TYSABRI SAFETY: A WELL-UNDERSTOOD PROFILE

A complete benefit-risk assessment of TYSABRI starts by evaluating the 3 known PML risk factors1,a

  • PML is an opportunistic viral infection of the brain caused by the John Cunningham virus (JCV) that usually leads to death or severe disability. JCV infection 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
    • PML is not the only factor to consider when assessing the safety profile of TYSABRI
  • Regular anti-JCV antibody testing may help mitigate risk of PML and help identify patients suitable for starting or continuing on TYSABRI
  • Based on postmarketing data, the estimated US incidence of PML is stratified out to 8 yearsb

aPML risk is inferred from the estimated US incidence. The risk estimates are based on postmarketing data in the United States from approximately 100,000 TYSABRI-exposed patients. The anti-JCV antibody status was determined using an anti-JCV antibody test (ELISA) that has been analytically and clinically validated and is configured with detection and inhibition steps to confirm the presence of JCV-specific antibodies with an analytical false-negative rate of 3%. 

bAs of June 2020. 

Explore the safety profile of TYSABRI in real-world use

Your patients may benefit from the powerful efficacy of TYSABRI, which has a PML risk of 0.01% for JCV– patients and ≤0.7% for JCV+ patients out to 8 years

Regular anti-JCV antibody testing may help mitigate the risk of PML and help identify patients suitable for starting or continuing TYSABRI1

Free and frequent testing supports PML risk mitigation1

  • JCV infection is required for the development of PML
  • Patients taking TYSABRI should be tested regularly to assess whether their status has changed
  • The JCV seroconversion rate from negative to positive in patients with MS is 3–8% annually

Early detection of PML is important1

  • MRI findings may be apparent before clinical signs or symptoms suggestive of PML. Periodic monitoring for radiographic signs consistent with PML should be considered to allow for early diagnosis of PML
    • Consider monitoring patients at high risk of 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. It is not known whether these differences are due to early detection and discontinuation of TYSABRI or due to differences in disease in these patients
Continually evaluate treatment response and disease activity as measured by MRI activity, relapse rate, and EDSS progression2

Typical symptoms associated with PML are diverse, progress over days to weeks, and may include1:

  • Progressive weakness on one side of the body or clumsiness of limbs
  • Disturbances of speech or vision
  • Changes in thinking, memory, and orientation leading to confusion and personality changes

Upon initial suspicion of PML, follow these 4 steps1:

1. Withhold suspected treatment immediately
2. Obtain MRI
3. Obtain cerebrospinal fluid (CSF) and have it tested for JCV DNA
4. Obtain additional tests and patient history

Call Biogen (1-866-633-4636) as soon as possible to report the adverse event.

To make the diagnosis of PML, various MRI evaluations, including gadolinium-enhanced and T2-weighted scans, as well as PCR analysis of CSF for JC viral DNA, are recommended1

There are no known interventions that can reliably prevent or that can adequately treat PML if it occurs.

  • Although PLEX has not been prospectively 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. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML
  • PML has been reported following 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 following discontinuation of TYSABRI

This information is provided as an educational resource for healthcare providers. It is not intended to be a substitute for consultation with your patients and review of reference material and medical literature. Healthcare providers should make all treatment decisions based on the context of the situation and their own clinical judgment.

Explore the safety profile of TYSABRI in real-world use

Learn more about monitoring with TOUCH®

Because of the risk of PML, TYSABRI is available only under a restricted distribution program, the TOUCH Prescribing Program.

Only prescribers, pharmacies, and administration sites enrolled in the TOUCH Prescribing Program (REMS program) are able to prescribe, distribute, or infuse TYSABRI.

Learn More About TOUCH®
NEXT: Adverse Reactions

INDICATION

TYSABRI® (natalizumab) is indicated as monotherapy for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, in adults. 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.

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 the presence of anti-JCV antibodies, duration of therapy, and prior use of immunosuppressants. 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 at least 6 months after discontinuation of TYSABRI
  • Adverse events that may occur during plasma exchange (PLEX) include clearance of other medications and volume shifts, which have the potential to lead to hypotension or pulmonary edema. Although PLEX has not been prospectively 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. There is no evidence that PLEX has any benefit in the treatment of opportunistic infections such as PML
  • 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 PLEX 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 PLEX. 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

Thrombocytopenia

  • Cases of thrombocytopenia, including immune thrombocytopenic purpura (ITP), have been reported with the use of TYSABRI in the postmarketing setting. Symptoms of thrombocytopenia may include easy bruising, abnormal bleeding, and petechiae. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. If thrombocytopenia is suspected, TYSABRI should be discontinued
  • Cases of neonatal thrombocytopenia, at times associated with anemia, have been reported in newborns with in utero exposure to TYSABRI. A CBC should be obtained in neonates with in utero exposure to TYSABRI

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.

PML=progressive multifocal leukoencephalopathy; ELISA=enzyme-linked immunosorbent assay; EDSS=Expanded Disability Status Scale; MRI=magnetic resonance imaging; PCR=polymerase chain reaction; REMS=Risk Evaluation and Mitigation Strategy.

References: 1. TYSABRI Prescribing Information, Cambridge, MA: Biogen. 2. Giovannoni G, Butzkueven H, Dhib-Jalbut S, et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016;9(supp 1):S5-S48.

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