TYRUKO 300mg 20mg / ml perfusive solution concentrate medication leaflet

Tyruko 300 mg concentrate for solution for infusion

Each mL of concentrate contains 20 mg of natalizumab.

When diluted (see section 6.6), the solution for infusion contains approximately 2.6 mg per mL ofnatalizumab.

Natalizumab is a recombinant humanised anti-α4-integrin antibody produced in a Chinese Hamster

Ovary (CHO) cell line by recombinant DNA technology.

Each vial contains 2.3 mmol (or 52 mg) sodium (see section 4.4 for further information).

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion (sterile concentrate)

Colourless, clear to slightly opalescent solution.

Tyruko is indicated as single disease modifying therapy in adults with highly active relapsingremitting multiple sclerosis (RRMS) for the following patient groups:

* Patients with highly active disease despite a full and adequate course of treatment with at leastone disease modifying therapy (DMT) (for exceptions and information about washout periodssee sections 4.4 and 5.1)or

* Patients with rapidly evolving severe RRMS defined by 2 or more disabling relapses in oneyear, and with 1 or more Gadolinium enhancing lesions on brain Magnetic Resonance Imaging(MRI) or a significant increase in T2 lesion load as compared to a previous recent MRI.

Therapy is to be initiated and continuously supervised by specialised physicians experienced in thediagnosis and treatment of neurological conditions, in centres with timely access to MRI.

Patients treated with this medicinal product must be given the patient alert card and be informed aboutthe risks of the medicinal product (see also package leaflet). After 2 years of treatment, patients shouldbe re-informed about the risks, especially the increased risk of Progressive Multifocal

Leukoencephalopathy (PML), and should be instructed together with their caregivers on early signsand symptoms of PML.

Resources for the management of hypersensitivity reactions and access to MRI should be available.

Some patients may have been exposed to immunosuppressive medicinal products (e.g. mitoxantrone,cyclophosphamide, azathioprine). These medicinal products have the potential to cause prolongedimmunosuppression, even after dosing is discontinued. Therefore the physician must confirm that suchpatients are not immunocompromised before starting treatment (see section 4.4).

Tyruko 300 mg is administered by intravenous infusion once every 4 weeks.

Continued therapy must be carefully reconsidered in patients who show no evidence of therapeuticbenefit beyond 6 months.

Data on the safety and efficacy of natalizumab at 2 years were generated from controlled, double-blind studies. After 2 years continued therapy should be considered only following a reassessment ofthe potential for benefit and risk. Patients should be re-informed about the risk factors for PML, likeduration of treatment, immunosuppressant use prior to receiving the medicinal product and thepresence of anti-John Cunningham virus (JCV) antibodies (see section 4.4).

The efficacy of re-administration has not been established, (for safety see section 4.4).

This medicinal product is not recommended for use in patients aged over 65 due to a lack of data inthis population.

Studies have not been conducted to examine the effects of renal or hepatic impairment.

The mechanism for elimination and results from population pharmacokinetics suggest that doseadjustment would not be necessary in patients with renal or hepatic impairment.

The safety and efficacy of natalizumab in children and adolescents up to 18 years have not beenestablished. Currently available data are described in sections 4.8 and 5.1 but no recommendation on aposology can be made.

This medicinal product is for intravenous use.

For instructions on dilution of the medicinal product before administration (see section 6.6).

After dilution (see section 6.6), the infusion is to be administered over approximately 1 hour andpatients are to be observed during the infusion and for 1 hour after the completion of the infusion forsigns and symptoms of hypersensitivity reactions.

After the first 12 intravenous doses, patients should continue to be observed during infusion. If thepatients have not experienced any infusion reactions, the post dose observation time may be reducedor removed according to clinical judgement.

Patients restarting natalizumab treatment after a treatment gap ≥ 6 months are to be observed duringthe infusion and for 1 hour after the completion of the infusion for signs and symptoms ofhypersensitivity reactions for the first 12 intravenous infusions after restarting therapy.

Tyruko 300 mg concentrate for solution for infusion must not be administered as a bolus injection.

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Patients with increased risk for opportunistic infections, including immunocompromised patients(including those currently receiving immunosuppressive therapies or those immunocompromised byprior therapies (see sections 4.4 and 4.8)).

Combination with other DMTs.

Known active malignancies, except for patients with cutaneous basal cell carcinoma.

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

Use of natalizumab has been associated with an increased risk of PML, an opportunistic infectioncaused by JC virus, which may be fatal or result in severe disability. Due to this increased risk ofdeveloping PML, the benefits and risks of treatment should be individually reconsidered by thespecialist physician and the patient; patients must be monitored at regular intervals throughout andshould be instructed together with their caregivers on early signs and symptoms of PML. JC virus alsocauses JCV granule cell neuronopathy (GCN) which has been reported in patients treated withnatalizumab. 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-informedabout 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 topatients who are anti-JCV antibody negative. Patients who have all three risk factors for PML (i.e., areanti-JCV antibody positive and have received more than 2 years of therapy with natalizumab andhave received prior immunosuppressant therapy) have a significantly higher risk of PML.

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

In anti-JCV antibody positive patients, extended interval dosing of natalizumab (average dosinginterval of approximately 6 weeks) is suggested to be associated with a lower PML risk compared toapproved dosing. If utilising extended interval dosing, caution is required because the efficacy ofextended interval dosing has not been established and the associated benefit/risk balance is currentlyunknown (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 benefitsoutweigh the risks. For the estimation of PML risk in the different patient subgroups, please refer tothe Physician Information and Management Guidelines.

Anti-JCV antibody testing provides supportive information for risk stratification of treatment with thismedicinal product. Testing for serum anti-JCV antibody prior to initiating therapy or in patientsreceiving the medicinal product with an unknown antibody status is recommended. Anti-JCV antibodynegative patients may still be at risk of PML for reasons such as a new JCV infection, fluctuatingantibody status or a false negative test result. Re-testing of anti-JCV antibody negative patients every6 months is recommended. Retesting low index patients who have no history of priorimmunosuppressant 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 ofplasmapheresis/plasma exchange (PLEX) or intravenous immunoglobulin (IVIg) can affectmeaningful 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 within6 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 thecorresponding intended purpose. If the CE-marked IVD is not available, testing for serum anti-JCVantibody should be performed using an alternative validated test.

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

Management Guidelines.

Before initiation of treatment with this medicinal product, a recent (usually within 3 months) MRIshould 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 higherrisk of PML. This includes:

* Patients who have all three risk factors for PML (i.e., are anti-JCV antibody positive and havereceived more than 2 years of therapy with this medicinal product and have received priorimmunosuppressant therapy),or

* Patients with a high anti-JCV antibody index who have received more than 2 years of therapywith 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 substantiallyat 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 (seethe Physician Information and Management Guidelines for further information).

No studies have been performed to evaluate the efficacy and safety of natalizumab when switchingpatients from DMTs with an immunosuppressant effect. It is unknown if patients switching from thesetherapies to this treatment have an increased risk of PML, therefore these patients should be monitoredmore 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 withneurological symptoms and/or new brain lesions in MRI. Cases of asymptomatic PML based on MRIand positive JCV DNA in the cerebrospinal fluid have been reported.

Physicians should refer to the Physician Information and Management Guidelines for furtherinformation 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 beenexcluded.

The specialised physician should evaluate the patient to determine if the symptoms are indicative ofneurological dysfunction and, if so, whether these symptoms are typical of MS or possibly suggestiveof PML or JCV GCN. If any doubt exists, further evaluation, including MRI scan preferably withcontrast (compared with pre-treatment baseline MRI), CSF testing for JC Viral DNA and repeatneurological 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 clinicalsuspicion remains), dosing may resume.

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

PML has been reported following discontinuation of natalizumab in patients who did not have findingssuggestive of PML at the time of discontinuation. Patients and physicians should continue to followthe 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 improvedoutcome has been seen.

Based on a retrospective analysis of natalizumab-treated patients since its approval, no difference wasobserved on 2-year survival after PML diagnosis between patients who received PLEX and those whodid not. For other considerations on the management of PML, see the Physician Information and

Management Guidelines.

IRIS occurs in almost all PML patients treated with natalizumab after withdrawal or removal of themedicinal 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 fordevelopment of IRIS and appropriate treatment of the associated inflammation during recovery from

PML should be undertaken (see the Physician Information and Management Guidelines for furtherinformation).

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, howeverincreased risk of other opportunistic infections with use of the medicinal product in patients withoutthese co-morbidities cannot currently be excluded. Opportunistic infections were also detected in MSpatients treated with natalizumab as a monotherapy (see section 4.8).

This treatment increases the risk of developing encephalitis and meningitis caused by herpes simplexand varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported inthe post-marketing setting in multiple sclerosis patients receiving the treatment (see section 4.8). Ifherpes encephalitis or meningitis occurs, the medicinal product should be discontinued, andappropriate 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 ofherpes viruses (e.g. varicella zoster). ARN has been observed in patients being administerednatalizumab and can be potentially blinding. Patients presenting with eye symptoms such as decreasedvisual acuity, redness and painful eye should be referred for retinal screening for ARN. Followingclinical diagnosis of ARN, discontinuation of this medicinal product should be considered in thesepatients.

Prescribers should be aware of the possibility that other opportunistic infections may occur duringtherapy 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 suchinfections can be excluded through further evaluations.

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

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 providethem with a patient alert card. Patients should be instructed that if they develop any infection then theyshould 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 earlymonths of treatment (see hypersensitivity).

Hypersensitivity reactions have been associated with natalizumab, including serious systemicreactions (see section 4.8). These reactions usually occurred during the infusion or up to 1 hour aftercompletion of the infusion. The risk for hypersensitivity was greatest with early infusions and inpatients re-exposed to treatment following an initial short exposure (one or two infusions) andextended period (three months or more) without treatment. However, the risk of hypersensitivityreactions 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 (seesection 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 ofhypersensitivity.

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

The safety and efficacy of natalizumab in combination with other immunosuppressive andantineoplastic therapies have not been fully established. Concurrent use of these agents with thismedicinal product may increase the risk of infections, including opportunistic infections, and iscontraindicated (see section 4.3).

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

Patients with a treatment history of immunosuppressant medications are at increased risk for PML. Nostudies have been performed to evaluate the efficacy and safety of the medicinal product whenswitching patients from DMTs with an immunosuppressant effect. It is unknown if patients switchingfrom these therapies to this medicinal product have an increased risk of PML, therefore these patientsshould be monitored more frequently (i.e. similarly to patients switching from immunosuppressants tothis medicinal product, see MRI screening for PML).

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

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

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

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

Following discontinuation of fingolimod, lymphocyte count progressively returns to normal rangewithin 1 to 2 months after stopping therapy. The washout period should be sufficient for lymphocytecount 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 acceleratedelimination procedure as defined in the teriflunomide Summary of Product Characteristics isrecommended or alternatively washout period should not be shorter than 3.5 months. Cautionregarding potential concomitant immune effects is required when switching patients fromteriflunomide to this medicinal product.

Alemtuzumab has profound prolonged immunosuppressive effects. As the actual duration of theseeffects is unknown, initiating treatment with this medicinal product after alemtuzumab is notrecommended unless the benefits clearly outweigh the risks for the individual patient.

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

Since patients who have received an initial short exposure to natalizumab and then had an extendedperiod without treatment are at a higher risk of developing anti-natalizumab antibodies and/orhypersensitivity upon redosing, the presence of antibodies should be evaluated and if these remainpositive in a confirmatory test after at least 6 weeks, the patient should not receive further treatmentwith natalizumab (see section 5.1).

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

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

If a decision is made to stop treatment with natalizumab, the physician needs to be aware thatnatalizumab remains in the blood, and has pharmacodynamic effects (e.g increased lymphocytecounts) for approximately 12 weeks following the last dose. Starting other therapies during thisinterval will result in a concomitant exposure to natalizumab. For medicinal products such asinterferon and glatiramer acetate, concomitant exposure of this duration was not associated with safetyrisks in clinical trials. No data are available in MS patients regarding concomitant exposure withimmunosuppressant medication. Use of these medicinal products soon after the discontinuation ofnatalizumab may lead to an additive immunosuppressive effect. This should be carefully consideredon a case-by-case basis, and a wash-out period of natalizumab might be appropriate. Short courses ofsteroids used to treat relapses were not associated with increased infections in clinical trials.

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).

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

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

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

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

The completed prospective natalizumab pregnancy registry contained 355 pregnancies with availableoutcomes. There were 316 live births, 29 of which were reported to have birth defects. Sixteen of the29 were classified as major defects. The rate of defects corresponds to the defect rates reported inother pregnancy registries involving MS patients. There is no evidence of a specific pattern of birthdefects 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 pregnancywere reported in the post-marketing setting. Monitoring of platelet counts, haemoglobin, andhaematocrit 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 becomespregnant while taking natalizumab, discontinuation of natalizumab should be considered.

Natalizumab is excreted in human milk. The effect of natalizumab on newborns/infants is unknown.

Breast-feeding should be discontinued during treatment with natalizumab.

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

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

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 withnatalizumab (placebo: 4.8%). Over the 2-year duration of the studies, 43.5% of patients treated withnatalizumab reported adverse reactions (placebo: 39.6%).

In clinical trials in 6 786 patients treated with natalizumab (intravenous infusion and subcutaneousinjection), 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.

Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneousreports are presented in Table 1, below. Within the system organ classes they are listed under thefollowing 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 fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

Table 1: Adverse reactions

MedDRA Frequency of adverse reactions

System Organ Very Common Common Uncommon Rare Not known

Class

Infections and Nasopharyngitis Herpes Progressive multifocal Herpes ophthalmic Meningoencephalitisinfestations Urinary tract infection leukoencephalopathy herpeticinfection JC virus granulecell neuropathy

MedDRA Frequency of adverse reactions

System Organ Very Common Common Uncommon Rare Not known

Class

Necrotisingherpetic retinopathy

Blood and Anaemia Thrombocytopenia, Haemolytic anaemialymphatic Immune Nucleated red cellssystem disorders thrombocytopenicpurpura (ITP)

Eosinophilia

Immune system Hypersensitivity Anaphylacticdisorders reaction

Immunereconstitutioninflammatorysyndrome

Nervous system Dizzinessdisorders Headache

Vascular Flushingdisorders

Respiratory, Dyspnoeathoracic andmediastinaldisorders

Gastrointestinal Nausea Vomitingdisorders

Hepatobiliary Hyperbilirubinaemia Liver injurydisorders

Skin and Pruritus Angioedemasubcutaneous Rashtissue disorders Urticaria

Musculoskeletal Arthralgiaand connectivetissue disorders

General Fatigue Pyrexia Face oedemadisorders and Chillsadministration Infusion sitesite conditions reaction

Injection sitereaction

Investigations Hepaticenzymeincreased

Drug specificantibodypresent

Injury, Infusion relatedpoisoning and reactionproceduralcomplications

Infusion-related reactions (IRR)

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

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

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

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

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

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

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

Cases of PML have been reported from clinical trials, post-marketing observational studies and post-marketing 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.

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

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

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

In 2-year controlled clinical trials in MS patients treatment with natalizumab was associated withincreases 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 countsremained 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 redblood cell counts (mean decrease 0.1 x 106/L) were seen. All changes in haematological variablesreturned to pre-treatment values, usually within 16 weeks of last dose of natalizumab and the changeswere not associated with clinical symptoms. In post-marketing experience, there have also beenreports of eosinophilia (eosinophil count >1,500/mm3) without clinical symptoms. In such cases wheretherapy was discontinued the elevated eosinophil levels resolved.

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

Serious adverse events were evaluated in 621 MS paediatric patients included in a meta-analysis (seealso section 5.1). Within the limitations of these data, there were no new safety signals identified inthis 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-treatedpaediatric patients in the post-marketing setting.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Safety of doses higher than 300 mg has not been adequately evaluated. The maximum amount ofnatalizumab that can be safely administered has not been determined.

There is no known antidote for natalizumab overdose. Treatment consists of discontinuation of themedicinal product and supportive therapy as needed.

Pharmacotherapeutic group: Immunosuppressants, monoclonal antibodies, ATC code: L04AG03

Tyruko is a biosimilar medicinal product. Detailed information is available on the website of the

European Medicines Agency http://www.ema.europa.eu.

Natalizumab is a selective adhesion-molecule inhibitor and binds to the α4-subunit of human integrins,which is highly expressed on the surface of all leukocytes, with the exception of neutrophils.

Specifically, natalizumab binds to the α4β1 integrin, blocking the interaction with its cognate receptor,vascular cell adhesion molecule-1 (VCAM-1), and ligands osteopontin, and an alternatively spliceddomain of fibronectin, connecting segment-1 (CS-1). Natalizumab blocks the interaction of α4β7integrin with the mucosal addressin cell adhesion molecule-1 (MadCAM-1). Disruption of thesemolecular interactions prevents transmigration of mononuclear leukocytes across the endothelium intoinflamed parenchymal tissue. A further mechanism of action of natalizumab may be to suppressongoing inflammatory reactions in diseased tissues by inhibiting the interaction of α4-expressingleukocytes with their ligands in the extracellular matrix and on parenchymal cells. As such,natalizumab may act to suppress inflammatory activity present at the disease site, and inhibit furtherrecruitment of immune cells into inflamed tissues.

In MS, lesions are believed to occur when activated T-lymphocytes cross the blood-brain barrier(BBB). Leukocyte migration across the BBB involves interaction between adhesion molecules oninflammatory cells and endothelial cells of the vessel wall. The interaction between α4β1 and itstargets is an important component of pathological inflammation in the brain and disruption of theseinteractions leads to reduced inflammation. Under normal conditions, VCAM-1 is not expressed in thebrain parenchyma. However, in the presence of pro-inflammatory cytokines, VCAM-1 is upregulatedon endothelial cells and possibly on glial cells near the sites of inflammation. In the setting of centralnervous system (CNS) inflammation in MS, it is the interaction of α4β1 with VCAM-1, CS-1 andosteopontin that mediates the firm adhesion and transmigration of leukocytes into the brainparenchyma and may perpetuate the inflammatory cascade in CNS tissue. Blockade of the molecularinteractions of α4β1 with its targets reduces inflammatory activity present in the brain in MS andinhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation orenlargement of MS lesions.

Efficacy as monotherapy has been evaluated in one randomised, double-blind, placebo-controlledstudy lasting 2 years (AFFIRM study) in RRMS patients who had experienced at least 1 clinicalrelapse during the year prior to entry and had a Kurtzke Expanded Disability Status Scale (EDSS)score between 0 and 5. Median age was 37 years, with a median disease duration of 5 years. Thepatients were randomised with a 2:1 ratio to receive natalizumab-300 mg (n = 627) or placebo(n = 315) every 4 weeks for up to 30 infusions. Neurological evaluations were performed every12 weeks and at times of suspected relapse. MRI evaluations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.

Study features and results are presented in the Table 2.

Table 2. AFFIRM study: Main features and results

Design Monotherapy; randomised double-blind placebo-controlledparallel-group trial for 120 weeks

Subjects RRMS (McDonald criteria)

Treatment Placebo/Natalizumab 300 mg i.v. every 4 weeks

One year endpoint Relapse rate

Two year endpoint Progression on EDSS

Secondary endpoints Relapse rate derived variables/MRI-derived variables

Subjects Placebo Natalizumab

Randomised 315 627

Completing 1 years 296 609

Completing 2 years 285 589

Age yrs, median (range) 37 (19-50) 36 (18-50)

MS-history yrs, median (range) 6.0 (0-33) 5.0 (0-34)

Time since diagnosis, yrs median 2.0 (0-23) 2.0 (0-24)(range)

Relapses in previous 12 months, 1.0 (0-5) 1.0 (0-12)median (range)

EDSS-baseline, median (range) 2 (0-6.0) 2 (0-6.0)

RESULTS

Annual relapse rate

After one year (primary endpoint) 0.805 0.261

After two years 0.733 0.235

One year Rate ratio 0.33 CI95% 0.26 ; 0.41

Two years Rate ratio 0.32 CI95% 0.26 ; 0.40

Relapse free

After one year 53% 76%

After two years 41% 67%

Disability

Proportion progressed1(12-weekconfirmation; primary outcome) 29% 17%

Hazard ratio 0.58, CI95% 0.43; 0.73, p<0.001

Proportion progressed1(24-weekconfirmation) 23% 11%

Hazard ratio 0.46, CI95% 0.33; 0.64, p<0.001

Table 2. AFFIRM study: Main features and results

MRI (0-2 years)

Median % change in T2- -9.4%hyperintense lesion volume +8.8% (p<0.001)

Mean number of new or newly- 1.9enlarging T2-hyperintense lesions 11.0 (p<0.001)

Mean number of T1-hypointense 1.1lesions 4.6 (p<0.001)

Mean number of Gd-enhancing 0.1lesions 1.2 (p<0.001)1 Progression of disability was defined as at least a 1.0 point increase on the EDSS from a baseline EDSS >=1.0 sustainedfor 12 or 24 weeks or at least a 1.5 point increase on the EDSS from a baseline EDSS = 0 sustained for 12 or 24 weeks.

In the sub-group of patients indicated for treatment of rapidly evolving RRMS (patients with 2 or morerelapses and 1 or more Gd+ lesion), the annualised relapse rate was 0.282 in the natalizumab-treatedgroup (n = 148) and 1.455 in the placebo group (n = 61) (p <0.001). Hazard ratio for disabilityprogression was 0.36 (95% CI: 0.17, 0.76) p = 0.008. These results were obtained from a post hocanalysis and should be interpreted cautiously. No information on the severity of the relapses beforeinclusion of patients in the study is available.

Natalizumab observational program

Interim analysis of results (as of May 2015) from an ongoing natalizumab observational program, aphase 4, multicentre, single-arm study (n = 5,770) demonstrated that patients switching from betainterferon (n = 3,255) or glatiramer acetate (n = 1,384) to natalizumab showed a sustained, significantdecrease in annualised relapse rate (p <0.0001). Mean EDSS scores remained stable over 5 years.

Consistent with efficacy results observed for patients switching from beta interferon or glatirameracetate to natalizumab, for patients switching from fingolimod (n = 147) to natalizumab, a significantdecrease in annualised relapse rate (ARR) was observed, which remained stable over 2 years, andmean EDSS scores remained similar from baseline to Year 2. The limited sample size and shorterduration of natalizumab exposure for this subgroup of patients should be considered when interpretingthese data.

A post-marketing meta-analysis was conducted using data from 621 paediatric MS patients treatedwith natalizumab (median age 17 years, range was 7 to 18 years, 91% aged ≥14 years). Within thisanalysis, a limited subset of patients with data available prior to treatment (158 of the 621 patients)demonstrated a reduction in ARR from 1.466 (95% CI 1.337, 1.604) prior to treatment to 0.110(95% CI 0.094, 0.128).

In a pre-specified, retrospective analysis of US anti-JCV antibody positive natalizumab patientsintravenously administered, the risk of PML was compared between patients treated with the approveddosing interval and patients treated with extended interval dosing as identified in the last 18 months ofexposure (EID, average dosing intervals of approximately 6 weeks). The majority (85%) of patientsdosed with EID had received the approved dosing for ≥1 year prior to switching to EID. The analysisshowed a lower risk of PML in patients treated with EID (hazard ratio = 0.06, 95% CI of hazardratio = 0.01 to 0.22).

Efficacy has been modelled for patients who switch to longer dosing after ≥1 year of approved dosingwith this medicinal product under intravenous administration and who did not experience a relapse inthe year prior to switching. Current pharmacokinetic/pharmacodynamic statistical modelling andsimulation indicate that the risk of MS disease activity for patients switching to longer dosing intervalsmay be higher for patients with dosing intervals ≥7 weeks. No prospective clinical studies have beencompleted to validate these findings.

The efficacy of natalizumab when administered with EID has not been established, therefore thebenefit/risk balance of EID is unknown (see “Intravenous administration Q6W”).

Intravenous administration Q6W

Efficacy and safety were evaluated in a prospective, randomized, interventional, controlled, open-label, rater-blinded, international phase 3 study (NOVA, 101MS329), involving subjects withrelapsing-remitting MS according to the 2017 McDonald criteria dosed intravenously every six weekswith natalizumab. The study was designed to estimate an efficacy difference between Q6W and Q4Wdosing regimens.

The study randomized 499 subjects aged 18-60, with an EDSS score ≤ 5.5 at screening, who receivedat least 1 year of natalizumab treatment IV Q4W and were clinically stable (no relapse in the last12 months, no gadolinium (Gd) enhancing T1 lesions at screening). In the study, subjects whoswitched to Q6W after at least one year of IV Q4W treatment with natalizumab were evaluated inrelation to subjects who continued on IV Q4W treatment.

Baseline demographic subgroups of age, sex, duration of natalizumab exposure, country, body weight,anti-JCV status and number of relapses in the year prior to the first dose, number of relapses while onnatalizumab, number of prior DMTs, and type of prior DMT were similar between the Q6W and Q4Wdosing treatment arms.

Table 3. NOVA study: Main features and results

Monotherapy; phase 3b prospective, randomized,

Design interventional, controlled, open-label, rater-blinded,international study

Subjects RRMS (McDonald criteria)

Treatment administration (part 1) Natalizumab Q4W Natalizumab Q6W300 mg I.V. 300 mg I.V.

Randomized 248 251

RESULTSmITTa population for part 1 at week 72 242 247

New/newly enlarging (N/NE) T2 lesionsfrom baseline to Week 72

Subjects with number of lesions = 0 189 (78.1%) 202 (81.8%)= 1 7 (3.6%) 5 (2.0%)= 2 1 (0.5%) 2 (0.8%)= 3 0 0= 4 0 0≥ 5 0 2* (0.8%)missing 45 (18.6%) 36 (14.6%)

Adjusted mean N/NE T2-hyperintenselesions (primary endpoint)*95% CIb,c0.05 0.20(0.01, 0.22) (0.07, 0.63)p = 0.0755

Proportion of subjects that developed N/NE

T2 lesions 4.1% 4.3%

Proportion of subjects who developed T1-hypointense lesions 0.8% 1.2%

Table 3. NOVA study: Main features and results

Proportion of subjects who developed Gd-enhancing lesions 0.4% 0.4%

Adjusted annualized relapse rate 0.00010 0.00013

Proportion of subjects free of relapse** 97.6% 96.9%

Proportion free of 24-week confirmed

EDSS worsening 92% 90%a mITT population, which included all randomized participants who received at least 1 dose of study treatment(natalizumab SID or natalizumab EID) and had at least 1 postbaseline result from the following clinical efficacyassessments: MRI efficacy assessments, relapses, EDSS, 9-HPT, T25FW, SDMT, TSQM, CGI scale.

b Estimated using negative binomial regression with treatment as classification and baseline body weight(≤ 80 vs > 80 kg), duration of natalizumab exposure at baseline (≤ 3 vs > 3 years), and region (North America, the UK,

Europe and Israel, and Australia) as covariates.

c Observed lesions are included for analysis regardless of intercurrent events, and missing values due to efficacy or safety(6 subjects switched to Q4W dosing and 1 subject each on Q6W and Q4W dosing discontinued treatment) are imputedby the worst case of subjects on treatment at the same visit in the same treatment group or otherwise via multipleimputation.

* The numerical difference seen in the N/NE lesions between the two treatment groups was driven by a high number oflesions occurring in two subjects in the Q6W arm - one subject who developed lesions three months after treatmentdiscontinuation and a second subject who was diagnosed with asymptomatic PML at week 72.

** Relapses - clinical relapses were assessed as defined by new or recurrent neurologic symptoms notassociated with fever or infection having a minimum duration of 24 hours.

Following the repeat intravenous administration of a 300 mg dose of natalizumab to MS patients, themean maximum observed serum concentration was 110 ± 52 μg/mL. Mean average steady-statetrough natalizumab concentrations over the dosing period ranged from 23 μg/mL to 29 μg/mL in Q4Wdosing. At any time, mean trough concentrations for the Q6W regimen were approximately60 to 70% lower than for the Q4W regimen. The predicted time to steady state was approximately24 weeks. Population pharmacokinetic analysis includes 12 studies and 1,781 subjects receiving dosesranging from 1 to 6 mg/kg and fixed doses of 150/300 mg.

Median steady-state volume of distribution was 5.96 L (5.59-6.38 L, 95% confidence interval).

Population median estimate for linear clearance was 6.08 mL/h (5.75-6.33 mL/h, 95% confidenceinterval) and the estimated median half-life was 28.2 days. The 95th percentile interval of the terminalhalf-life is from 11.6 to 46.2 days.

The population analysis of 1,781 patients explored the effects of selected covariates including bodyweight, age, gender, presence of anti-natalizumab antibodies and formulation on pharmacokinetics.

Only body weight, the presence of anti-natalizumab antibodies and the formulation used in phase 2studies were found to influence natalizumab disposition. Natalizumab clearance increased with bodyweight in a less-than-proportional manner, such that a +/-43% change in body weight resulted in onlya -33% to 30% change in clearance. The presence of persistent anti-natalizumab antibodies increasednatalizumab clearance approximately 2.45-fold, consistent with reduced serum natalizumabconcentrations observed in persistently antibody-positive patients.

The pharmacokinetics of natalizumab in paediatric MS patients has not been established.

The pharmacokinetics of natalizumab in patients with renal insufficiency has not been studied.

The pharmacokinetics of natalizumab in patients with hepatic insufficiency has not been studied.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity and genotoxicity.

Consistent with the pharmacological activity of natalizumab, altered trafficking of lymphocytes wasseen as white blood cell increases as well as increased spleen weights in most in vivo studies. Thesechanges were reversible and did not appear to have any adverse toxicological consequences.

In studies conducted in mice, growth and metastasis of melanoma and lymphoblastic leukaemiatumour cells was not increased by the administration of natalizumab.

No clastogenic or mutagenic effects of natalizumab were observed in the Ames or humanchromosomal aberration assays. Natalizumab showed no effects on in vitro assays of α4-integrin-positive tumour line proliferation or cytotoxicity.

Reductions in female guinea pig fertility were observed in one study at doses in excess of the humandose; natalizumab did not affect male fertility.

The effect of natalizumab on reproduction was evaluated in 5 studies, 3 in guinea pigs and 2 incynomolgus monkeys. These studies showed no evidence of teratogenic effects or effects on growth ofoffspring. In one study in guinea pigs, a small reduction in pup survival was noted. In a study inmonkeys, the number of abortions was doubled in the natalizumab 30 mg/kg treatment groups versusmatching control groups. This was the result of a high incidence of abortions in treated groups in thefirst cohort that was not observed in the second cohort. No effects on abortion rates were noted in anyother study. A study in pregnant cynomolgus monkeys demonstrated natalizumab-related changes inthe foetus that included mild anaemia, reduced platelet counts, increased spleen weights and reducedliver and thymus weights. These changes were associated with increased splenic extramedullaryhaematopoiesis, thymic atrophy and decreased hepatic haematopoiesis. Platelet counts were alsoreduced in offspring born to mothers treated with natalizumab until parturition, however there was noevidence of anaemia in these offspring. All changes were observed at doses in excess of the humandose and were reversed upon clearance of natalizumab.

In cynomolgus monkeys treated with natalizumab until parturition, low levels of natalizumab weredetected in the breast milk of some animals.

Sodium chloride

Histidine

Histidine monohydrochloride

Polysorbate 80 (E 433)water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 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.

Unopened vial3 years

From a microbiological point of view, after dilution with sodium chloride 9 mg/mL (0.9%) solutionfor injection, immediate use is recommended. If not used immediately, the diluted solution must bestored at 2 ˚C to 8 ˚C and infused within 24 hours of dilution. In-use storage times and conditions priorto use are the responsibility of the user.

Store in a refrigerator (2 ˚C to 8 ˚C).

Do not freeze.

Keep the vial in the outer carton in order to protect from light.

For storage conditions after dilution of the medicinal product see section 6.3.

15 mL concentrate in a vial (type I glass) with a stopper (bromobutyl rubber) and a seal (aluminium)with a flip-off cap.

Pack size of one vial per carton.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

* Inspect the vial for particles prior to dilution and administration. If particles are observed and/orthe liquid in the vial is not colourless, clear to slightly opalescent, the vial must not be used.

* Use aseptic technique when preparing the solution for intravenous (IV) infusion. Remove flip-off cap from the vial. Insert the syringe needle into the vial through the centre of the rubberstopper and remove 15 mL concentrate for solution for infusion.

* Add the 15 mL concentrate for solution for infusion to 100 mL sodium chloride 9 mg/mL(0.9%) solution for injection. Gently invert the solution to mix completely. Do not shake.

* This medicinal product must not be mixed with other medicinal products or diluents.

* Visually inspect the diluted medicinal product for particles or discolouration prior toadministration. Do not use if it is discoloured or if foreign particles are seen.

* The diluted medicinal product is to be used as soon as possible and within 24 hours of dilution.

If the diluted medicinal product is stored at 2 ˚C to 8 ˚C (do not freeze), allow the solution towarm to room temperature prior to infusion.

* The diluted solution is to be infused intravenously over 1 hour at a rate of approximately 2 mLper minute.

* After the infusion is complete, flush the intravenous line with sodium chloride 9 mg/mL (0.9%)solution for injection.

* Each vial is for single-use only.

Sandoz GmbH

Biochemiestrasse 106250 Kundl

Austria

EU/1/23/1745/001

Date of first authorisation: 22 September 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.