Tysabri

Natalizumab

THERAPY

Protocols

Before Initiation of Therapy :

Monitoring During Therapy :

Discontinue Therapy :

Product Monograph

Specific Concerns

Averse Events :

Progressive Multifocal Leukoencephalopathy (PML) :

JCV CNS infection can occur subsequent to immunosuppression by several different medications ( dimethyl fumarate, ocrelizumab, fingolimod, rituximab, ofatumumab, cladribine, ibrutinib, alemtuzumab) used in MS but the incidence is highest with Tysabri. The global incidence of Tysabri associated PML appears to have plateaued in 2016 at 4/1000 and appears to be diminishing since. The later is attributed to the introduction of risk minimizing strategies such as the recognition of risk factors; JCV index, prior use of immunosuppressant and duration of Tysabri use beyond 2 years. JCV index of 0.9 or less is associated with a risk of less than 1/1000 while an index greater than 1.5 is associated with a risk of 11/1000 and JCV negative of 0.01/1000. The duration of Tysabri use beyond two years is associated with a progressive increase in the risk of PML. It is of note that for patients who become JCV+ while receiving Tysabri the clock begins at the time of seroconversion highlighting the need to monitor JCV serology in patients who are JCV negative or have low titers below 0.9. The implementation of these strategies have led to documented significant reduction in the national incidence of PML in countries where there are registries of MS patients such as France and Sweden.

More recently the reduction of Tysabri dosage by extending the interval between doses to 6 weeks has also shown multifold reduction in the risk of Tysabri associated PML. The impact of such strategies has yet to be documented in global or nation wide studies. Extended interval dosing (EID) however may be associated with a loss of clinical efficacy in some patients as documented in the Nova study. Greater clinical and MRI monitoring are recommended when introducing EID in Tysabri patients.

JCV CNS infection clinical manifestations have evolved to now include the classic PML, cerebellar granule cell neuronopathy, acute encephalopathy and meningitis. Management approach of Tysabri associated PML and its associated IRIS are discussed in the Common Concern section of the website.