TYRUKO Concentrate for solution for infusion Ref.[51265] Active ingredients: Natalizumab

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered product should be clearly recorded.

Progressive Multifocal Leukoencephalopathy (PML)

Use of natalizumab 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 natalizumab. 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.
• 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 natalizumab 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 natalizumab (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). For further information, refer to the Physician Information and Management Guidelines.

Patients considered at high risk treatment with this treatment should only be continued if the benefits outweigh the risks. For the estimation of PML risk in the different patient subgroups, please refer to the Physician Information and Management Guidelines.

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 antiJCV 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).

Testing for serum anti-JCV antibody should be performed using a CE-marked IVD with the corresponding intended purpose. If the CE-marked IVD is not available, testing for serum anti-JCV antibody should be performed using an alternative validated test.

For further information on anti-JCV antibody testing please see Physician Information and Management Guidelines.

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 with this medicinal product and without prior history of immunosuppressant therapy.

Current evidence suggests that the risk of PML is low at low index values and increases substantially at high index values for patients who have been on treatment with natalizumab for longer than 2 years. Index threshold values for low/high PML risk depend on the specific anti-JCV antibody test used (see the Physician Information and Management Guidelines for further information).

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 Tyruko 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.

Physicians should refer to the Physician Information and Management Guidelines for further information on managing the risk of PML in natalizumab-treated patients.

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 as described in the Physician Information and Management Guidelines (see Educational guidance). 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 natalizumab 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 Tyruko.

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. For other considerations on the management of PML, see the Physician Information and Management Guidelines.

PML and IRIS (Immune Reconstitution Inflammatory Syndrome)

IRIS occurs in almost all PML patients treated with natalizumab 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 (see the Physician Information and Management Guidelines for further information).

Infections including other opportunistic infections

Other opportunistic infections have been reported with use of natalizumab, 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 natalizumab 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 post-marketing 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 natalizumab 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 natalizumabtreated 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

All physicians who intend to prescribe the medicinal product must ensure they are familiar with the Physician Information and Management Guidelines.

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 natalizumab, 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 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 natalizumab 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.

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 natalizumab and an increased incidence of hypersensitivity reactions (see section 4.8).

Since patients who have received an initial short exposure to natalizumab 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.

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.

Natalizumab is contraindicated in combination with other DMTs (see section 4.3).

Immunisations

In a randomised, open label study of 60 patients with relapsing MS there was no significant difference in the humoral immune response to a recall antigen (tetanus toxoid) and only slightly slower and reduced humoral immune response to a neoantigen (keyhole limpet haemocyanin) was observed in patients who were treated with natalizumab for 6 months compared to an untreated control group. Live vaccines have not been studied.

Women of childbearing potential

If a woman becomes pregnant while taking this medicinal product, discontinuation should be considered. A benefit/risk evaluation of the use of this medicinal product during pregnancy should take into account the patient’s clinical condition and the possible return of disease activity after stopping the medicinal product.

Pregnancy

Studies in animals have shown reproductive toxicity (see section 5.3).

Data from clinical trials, a prospective pregnancy registry, post-marketing cases and available literature do not suggest an effect of natalizumab exposure on pregnancy outcomes.

The completed prospective natalizumab pregnancy registry contained 355 pregnancies with available outcomes. There were 316 live births, 29 of which were reported to have birth defects. Sixteen of the 29 were classified as major defects. The rate of defects corresponds to the defect rates reported in other pregnancy registries involving MS patients. There is no evidence of a specific pattern of birth defects with natalizumab.

There are no adequate and well-controlled studies of natalizumab therapy in pregnant women.

Thrombocytopenia and anaemia in infants born to women exposed to natalizumab during pregnancy were reported in the post-marketing setting. Monitoring of platelet counts and haemoglobin is recommended in neonates born to women exposed to natalizumab during pregnancy.

This medicinal product should be used during pregnancy only if clearly needed. If a woman becomes pregnant while taking natalizumab, discontinuation of natalizumab should be considered.

Breast-feeding

Natalizumab is excreted in human milk. The effect of natalizumab on newborns/infants is unknown. Breast-feeding should be discontinued during treatment with natalizumab.

Fertility

Reductions in female guinea pig fertility were observed in one study at doses in excess of the human dose; natalizumab did not affect male fertility. It is considered unlikely that natalizumab will affect fertility performance in humans following the maximum recommended dose.

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

Summary of the safety profile

In placebo-controlled trials in 1 617 MS patients treated with natalizumab for up to 2 years (placebo: 1 135), adverse events leading to discontinuation of therapy occurred in 5.8% of patients treated with natalizumab (placebo: 4.8%). Over the 2-year duration of the studies, 43.5% of patients treated with natalizumab reported adverse reactions (placebo: 39.6%).

In clinical trials in 6 786 patients treated with natalizumab (intravenous infusion and subcutaneous injection), the most frequently occurring adverse reactions were headache (32%), nasopharyngitis (27%), fatigue (23%), urinary tract infection (16%), nausea (15%), arthralgia (14%), and dizziness (11%) associated with natalizumab administration.

Tabulated list of adverse reactions

Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneous reports are presented in Table 1, below. Within the system organ classes they are listed under the following headings: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000), not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1. Adverse reactions:

Description of selected adverse reactions

Infusion-related reactions (IRR)

In 2-year controlled clinical trials in MS patients, an infusion-related event was defined as an adverse event occurring during the infusion or within 1 hour of the completion of the infusion. These occurred in 23.1% of MS patients treated with natalizumab (placebo: 18.7%). Events reported more commonly with natalizumab than with placebo included dizziness, nausea, urticaria and rigors.

Hypersensitivity reactions

In 2-year controlled clinical trials in MS patients, hypersensitivity reactions occurred in up to 4% of patients. Anaphylactic/anaphylactoid reactions occurred in less than 1% of patients receiving natalizumab. Hypersensitivity reactions usually occurred during the infusion or within the 1-hour period after the completion of the infusion (see section 4.4). In post-marketing experience, there have been reports of hypersensitivity reactions which have occurred with one or more of the following associated symptoms: hypotension, hypertension, chest pain, chest discomfort, dyspnoea, angioedema, in addition to more usual symptoms such as rash and urticaria.

Immunogenicity

Anti-natalizumab antibodies may develop during natalizumab treatment. Persistent antibodies were associated with a substantial decrease in the effectiveness of natalizumab and an increased incidence of hypersensitivity reactions. Additional infusion-related reactions associated with persistent antibodies included rigors, nausea, vomiting and flushing (see section 4.4).

If, after approximately 6 months of therapy, persistent antibodies are suspected, either due to reduced efficacy or due to occurrence of infusion-related events, they may be detected and confirmed with a subsequent test 6 weeks after the first positive test. Given that efficacy may be reduced or the incidence of hypersensitivity or infusion-related reactions may be increased in a patient with persistent antibodies, treatment should be discontinued in patients who develop persistent antibodies.

Infections, including PML and opportunistic infections

In 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per patient-year in both natalizumab- and placebo-treated patients. The nature of the infections was generally similar in natalizumab- and placebo-treated patients. A case of cryptosporidium diarrhoea was reported in MS clinical trials. In other clinical trials, cases of additional opportunistic infections have been reported, some of which were fatal. The majority of patients did not interrupt natalizumab therapy during infections and recovery occurred with appropriate treatment.

In clinical trials, herpes infections (Varicella-Zoster virus, Herpes-simplex virus) occurred slightly more frequently in natalizumab-treated patients than in placebo-treated patients. In post-marketing experience, serious, life-threatening, and sometimes fatal cases of encephalitis and meningitis caused by herpes simplex or varicella zoster have been reported in multiple sclerosis patients receiving natalizumab. The duration of treatment with natalizumab prior to onset ranged from a few months to several years (see section 4.4).

In post-marketing experience, rare cases of ARN have been observed in patients receiving natalizumab. Some cases have occurred in patients with central nervous system (CNS) herpes infections (e.g. herpes meningitis and encephalitis). Serious cases of ARN, either affecting one or both eyes, led to blindness in some patients. The treatment reported in these cases included anti-viral therapy and in some cases, surgery (see section 4.4).

Cases of PML have been reported from clinical trials, post-marketing observational studies and postmarketing passive surveillance. PML usually leads to severe disability or death (see section 4.4). Cases of JCV GCN have also been reported during post-marketing use of natalizumab. Symptoms of JCV GCN are similar to PML.

Hepatic events

Spontaneous cases of serious liver injuries, increased liver enzymes, hyperbilirubinaemia have been reported during the post-marketing phase (see section 4.4).

Anaemia and haemolytic anaemia

Rare, serious cases of anaemia and haemolytic anaemia have been reported in patients treated with natalizumab in post-marketing observational studies.

Malignancies

No differences in incidence rates or the nature of malignancies between natalizumab- and placebotreated patients were observed over 2 years of treatment. However, observation over longer treatment periods is required before any effect of natalizumab on malignancies can be excluded (see section 4.3).

Effects on laboratory tests

In 2-year controlled clinical trials in MS patients treatment with natalizumab was associated with increases in circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells. Elevations in neutrophils were not seen. Increases from baseline for lymphocytes, monocytes, eosinophils and basophils ranged from 35% to 140% for individual cell types but mean cell counts remained within normal ranges with IV administration. During treatment with IV form of natalizumab, small reductions in haemoglobin (mean decrease 0.6 g/dL), haematocrit (mean decrease 2%) and red blood cell counts (mean decrease 0.1 × 10⁶/L) were seen. All changes in haematological variables returned to pre-treatment values, usually within 16 weeks of last dose of natalizumab and the changes were not associated with clinical symptoms. In post-marketing experience, there have also been reports of eosinophilia (eosinophil count >1,500/mm³) without clinical symptoms. In such cases where therapy was discontinued the elevated eosinophil levels resolved.

Thrombocytopenia

In post-marketing experience, thrombocytopenia and immune thrombocytopenic purpura (ITP) have been reported with uncommon frequency.

Paediatric population

Serious adverse events were evaluated in 621 MS paediatric patients included in a meta-analysis (see also section 5.1). Within the limitations of these data, there were no new safety signals identified in this patient population. 1 case of herpes meningitis was reported in the meta-analysis. No cases of PML were identified in the meta-analysis, however, PML has been reported in natalizumab-treated paediatric patients in the post-marketing setting.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

No incompatibilities have been observed with polypropylene syringe, with polyvinyl chloride, polyethylene or polypropylene bags, and with polyvinyl chloride or polyurethane infusion lines.