THERAPY
Tysabri
Coverage
Protocols
Before Initiation of Therapy :
- CBC, creatinine, TSH, AST, ALT, LDH, alkaline phosphatase, bilirubin, HIV, VZV and measles serology, HepBsAg, HepBcAb, HepBsAb, HepC Ab, JCV index, CD4+, CD8+
- Pregnancy test
- Chest Xray and/or Quantiferon
- Immunization should be brought up to date and vaccination for Pneumococcus and Haemophilus Influenza type B and VZV should be done
- Brain MRI unless recently (<3 months) done
- When switching from Gilenya (fingolimod) a less than 2 month washout period is recommended
- When switching from Aubagio, cholestyramine 8 gms Q8H PO X 11 days or until serum levels are less than 0.02mg/L is recommended
- Live vaccines are contraindicated from 6 weeks prior to the first treatment, during and up to 2 weeks after stopping Tysabri
Monitoring During Therapy :
- Anti natalizumab antibody level after the 6th infusion and upon resuming tysabri after a prolonged absence such as pregnancy or anytime a patient develops serious infusion reactions or return of baseline disease activity
- CBC, liver enzymes is done Q1month for the first 7 months then Q4 months
- JCV index if negative or less than 1 .0 is repeated Q4months
- JCV index if >1.5 or becomes >1.5 once to confirmed does not need to be repeated
- Unenhanced cerebral MRI at 12 months and subsequently every 12 months if JCV index < 1 .0 or Q4-6 months if JCV index is > 0.9.
- An LP should be done for JCV PCR in CSF when; there is a new definite T2 MRI lesion and/or new progressive neurological symptoms ie progressive ataxia or cognitive deterioration or hemiparesis or aphasia or a de novo seizure.
- Tysabri should be delayed or suspended in patients with; active infection, suspected PML, elevated liver enzymes
Discontinue Therapy :
- MS baseline disease activity returns in the 3rd or 4th month after stopping Tysabri. Some patients however may experience a relpase that is more severe than their normal suggestive of a rebound. A switch to a new therapy should therefore be instituted prior to the 3rd month after stopping Tysabri.
- In patients that are JCV positive a recent cerebral MRI and an LP for JCV PCR in CSF should be done prior to switching to another therapy.
- Tysabri should be discontinued in patients with persisting neutralizing antibodies; anaphylactoid infusion reaction, hypersensitivity reaction, severe Tysabri related adverse events: polyarthragia, autoimmune hepatitis, hemolytic anemia, PML, CMV uveitis, disseminated Zoster;
Studies
Product Monograph
Specific Concerns
Averse Events :
- Infusion related reactions occurred in 23% of study patients but less than 1% were serious. Most can be controlled with premedication such as Benadryl and or prednisone.
- Hepatic injury has been reported in post marketing surveillance and appears to be reversible once Tysabri is stopped.
- Mild thrombocytopenia can occur.
- Serious infections with herpes simplex and varicella zoster virus meningitis, encephalitis or acute retinal necrosis have been reported in post marketing.
- Neutralizing antibody occurs in 6%. These usually occur by week 12 but can occur later and should be suspected in all patients with serious infusion reactions. They tend to be more common in patients who resume Tysabri therapy after a prolonged interruption ie pregnancy.
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.