Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use

Progressive Multifocal Leukoencephalopathy (PML)

Use of this medicinal product has been associated with an increased risk of PML, an opportunistic infection caused by JC virus, which may be fatal or result in severe disability. Due to this increased risk of developing PML, the benefits and risks of treatment should be individually reconsidered by the specialist physician and the patient; patients must be monitored at regular intervals throughout and should be instructed together with their caregivers on early signs and symptoms of PML. JC virus also causes JCV granule cell neuronopathy (GCN) which has been reported in patients treated with this medicinal product. Symptoms of JCV GCN are similar to symptoms of PML (i.e. cerebellar syndrome).

The following risk factors are associated with an increased risk of PML: 
• The presence of anti-JCV antibodies.

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• Treatment duration, especially beyond 2 years. After 2 years all patients should be re-informed about the risk of PML with the medicinal product.

• Immunosuppressant use prior to receiving the medicinal product.

Patients who are anti-JCV antibody positive are at an increased risk of developing PML compared to patients who are anti-JCV antibody negative. Patients who have all three risk factors for PML (i.e., are anti-JCV antibody positive and have received more than 2 years of therapy with this medicinal product and have received prior immunosuppressant therapy) have a significantly higher risk of PML.

In anti-JCV antibody positive natalizumab treated patients who have not used prior immunosuppressants the level of anti-JCV antibody response (index) is associated with the level of risk for PML.

In anti-JCV antibody positive patients, extended interval dosing of Tysabri (average dosing interval of approximately 6 weeks) is suggested to be associated with a lower PML risk compared to approved dosing. If utilising extended interval dosing, caution is required because the efficacy of extended interval dosing has not been established and the associated benefit risk balance is currently unknown (see section 5.1, Intravenous administration Q6W).

Patients considered at high risk treatment with this treatment should only be continued if the benefits outweigh the risks.

Anti-JCV antibody testing

Anti-JCV antibody testing provides supportive information for risk stratification of treatment with this medicinal product. Testing for serum anti-JCV antibody prior to initiating therapy or in patients receiving the medicinal product with an unknown antibody status is recommended. Anti-JCV antibody negative patients may still be at risk of PML for reasons such as a new JCV infection, fluctuating antibody status or a false negative test result. Re-testing of anti-JCV antibody negative patients every 6 months is recommended. Retesting low index patients who have no history of prior immunosuppressant use every 6 months once they reach the 2 year treatment point is recommended.

The anti-JCV antibody assay (ELISA) should not be used to diagnose PML. Use of plasmapheresis/plasma exchange (PLEX) or intravenous immunoglobulin (IVIg) can affect meaningful interpretation of serum anti-JCV antibody testing. Patients should not be tested for anti- JCV antibodies within 2 weeks of PLEX due to removal of antibodies from the serum, or within 6 months of IVIg (i.e. 6 months = 5x half-life for immunoglobulins).


MRI screening for PML
Before initiation of treatment with this medicinal product, a recent (usually within 3 months) MRI should be available as a reference, and be repeated at least on a yearly basis. More frequent MRIs (e.g.
on a 3 to 6 monthly basis) using an abbreviated protocol should be considered for patients at higher risk of PML. This includes:

• Patients who have all three risk factors for PML (i.e., are anti-JCV antibody positive and have received more than 2 years of therapy with this medicinal product and have received prior immunosuppressant therapy),
or
• Patients with a high anti-JCV antibody index who have received more than 2 years of therapy 4
with this medicinal product and without prior history of immunosuppressant therapy.

Current evidence suggests that the risk of PML is low at an index equal to or below 0.9 and increases substantially above 1.5 for patients who have been on treatment with this medicinal product for longer than 2 year.

No studies have been performed to evaluate the efficacy and safety of natalizumab when switching patients from DMTs with an immunosuppressant effect. It is unknown if patients switching from these therapies to this treatment have an increased risk of PML, therefore these patients should be monitored more frequently (i.e. similarly to patients switching from immunosuppressants to natalizumab).

PML should be considered as a differential diagnosis in any MS patient taking Tysabri presenting with neurological symptoms and/or new brain lesions in MRI. Cases of asymptomatic PML based on MRI and positive JCV DNA in the cerebrospinal fluid have been reported.

If PML or JCV GCN is suspected, further dosing must be suspended until PML has been excluded.

The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction and, if so, whether these symptoms are typical of MS or possibly suggestive of PML or JCV GCN. If any doubt exists, further evaluation, including MRI scan preferably with contrast (compared with pre-treatment baseline MRI), CSF testing for JC Viral DNA and repeat neurological assessments, should be considered.
Once the clinician has excluded PML and/or JCV GCN (if necessary, by repeating clinical, imaging and/or laboratory investigations if clinical suspicion remains), dosing may resume.

The physician should be particularly alert to symptoms suggestive of PML or JCV GCN that the patient may not notice (e.g. cognitive, psychiatric symptoms or cerebellar syndrome). Patients should also be advised to inform their partner or caregivers about their treatment, since they may notice symptoms that the patient is not aware of.

PML has been reported following discontinuation of this medicinal product in patients who did not have findings suggestive of PML at the time of discontinuation. Patients and physicians should continue to follow the same monitoring protocol and be alert for any new signs or symptoms that may be suggestive of PML for approximately 6 months following discontinuation of TYSABRI.

If a patient develops PML the dosing of natalizumab must be permanently discontinued.

Following reconstitution of the immune system in immunocompromised patients with PML improved outcome has been seen.

Based on a retrospective analysis of natalizumab-treated patients since its approval, no difference was observed on 2-year survival after PML diagnosis between patients who received PLEX and those who did not.

PML and IRIS (Immune Reconstitution Inflammatory Syndrome)

IRIS occurs in almost all PML patients treated with this medicinal product after withdrawal or removal of the medicinal product. IRIS is thought to result from the restoration of immune function in patients with PML, which can lead to serious neurological complications and may be fatal. Monitoring for development of IRIS and appropriate treatment of the associated inflammation during recovery from PML should be undertaken.

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Infections including other opportunistic infections

Other opportunistic infections have been reported with use of this medicinal product, primarily in patients with Crohn’s disease who were immunocompromised or where significant co-morbidity existed, however increased risk of other opportunistic infections with use of the medicinal product in patients without these co-morbidities cannot currently be excluded. Opportunistic infections were also detected in MS patients treated with this medicinal product as a monotherapy (see section 4.8).

This treatment 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 the treatment (see section 4.8). If herpes encephalitis or meningitis occurs, the medicinal product should be discontinued, and appropriate treatment for herpes encephalitis or meningitis should be administered.


Acute retinal necrosis (ARN) is a rare fulminant viral infection of the retina caused by the family of herpes viruses (e.g. varicella zoster). ARN has been observed in patients being administered this medicinal product and can be potentially blinding. Patients presenting with eye symptoms such as decreased visual acuity, redness and painful eye should be referred for retinal screening for ARN.
Following clinical diagnosis of ARN, discontinuation of this medicinal product should be considered in these patients.

Prescribers should be aware of the possibility that other opportunistic infections may occur during therapy and should include them in the differential diagnosis of infections that occur in natalizumab-treated patients. If an opportunistic infection is suspected, dosing is to be suspended until such infections can be excluded through further evaluations.

If a patient receiving this medicinal product develops an opportunistic infection, dosing of the medicinal product must be permanently discontinued.

Educational guidance

Physicians must discuss the benefits and risks of natalizumab therapy with the patient and provide them with a patient alert card. Patients should be instructed that if they develop any infection then they should inform their physician that they are being treated with this medicinal product.

Physicians should counsel patients on the importance of uninterrupted dosing, particularly in the early months of treatment (see hypersensitivity).

Hypersensitivity

Hypersensitivity reactions have been associated with this medicinal product, including serious systemic reactions (see section 4.8). These reactions usually occurred during the infusion or up to 1 hour after completion of the infusion. The risk for hypersensitivity was greatest with early infusions and in patients re-exposed to treatment following an initial short exposure (one or two infusions) and extended period (three months or more) without treatment. However, the risk of hypersensitivity reactions should be considered for every infusion administered.

Patients are to be observed during the infusion and for 1 hour after the completion of the infusion (see section 4.8). Resources for the management of hypersensitivity reactions should be available.

This product should be discontinued and appropriate therapy initiated at the first symptoms or signs of 6
hypersensitivity.

Patients who have experienced a hypersensitivity reaction must be permanently discontinued from treatment with natalizumab.

Concurrent treatment with immunosuppressants

The safety and efficacy of this medicinal product in combination with other immunosuppressive and antineoplastic therapies have not been fully established. Concurrent use of these agents with this medicinal product may increase the risk of infections, including opportunistic infections, and is contraindicated (see section 4.3).

In phase 3 MS clinical trials with natalizumab intravenous infusion concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection. Short courses of corticosteroids can be used in combination with this medicinal product.

Prior treatment with immunosuppressive or immunomodulatory therapies

Patients with a treatment history of immunosuppressant medications are at increased risk for PML. No studies have been performed to evaluate the efficacy and safety of the medicinal product when switching patients from DMTs with an immunosuppressant effect. It is unknown if patients switching from these therapies to this medicinal product have an increased risk of PML, therefore these patients should be monitored more frequently (i.e. similarly to patients switching from immunosuppressants to this medicinal product, see MRI screening for PML).

Care should be taken with patients who have previously received immunosuppressants to allow sufficient time for immune function recovery to occur. Physicians must evaluate each individual case to determine whether there is evidence of an immunocompromised state prior to commencing treatment (see section 4.3).

When switching patients from another DMT to this medicinal product, the half-life and mode of action of the other therapy must be considered in order to avoid an additive immune effect whilst at the same time minimising the risk of disease reactivation. A Complete Blood Count (CBC, including lymphocytes) is recommended prior to initiating treatment to ensure that immune effects of the previous therapy (i.e. cytopenia) have resolved.

Patients can switch directly from beta interferon or glatiramer acetate to natalizumab providing there are no signs of relevant treatment-related abnormalities e.g. neutropenia and, lymphopenia.

When switching from dimethyl fumarate, the washout period should be sufficient for lymphocyte count to recover before treatment is started.

Following discontinuation of fingolimod, lymphocyte count progressively returns to normal range within 1 to 2 months after stopping therapy. The washout period should be sufficient for lymphocyte count to recover before treatment is started.

Teriflunomide is eliminated slowly from the plasma. Without an accelerated elimination procedure, clearance of teriflunomide from plasma can take from several months up to 2 years. An accelerated elimination procedure as defined in the teriflunomide Summary of Product Characteristics is recommended or alternatively washout period should not be shorter than 3.5 months. Caution regarding potential concomitant immune effects is required when switching patients from teriflunomide to this medicinal product.
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Alemtuzumab has profound prolonged immunosuppressive effects. As the actual duration of these effects is unknown, initiating treatment with this medicinal product after alemtuzumab is not recommended unless the benefits clearly outweigh the risks for the individual patient.

Immunogenicity

Disease exacerbations or infusion related events may indicate the development of antibodies against natalizumab. In these cases the presence of antibodies should be evaluated and if these remain positive in a confirmatory test after at least 6 weeks, treatment should be discontinued, as persistent antibodies are associated with a substantial decrease in efficacy of this medicinal product and an increased incidence of hypersensitivity reactions (see section 4.8).

Since patients who have received an initial short exposure to this medicinal product and then had an extended period without treatment are at a higher risk of developing anti-natalizumab antibodies and/or hypersensitivity upon redosing, the presence of antibodies should be evaluated and if these remain positive in a confirmatory test after at least 6 weeks, the patient should not receive further treatment with natalizumab (see section 5.1).

Hepatic events

Spontaneous serious adverse reactions of liver injury have been reported during the post-marketing phase (see section 4.8). These liver injuries may occur at any time during treatment, even after the first dose. In some instances, the reaction reoccurred when treatment was reintroduced. Some patients with a past medical history of an abnormal liver test have experienced an exacerbation of abnormal liver test while on treatment. Patients should be monitored as appropriate for impaired liver function, and be instructed to contact their physician in case signs and symptoms suggestive of liver injury occur, such as jaundice and vomiting. In cases of significant liver injury this medicinal product should be discontinued.

Thrombocytopenia

Thrombocytopenia, including immune thrombocytopenic purpura (ITP), has been reported with the use of natalizumab. Delay in the diagnosis and treatment of thrombocytopenia may lead to serious and life-threatening sequelae. Patients should be instructed to report to their physician immediately if they experience any signs of unusual or prolonged bleeding, petechiae, or spontaneous bruising. If thrombocytopenia is identified, discontinuation of natalizumab should be considered.


Stopping therapy
If a decision is made to stop treatment with natalizumab, the physician needs to be aware that natalizumab remains in the blood, and has pharmacodynamic effects (e.g increased lymphocyte counts) for approximately 12 weeks following the last dose. Starting other therapies during this interval will result in a concomitant exposure to natalizumab. For medicinal products such as interferon and glatiramer acetate, concomitant exposure of this duration was not associated with safety risks in clinical trials. No data are available in MS patients regarding concomitant exposure with immunosuppressant medication. Use of these medicinal products soon after the discontinuation of natalizumab may lead to an additive immunosuppressive effect. This should be carefully considered on a case-by-case basis, and a wash-out period of natalizumab might be appropriate. Short courses of steroids used to treat relapses were not associated with increased infections in clinical trials.
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Sodium content

Before dilution, this medicinal product contains 52 mg sodium per vial of medicinal product, equivalent to 2.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Effects on Driving

4.7       Effects on ability to drive and use machines

Tysabri has a minor influence on the ability to drive and use machines. Dizziness may occur following administration of this medicinal product (see section 4.8).