INDICATION

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.

In relapsing MS, prompt decision-making early in the disease course and throughout treatment may affect patient outcomes1-4

There may be a therapeutic window of opportunity in optimizing treatment9-12

  • The volume and the accumulation of T2 lesions over 2 years were significantly correlated with future physical disability13
  • Brain lesions at baseline were predictive of physical disability status after 10 years14

MRI can help detect subclinical disease1,15,16,a

  • After 1 year of treatment15,16:
    • Relapse-free patients continued to show active disease on MRI and significant risk of worsening physical function
    • Risk of disease progression has been shown to rise as lesion load and relapse rate increase

Monitor for an inadequate response after the first 6 to 12 months of therapy. An inadequate response can be defined by a combination of parameters, which may include15,17,18:

MRI ACTIVITY

  • Ongoing disease activity detected by MRI15,19
  • ≥1 Gd+ lesion or new or enlarging T2-hyperintense lesion within 1 year15,17

LEVEL OF PHYSICAL DISABILITY

  • An increase in EDSS score on new therapy9,17
  • ≥1-point EDSS score increase at 6 months20

RELAPSE FREQUENCY

  • ≥1 relapse after treatment initiation15,19

Proportion of patients on first-line therapies with an inadequate response can vary based on criteria used. Some studies prior to 2010 show that up to two-thirds of patients may exhibit an inadequate response after relapsing MS treatment initiation.9,17,21

Indication

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.

IMPORTANT SAFETY INFORMATION

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.

Contraindications

  • 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.

Hepatotoxicity

  • 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.

Immunosuppression/Infections

  • 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.

References: 1. TYSABRI Prescribing Information, Cambridge, MA: Biogen. 2. Polman CH, O'Connor PW, Havrdova E, et al; the AFFIRM Investigators. A randomized, placebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med. 2006;354(9):899-910.


aPlatform therapies include interferon-beta (IFNβ) and glatiramer acetate (GA).

References: 1. Trapp BD, Ransohoff RM, Fisher E, Rudick RA. Neurodegeneration in multiple sclerosis: relationship to neurological disability. Neuroscientist. 1999;5(1):48-57. 2. Jeffery DR. Early intervention with immunomodulatory agents in the treatment of multiple sclerosis. J Neurol Sci. 2002;197(1-2):1-8. 3. Lizak N, Lugaresi A, Alroughani R, et al; MSBase Study Group. Highly active immunomodulatory therapy ameliorates accumulation of disability in moderately advanced and advanced multiple sclerosis. J Neurol Neurosurg Psychiatry. 2017;88(3):196-203. 4. Comi G. Early treatment. Neurol Sci. 2006;27(suppl 1):S8-S12. 5. Filippi M, Horsfield MA, Morrissey SP, et al. Quantitative brain MRI lesion load predicts the course of clinically isolated syndromes suggestive of multiple sclerosis. Neurology. 1994;44(4):635-641. 6. Comi G. Shifting the paradigm toward earlier treatment of multiple sclerosis with interferon beta. Clin Ther. 2009;31(6):1142-1157. 7. Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502-1517. 8. Fisniku LK, Brex PA, Altmann DR, et al. Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain. 2008:131(pt 3):808-817. 9. Hutchinson M. Predicting and preventing the future: actively managing multiple sclerosis. Pract Neurol. 2009;9(3):133-143. 10. Leray E, Yaouanq J, Le Page E, et al. Evidence of two-stage disability progression in multiple sclerosis. Brain. 2010;133(pt 7):1900-1913. 11. Giovannoni G, Butzkueven H, Djib-Jalbut S, et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016;9(suppl 1):S5-S48. 12. Comi G, Radaelli M, Soelberg Sørensen P. Evolving concepts in the treatment of relapsing multiple sclerosis. Lancet. 2017;389(10076):1347-1356. 13. Rudick RA, Lee JC, Simon J, Fisher E. Significance of T2 lesions in multiple sclerosis: a 13-year longitudinal study. Ann Neurol. 2006;60(2):236-242. 14. Giorgio A, Stromillo ML, Bartolozzi ML, et al. Relevance of hypointense brain MRI lesions for long-term worsening of clinical disability in relapsing multiple sclerosis. Mult Scler. 2014;20(2):214-219. 15. Prosperini L, Gallo V, Petsas N, Borriello G, Pozzilli C. One-year MRI scan predicts clinical response to interferon beta in multiple sclerosis. Eur J Neurol. 2009;16(11):1202-1209. 16. Sormani MP, Gasperini C, Romeo M, et al; MAGNIMS study group. Assessing response to interferon-β in a multicenter dataset of patients with MS. Neurology. 2016:87(2):134-140. 17. Rudick RA, Polman CH. Current approaches to the identification and management of breakthrough disease in patients with multiple sclerosis. Lancet Neurol. 2009;8(6):545-559. 18. Freedman MS, Patry DG, Grand’Maison F, Myles ML, Paty DW, Selchen DH; Canadian MS Working Group. Treatment optimization in multiple sclerosis. Can J Neurol Sci. 2004;31(2):157-168. 19. Coyle PK, Foley JF, Fox EJ, Jeffery DR, Munschauer FE, Tornatore C. Best practice recommendations for the selection and management of patients with multiple sclerosis receiving natalizumab therapy. Mult Scler. 2009;15(suppl 4):S26-S36. 20. Río J, Nos C, Tintoré M, et al. Assessment of different treatment failure criteria in a cohort of relapsing-remitting multiple sclerosis patients treated with interferon β: implications for clinical trials. Ann Neurol. 2002;52(4):400-406. 21. Coyle PK. Switching algorithms: from one immunomodulatory agent to another. J Neurol. 2008;255(suppl 1):44-50.