescribers evaluate patients at 3 months and 6 months after the first infusion, every 6 months thereafter, and for at least 6 months after discontinuation. The Patient Status Report and Reauthorization Questionnaire is submitted to Biogen every 6 months, and discontinuation questionnaires must be completed when natalizumab is stopped. Beyond the REMS framework, structured surveillance for PML, infection, hepatic injury, hematologic abnormalities, and hypersensitivity is essential.
-
Anti-JCV antibody status (with index when relevant)
Before initiation; periodically (at least every 6 months) in anti-JCV antibody-negative patients due to 3–8% annual seroconversion rate; recheck before any treatment continuation beyond 24 months and before any treatment break
Routine Use the analytically and clinically validated ELISA. Wait ≥2 weeks after PLEX (false negatives) and ≥6 months after IVIG (false positives) before testing. Once positive, the patient is considered antibody-positive for risk-stratification purposes regardless of subsequent test results. -
Brain MRI
Baseline (before initiation); periodically thereafter (more frequently in higher-risk patients, e.g., anti-JCV positive with prior IS or treatment >2 years); urgently for any new or progressive neurological symptoms or PML suspicion
Routine + Trigger-based Baseline MRI helps differentiate subsequent MS symptoms from PML. MRI findings of PML may precede clinical symptoms; suspicious findings warrant immediate withholding and CSF JC viral DNA evaluation. -
Symptoms suggestive of PML and JCV GCN
Before each infusion (TOUCH® screening questionnaire); during therapy and for at least 6 months after discontinuation
Routine Vigilance for unilateral weakness, clumsiness, vision disturbance, cognitive/personality change (PML); and cerebellar dysfunction such as ataxia, incoordination, or visual disorders (JCV GCN). -
Liver function (ALT, AST, alkaline phosphatase, total bilirubin)
Baseline; periodically during therapy; promptly for any symptoms of liver injury
Routine Acute liver failure requiring transplant has been reported as early as 6 days after first dose. Discontinue in jaundice or significant transaminase + bilirubin elevations without obstructive cause. -
Complete blood count (CBC) with platelets
Baseline; periodically during therapy; obtain in any neonate exposed to natalizumab in utero
Routine Postmarketing reports of thrombocytopenia (including ITP), hemolytic anemia, and neonatal thrombocytopenia/anemia underlie the 3/2025 W&P 5.8 update. Discontinue in suspected thrombocytopenia. -
Symptoms of infection (including herpes encephalitis/meningitis and acute retinal necrosis)
At every clinical contact during therapy and for at least 6 months after discontinuation
Routine Investigate fever, headache with confusion, persistent eye pain or vision change, or signs of opportunistic infection promptly; CSF PCR for herpesviruses if encephalitis/meningitis suspected. -
Infusion-related and hypersensitivity reactions
During every infusion and for 1 hour post-infusion (infusions 1–12); per clinical judgment thereafter
Routine Most acute reactions occur within 2 hours of infusion start. Immediately discontinue infusion at first sign of hypersensitivity-type reaction; permanently discontinue natalizumab. -
Anti-natalizumab antibodies
Trigger-based: after suspected hypersensitivity reaction; before re-initiation after dose interruption
Trigger-based Confirm persistent positivity with repeat testing ≥3 months after the initial positive. Persistent positivity reduces efficacy and increases hypersensitivity risk; reassess benefit-risk. -
CD-specific: Crohn’s disease activity (CDAI / clinical assessment / CRP)
Baseline; at week 12 (induction endpoint); periodically during maintenance
Routine Discontinue if no therapeutic benefit by 12 weeks of induction. Reassess every 6 months and discontinue if patient cannot taper off chronic steroids within 6 months. -
Pregnancy testing & counselling
Before initiation in females of reproductive potential; throughout therapy if clinically indicated
Routine May cause fetal harm; neonatal thrombocytopenia and anemia have been reported. Obtain neonatal CBC for any in utero exposure. Plan transitions thoughtfully — disability rebound risk vs fetal risk. -
TOUCH® Patient Status Report
At 6 months and every 6 months thereafter
Routine (REMS) Required for continued authorization of treatment under the REMS. Discontinuation Questionnaire required when natalizumab is stopped.
Beyond the absolute prompts (suspicion of PML, JCV GCN, hypersensitivity reaction, significant liver injury, thrombocytopenia, treatment failure in CD by week 12), the most consequential clinical decision is when to stop natalizumab in the patient with rising PML risk — typically the anti-JCV-antibody-positive patient approaching 24 months of therapy, especially with prior immunosuppressant use. Switching options must account for the post-discontinuation rebound risk in MS, the lingering pharmacodynamic effect of natalizumab (~6 months for full receptor occupancy decay), and the appropriate washout for the next agent. Engage the MS specialist for any switch decision.
Contraindications & Cautions
Absolute Contraindications
- Patients who have or have had progressive multifocal leukoencephalopathy (PML).
- Patients who have had a hypersensitivity reaction to natalizumab — observed reactions range from urticaria to anaphylaxis; re-treatment after a hypersensitivity reaction is contraindicated.
Relative Contraindications — Specialist Input Recommended
- Active acute or chronic infection, especially serious bacterial, viral, fungal, or opportunistic infection — defer until resolved.
- Significantly compromised immune system function from systemic medical conditions (e.g., HIV/AIDS, leukemia, lymphoma, organ transplant) — natalizumab ordinarily should not be used.
- Concurrent chronic immunosuppressant or immunomodulatory therapy (mitoxantrone, azathioprine, methotrexate, cyclophosphamide, mycophenolate, cyclosporine, anti-TNF agents, anti-CD20 agents) — increased PML and infection risk; combination is prohibited in CD.
- Anti-JCV antibody positive status — particularly with prior immunosuppressant use and treatment duration >2 years; reassess benefit-risk regularly using the PML risk-stratification table.
- Recent or planned use of live vaccines.
- Pregnancy or pregnancy planning — natalizumab may cause fetal harm; neonatal thrombocytopenia/anemia reported; weigh against MS or CD activity and rebound risk.
- Significant liver disease — interrupt at first signs of hepatic injury; do not rechallenge after suspected drug-induced liver injury (recurrence on rechallenge documented).
- Active or recent hematologic abnormality (thrombocytopenia, anemia) — investigate and stabilize before initiation; discontinue if thrombocytopenia develops.
Use With Caution
- Pregnancy and lactation — present in animal milk; effects on the breastfed infant unknown.
- Geriatric patients (≥65 years) — limited clinical experience.
- Pediatric patients <18 years — safety and effectiveness not established; not indicated.
- Patients with active herpes virus infection (oral, genital, or ocular) — vigilance for reactivation, dissemination, and acute retinal necrosis.
- Patients with persistent anti-natalizumab antibodies — reduced efficacy, increased infusion reactions; reassess.
- Patients with prior PML on another agent (e.g., natalizumab biosimilar, rituximab, fingolimod) — contraindication if PML history; otherwise consider alternative therapies.
Prescribers must be enrolled and certified, sign Prescriber Enrollment Forms, and complete patient education and Patient Enrollment Forms; evaluate patients at 3 and 6 months after the first infusion, every 6 months thereafter, and for at least 6 months after discontinuation; submit Patient Status Reports and Reauthorization Questionnaires every 6 months; complete Discontinuation Questionnaires when treatment ends; report PML, opportunistic-infection hospitalizations, and deaths to Biogen at 1-800-456-2255.
Patients must be enrolled, read the Medication Guide, and sign the Patient Enrollment Form. Pharmacies and infusion centers must be specially certified to dispense or infuse natalizumab.
Natalizumab carries no other absolute contraindications beyond PML history and prior hypersensitivity to natalizumab, but the W&P sections (5.1 PML, 5.2 TOUCH®, 5.3 herpes infections, 5.4 hepatotoxicity, 5.5 hypersensitivity, 5.6 immunosuppression/infections, 5.7 lab abnormalities, 5.8 hematological abnormalities [updated 3/2025], 5.9 immunizations) function as critical clinical limits.
Patient Counselling
Purpose of Therapy
Explain that natalizumab is a high-efficacy intravenous medication used to treat relapsing forms of multiple sclerosis (in adults) or moderately-to-severely active Crohn’s disease (in adults who have not responded to or cannot tolerate other treatments including TNF-α inhibitors). It does not cure these conditions, but pivotal trials and long-term extension data show large reductions in MS relapse rate, disability progression, and MRI lesion activity (about a two-thirds reduction in relapses in AFFIRM) and substantially higher rates of clinical response and steroid-free remission in Crohn’s disease.
How to Take
Natalizumab is given as an intravenous infusion over about one hour, every 4 weeks, in a certified infusion center. Before the first dose, patients must be enrolled in the TOUCH® Prescribing Program (or the Tyruko REMS Program). At each visit, the patient is screened for any new neurological symptoms or infection. After the infusion, patients are observed for at least one hour for the first 12 doses; thereafter the post-infusion observation may be adjusted by the clinical team. The patient should not skip the 6-month review with the prescriber, as continued authorization of treatment depends on it.
Sources
- Biogen Inc. Tysabri (natalizumab) injection — full prescribing information. Revised March 2025. Available via FDA at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/125104s984lbl.pdf Authoritative current source for the boxed warning, indications (relapsing MS and Crohn’s disease), 300 mg IV every-4-week dosing, the 9 Warnings and Precautions sections, the integrated PML risk-stratification table, the integrated MS Study MS1 and CD Studies CD1/CD2/CD3 adverse-reaction tables, immunogenicity data, pharmacokinetics, and the TOUCH® Prescribing Program requirements. The 3/2025 update revised W&P 5.8 to incorporate neonatal thrombocytopenia/anemia.
- Sandoz Inc. Tyruko (natalizumab-sztn) injection — full prescribing information. Available via the manufacturer at: https://www.tyruko.com First FDA-approved natalizumab biosimilar (approved August 2023); shares the boxed warning and indications of the originator and is dispensed through the Tyruko REMS Program.
- U.S. Food and Drug Administration. Natalizumab (Tysabri) Information. Available at: https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/ FDA Drug Safety Communications and approval history relevant to natalizumab, including the 2005 voluntary withdrawal, the 2006 reinstatement under TOUCH®, the 2008 expansion to Crohn’s disease, and subsequent PML-related communications.
- Polman CH, O’Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW; AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899–910. doi: 10.1056/NEJMoa044397 (PMID: 16510744) Pivotal Phase III AFFIRM trial (Study MS1 in the PI). Demonstrated 67% relative reduction in annualised relapse rate and 42% relative risk reduction in sustained disability progression vs placebo over 2 years; basis for relapsing MS approval.
- Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW; SENTINEL Investigators. Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):911–923. doi: 10.1056/NEJMoa044396 (PMID: 16510745) SENTINEL trial (Study MS2 in the PI). Demonstrated efficacy of natalizumab when added to intramuscular interferon beta-1a in patients with breakthrough disease. Two cases of PML in this trial were the proximate cause of the 2005 withdrawal; combination therapy is no longer recommended.
- Sandborn WJ, Colombel JF, Enns R, Feagan BG, Hanauer SB, Lawrance IC, Panaccione R, Sanders M, Schreiber S, Targan S, van Deventer S, Goldblum R, Despain D, Hogge GS, Rutgeerts P; ENACT-1 and ENACT-2 Trial Groups. Natalizumab induction and maintenance therapy for Crohn’s disease. N Engl J Med. 2005;353(18):1912–1925. doi: 10.1056/NEJMoa043335 ENACT-1 (induction, Study CD1) and ENACT-2 (maintenance, Study CD3) Phase III trials supporting Crohn’s disease approval. Maintenance Study CD3 demonstrated sustained clinical response (61% vs 29%) and remission through month 9 in patients responding to induction.
- Targan SR, Feagan BG, Fedorak RN, Lashner BA, Panaccione R, Present DH, Spehlmann ME, Rutgeerts PJ, Tulassay Z, Volfova M, Wolf DC, Hernandez C, Bornstein J, Sandborn WJ; ENCORE Trial Group. Natalizumab for the treatment of active Crohn’s disease: results of the ENCORE Trial. Gastroenterology. 2007;132(5):1672–1683. doi: 10.1053/j.gastro.2007.03.024 (PMID: 17484865) ENCORE trial (Study CD2 in the PI). Demonstrated induction of clinical response (48% vs 32%) and remission (26% vs 16%) at both weeks 8 and 12 in CRP-positive Crohn’s disease patients; established the elevated-CRP population as the optimal target for natalizumab in CD.
- Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A, Lee S, Plavina T, Scanlon JV, Sandrock A, Bozic C. Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012;366(20):1870–1880. doi: 10.1056/NEJMoa1107829 Foundational analysis of PML risk by anti-JCV antibody status, treatment duration, and prior immunosuppressant use that informs the current PI risk-stratification table.
- Plavina T, Subramanyam M, Bloomgren G, Richman S, Pace A, Lee S, Schlain B, Campagnolo D, Belachew S, Ticho B. Anti-JC virus antibody levels in serum or plasma further define risk of natalizumab-associated progressive multifocal leukoencephalopathy. Ann Neurol. 2014;76(6):802–812. doi: 10.1002/ana.24286 Established the anti-JCV antibody index as a quantitative refinement of PML risk stratification within the antibody-positive population, particularly in patients without prior immunosuppressant exposure.
- Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med. 2006;354(9):924–933. doi: 10.1056/NEJMoa054693 Original investigation of the first PML cases in natalizumab-treated patients, defining diagnostic criteria for PML and shaping the post-2006 risk-management approach.
- Rae-Grant A, Day GS, Marrie RA, Rabinstein A, Cree BAC, Gronseth GS, Haboubi M, Halper J, Hosey JP, Jones DE, Lisak R, Pelletier D, Potrebic S, Sitcov C, Sommers R, Stachowiak J, Getchius TSD, Merillat SA, Pringsheim T. Practice guideline recommendations summary: Disease-modifying therapies for adults with multiple sclerosis: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology. Neurology. 2018;90(17):777–788. doi: 10.1212/WNL.0000000000005347 (Reaffirmed October 2024) AAN consensus practice guideline that situates natalizumab as a high-efficacy DMT and addresses initiation, switching (including from natalizumab in the setting of rising PML risk), and discontinuation.
- Montalban X, Gold R, Thompson AJ, et al. ECTRIMS/EAN guideline on the pharmacological treatment of people with multiple sclerosis. Mult Scler. 2018;24(2):96–120. doi: 10.1177/1352458517751049 (PMID: 29353550) Joint European guideline addressing natalizumab use, JCV-based risk stratification, and switching strategies for patients reaching the higher PML-risk stratum.
- Lichtenstein GR, Loftus EV, Isaacs KL, Regueiro MD, Gerson LB, Sands BE. ACG Clinical Guideline: Management of Crohn’s Disease in Adults. Am J Gastroenterol. 2018;113(4):481–517. doi: 10.14309/ajg.0000000000000152 (PMID: 29610508) American College of Gastroenterology guideline addressing natalizumab in the context of moderate-to-severe Crohn’s disease unresponsive to or intolerant of conventional therapy and TNF-α inhibitors.