TYSABRI® (natalizumab) is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. TYSABRI increases the risk of PML. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk. See Important Safety Information regarding the risk of PML with TYSABRI. 

Click here to see additional Important Safety Information including Boxed Warning.

Real-world, 5-year, interim TYSABRI Observational Program (TOP) data show the overall safety profile of TYSABRI to be consistent with clinical studies, and demonstrate its efficacy in clinical practice

Study description: TOP is an ongoing open-label, multinational, observational, 10-year prospective study assessing the long-term safety and efficacy of TYSABRI in 4821 patients with relapsing MS.a


  • The study is ongoing and observational, without randomization or a placebo control group
  • Of the 4821 patients enrolled, 1222 discontinued TYSABRI treatment and 740 withdrew from TOP; 523 patients discontinued TYSABRI and withdrew from study follow-up


Interim safety findings were consistent with previous studies of TYSABRI, and no new safety concerns were identified in a clinical practice setting for up to 5 years


  • 18/4821 patients diagnosed with PML after a median of 29 TYSABRI infusions (range 11-44)
    • 16 patients were alive at the time of analysis (December 2012)
    • 4 patients previously used immunosuppressants
    • 13 patients had received ≥1 DMT prior to TYSABRI
    • 14 patients had received TYSABRI for ≥2 years
    • 7 patients were confirmed JCV-positive ≥6 months (6-15 months) prior to PML development (serostatus ≥6 months prior to PML development was unknown or not reported for 11 patients)
  • In patients who are anti-JCV negative, prior immunosuppressant use and treatment duration do not affect PML risk, estimated at 0.1 cases per 1000 patients, as long as JCV status does not change
    • Direct comparison of risk estimates for these patients from the AFFIRM trial cannot be made with those derived from TOP data as anti-JCV antibody serostatus data were not collected throughout the protocol period
    • A recent protocol amendment has been approved to collect this information


EDSS scores of patients on TYSABRI remained stable over time, suggesting a delay in disability progression

  • 84% cumulative probability of no confirmed EDSS progression was observed at 5 years with TYSABRIe

Early use of TYSABRI showed a significant reduction in ARR for up to 5 years

Data demonstrate the benefits of transitioning to TYSABRI earlier in the disease course

  • Patients experienced lower ARR when TYSABRI was used:
    • At lower baseline EDSS scores (<3.0)
    • At lower pre-TYSABRI relapse rates (≤1 relapse in prior year)
    • Earlier in the treatment course (for treatment-naïve patients and those who are transitioning therapy)

TYSABRI also benefited patients when initiated later in the disease course

  • Patients with high EDSS scores (≥3.0), a higher number of relapses (>1 in prior year), and/or prior use of DMTs (>1) achieved significant reductions in clinical disease activity, as defined by ARR


TYSABRI® (natalizumab) is indicated as monotherapy for the treatment of patients with relapsing forms of multiple sclerosis. TYSABRI increases the risk of PML. When initiating and continuing treatment with TYSABRI, physicians should consider whether the expected benefit of TYSABRI is sufficient to offset this risk. See Important Safety Information regarding the risk of PML with TYSABRI.


WARNING: Progressive Multifocal Leukoencephalopathy (PML)

TYSABRI® (natalizumab) increases the risk of PML, an opportunistic viral infection of the brain that usually leads to death or severe disability. Risk factors for the development of PML include duration of therapy, prior use of immunosuppressants, and presence of anti-JCV antibodies. These factors should be considered in the context of expected benefit when initiating and continuing treatment with TYSABRI.

Healthcare professionals should monitor patients on TYSABRI for any new sign or symptom that may be suggestive of PML. TYSABRI dosing should be withheld immediately at the first sign or symptom suggestive of PML. For diagnosis, an evaluation including a gadolinium-enhanced MRI scan of the brain and, when indicated, cerebrospinal fluid analysis for JC viral DNA are recommended.

Because of the risk of PML, TYSABRI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the TOUCH Prescribing Program.

  • Infection by the JC Virus (JCV) is required for the development of PML.
  • There are no known interventions that can reliably prevent PML or that can adequately treat PML if it occurs.
  • Postmarketing data 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).
  • MRI findings may be apparent before clinical signs or symptoms suggestive of PML. 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. Consider monitoring patients at high risk for PML more frequently. Lower PML-related mortality and morbidity have been reported following TYSABRI discontinuation in patients with PML who were initially asymptomatic compared to patients with PML who had characteristic clinical signs and symptoms at diagnosis.
  • PML has been reported after discontinuation of TYSABRI in patients who did not have findings suggestive of PML at the time of discontinuation. Patients should continue to be monitored for any new signs or symptoms that may be suggestive of PML for approximately 6 months after discontinuation of TYSABRI.
  • Adverse events that may occur during plasma exchange include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although plasma exchange has not been studied in TYSABRI-treated patients with PML, it has been used in such patients in the postmarketing setting to remove TYSABRI more quickly from the circulation.
  • JCV infection of granule cell neurons in the cerebellum, i.e., JCV granule cell neuronopathy (GCN), with symptoms similar to PML, has been reported in patients treated with TYSABRI. JCV GCN can occur with or without concomitant PML and can cause cerebellar dysfunction. Diagnosis and management of JCV GCN should follow guidance provided for PML.
  • Immune reconstitution inflammatory syndrome (IRIS) has been reported in the majority of TYSABRI-treated patients who developed PML and subsequently discontinued TYSABRI. In almost all cases, IRIS occurred after plasma exchange was used to eliminate circulating TYSABRI. It presents as a clinical decline in the patient’s condition after TYSABRI removal (and, in some cases, after apparent clinical improvement) that may be rapid, can lead to serious neurological complications or death, and is often associated with characteristic changes in the MRI. TYSABRI has not been associated with IRIS in patients discontinuing treatment with TYSABRI for reasons unrelated to PML. In TYSABRI-treated patients with PML, IRIS has been reported within days to several weeks after plasma exchange. Monitoring for development of IRIS and appropriate treatment of the associated inflammation should be undertaken.


  • TYSABRI is contraindicated in patients who have or have had PML.
  • TYSABRI is contraindicated in patients who have had a hypersensitivity reaction to TYSABRI.

TYSABRI TOUCH Prescribing Program

  • Because of the risk of PML, TYSABRI is available only through a restricted distribution program under a REMS called the TOUCH® Prescribing Program.
  • Patients must be enrolled in the TOUCH Prescribing Program, read the Medication Guide, understand the risks associated with TYSABRI and complete and sign the Patient-Prescriber Enrollment Form.

Herpes Infections – Encephalitis, Meningitis and Acute Retinal Necrosis

  • TYSABRI increases the risk of developing encephalitis and meningitis caused by herpes simplex and varicella zoster viruses.
  • Serious, life-threatening, and sometimes fatal cases have been reported in the postmarketing setting in multiple sclerosis patients receiving TYSABRI.
  • The duration of treatment with TYSABRI prior to onset ranged from a few months to several years.
  • Monitor patients receiving TYSABRI for signs and symptoms of meningitis and encephalitis. If herpes encephalitis or meningitis occurs, TYSABRI should be discontinued, and appropriate treatment for herpes encephalitis/meningitis should be administered.
  • Patients being administered TYSABRI are at a higher risk of acute retinal necrosis (ARN), a fulminant viral infection of the retina caused by the family of herpes viruses. Patients with eye symptoms such as decreased visual acuity, redness or eye pain should be referred for retinal screening as serious cases of ARN can lead to blindness of one or both eyes.
  • Following clinical diagnosis of ARN, consider discontinuation of TYSABRI.


  • Clinically significant liver injury, including acute liver failure requiring transplant, has been reported in patients treated with TYSABRI in the postmarketing setting.
  • Signs of liver injury, including markedly elevated serum hepatic enzymes and elevated total bilirubin, occurred as early as six days after the first dose; signs of liver injury have also been reported for the first time after multiple doses.
  • TYSABRI should be discontinued in patients with jaundice or other evidence of significant liver injury (e.g., laboratory evidence).

Hypersensitivity/Antibody Formation

  • Hypersensitivity reactions have occurred in patients receiving TYSABRI, including serious systemic reactions (e.g., anaphylaxis) which occurred at an incidence of <1%.
  • Reactions usually occur within 2 hours of the start of the infusion. Symptoms associated with these reactions can include urticaria, dizziness, fever, rash, rigors, pruritus, nausea, flushing, hypotension, dyspnea, and chest pain.
  • If a hypersensitivity reaction occurs, discontinue administration of TYSABRI and initiate appropriate therapy. Patients who experience a hypersensitivity reaction should not be re-treated with TYSABRI.
  • Hypersensitivity reactions were more frequent in patients with antibodies to TYSABRI compared with patients who did not develop antibodies to TYSABRI in both MS and CD studies.
  • Patients who receive TYSABRI for a short exposure (1 to 2 infusions) followed by an extended period without treatment are at higher risk of developing anti-natalizumab antibodies and/or hypersensitivity reactions on re-exposure, compared to patients who received regularly scheduled treatment.


  • The immune system effects of TYSABRI may increase the risk for infections.
  • In Study MS1, certain types of infections—including pneumonias and urinary tract infections (including serious cases), gastroenteritis, vaginal infections, tooth infections, tonsillitis, and herpes infections—occurred more often in TYSABRI-treated patients than in placebo-treated patients. One opportunistic infection, a cryptosporidial gastroenteritis with a prolonged course, was observed in a patient who received TYSABRI in Study MS1.
  • In Studies MS1 and MS2, an increase in infections was seen in patients concurrently receiving short courses of corticosteroids. However, the increase in infections in TYSABRI-treated patients who received steroids was similar to the increase in placebo-treated patients who received steroids.
  • In a long-term safety study of patients, opportunistic infections (pulmonary mycobacterium avium intracellulare, aspergilloma, cryptococcal fungemia and meningitis, and Candida pneumonia) have been observed in <1% of TYSABRI-treated patients.
  • Concurrent use of antineoplastic, immunosuppressant, or immunomodulating agents may further increase the risk of infections over the risk observed with use of TYSABRI alone.
  • In Studies MS1 and MS2, the rate of any type of infection was approximately 1.5 per patient-year in both TYSABRI-treated patients and placebo-treated patients.
  • In Study MS1, the incidence of serious infections was approximately 3% in TYSABRI-treated patients and in placebo-treated patients. Most patients did not interrupt treatment with TYSABRI during infections.

Laboratory Test Abnormalities

  • In clinical trials, TYSABRI was observed to induce increases in circulating lymphocytes, monocytes, eosinophils, basophils, and nucleated red blood cells. Observed changes persisted during TYSABRI exposure, but were reversible, returning to baseline levels usually within 16 weeks after the last dose. Elevations of neutrophils were not observed. TYSABRI induces mild decreases in hemoglobin levels (mean decrease of 0.6 g/dL) that are frequently transient.

Adverse Reactions

  • The most common adverse reactions reported at an incidence of ≥10% with TYSABRI and ≥2% difference with placebo were headache (38% vs 33%), fatigue (27% vs 21%), infusion reactions (24% vs 18%), urinary tract infections (21% vs 17%), arthralgia (19% vs 14%), depression (19% vs 16%), pain in extremity (16% vs 14%), rash (12% vs 9%), gastroenteritis (11% vs 9%), and vaginitis (10% vs 6%).
  • The most frequently reported serious adverse reactions in Study MS1 were infections (3.2% vs 2.6% placebo), including urinary tract infection (0.8% vs 0.3%) and pneumonia (0.6% vs 0%), acute hypersensitivity reactions (1.1% vs 0.3%, including anaphylaxis/anaphylactoid reaction [0.8% vs 0%]), depression (1.0% vs 1.0%, including suicidal ideation or attempt [0.6% vs 0.3%]), and cholelithiasis (1.0% vs 0.3%).
  • Based on animal data, TYSABRI may cause fetal harm. TYSABRI should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Please see full Prescribing Information, including Boxed Warning.

ARR = annualized relapse rate; DMT = disease-modifying therapy; EDSS = Expanded Disability Status Scale.

aEligible patients met criteria for a TYSABRI prescription in their respective countries and had 3 or fewer TYSABRI infusions before enrollment in the TOP study.
bMedDRA lower-level term (LLT).
cFor incidence calculation, a patient is counted once per LLT.
d12 of the 97 serious infections were opportunistic, which included 2 herpes zoster, 2 herpes meningitides, and 2 pneumonia infections as well as 1 each of urinary tract infection, pyelonephritis, streptococcal meningitis, staphylococcal sepsis, encephalitis, and Mycobacterium kansasii infection.
eConfirmed EDSS progression was defined as an increase of ≥1.0 point in EDSS score sustained for 6 months.
fError bars indicate 95% confidence intervals.
gClinical relapse was defined as new or recurrent neurologic symptoms, not associated with fever, lasting for 24 hours or more, followed by a 30-day period of stability or improvement. Data beyond 5 years were excluded.
hP values are from a negative binomial regression model adjusted for sex, baseline EDSS score (<3.0 vs ≥3.0), relapse status in the past year (≤1 vs >1), prior DMT use (0, 1, and >1), disease duration (<8 vs ≥8 years), and treatment duration (<3 vs ≥3 years).

Reference: 1. Butzkueven H, Kappos L, Pellegrini F, et al; TYSABRI Observational Program (TOP) Investigators. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry. 2014;85(11):1190-1197.