TYSABRI 150mg injection solution in pre-filled syringe medication leaflet

Tysabri 150 mg solution for injection in pre-filled syringe

Each mL contains 150 mg of natalizumab.

Natalizumab is a recombinant humanised anti-α4-integrin antibody produced in a murine cell line byrecombinant DNA technology.

For the full list of excipients, see section 6.1.

Solution for injection (injection)

Colourless to slightly yellow, slightly opalescent to opalescent solution.

Tysabri 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, with timely access to MRI. Patients must bemonitored for early signs and symptoms of Progressive Multifocal Leukoencephalopathy (PML).

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).

In case of administration by a healthcare professional outside a clinical setting, self-administration oradministration by a caregiver (see below), the Pre-Administration Checklist should be provided (seesection 4.4 for educational guidance).

After 2 years of treatment, patients should be re-informed about the risks, especially the increased riskof PML, and should be instructed together with their caregivers on early signs and symptoms of PML.

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

There are limited data for the subcutaneous formulation in the Tysabri naïve patient population (seesection 4.4).

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).

The recommended dose for subcutaneous administration is 300 mg every 4 weeks. As each pre-filledsyringe contains 150 mg natalizumab two pre-filled syringes need to be administered.

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 (intravenous infusion) at 2 years were generated fromcontrolled, double-blind studies. After 2 years continued therapy should be considered only followinga reassessment of the potential for benefit and risk. Patients should be re-informed about the riskfactors for PML, like duration of treatment, immunosuppressant use prior to receiving the medicinalproduct and the presence 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).

Any switch in route of administration of the medicinal product should be made 4 weeks after theprevious dose.

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 this medicinal product in children and adolescents up to 18 years have notbeen established. Currently available data are described in sections 4.8 and 5.1.

Tysabri 150 mg solution for injection in pre-filled syringe is for subcutaneous (SC) injection only. It isnot intended for intravenous (IV) infusion.

Two pre-filled syringes should be administered (total dose 300 mg), one after the other withoutsignificant delay. The second injection should be administered no later than 30 minutes after the firstinjection.

The sites for subcutaneous injection are the thigh, abdomen (at least 6 cm away from the navel), or theposterior aspect of the upper arm (the latter only in case of injection by a healthcare professional or acaregiver). The injection should not be made into an area of the body where the skin is irritated,reddened, bruised, infected, or scarred in any way. When removing the syringe from the injection site,the plunger should be let go of while pulling the needle straight out. Letting go of the plunger willallow the needle guard to cover the needle. The second injection should be more than 3 cm away fromthe first injection location (see instructions for administration at the end of the package leaflet).

Natalizumab naïve patients should be observed during the injection and for 1 hour after for signs andsymptoms of injection reactions including hypersensitivity for the first six natalizumab doses. Forpatients currently receiving natalizumab and who have already received at least six doses, regardlessof the route of natalizumab administration used for the first six doses, the 1-hour post-injectionobservation time for subsequent subcutaneous injections may be reduced or removed according toclinical judgement if the patients have not experienced any injection/infusion reactions.

Administration outside the clinical setting (OCS)

Natalizumab injections administered by a healthcare professional outside a clinical setting (e.g. athome) may be considered for patients who have previously tolerated at least six doses of natalizumabwell, i.e. who have not experienced hypersensitivity reactions. The decision for a patient to receiveinjections outside a clinical setting should be made after evaluation and recommendation by thespecialised physician. Healthcare professionals should be vigilant for the early signs and symptoms of

PML (see section 4.4 for further information on PML and educational guidance).

Self-administration or administration by a caregiver

Self-administration by the patient or administration by a caregiver may be considered for patients whohave previously tolerated at least six doses of natalizumab well, i.e. who have not experiencedhypersensitivity reactions. The decision should be made after evaluation and recommendation by thespecialised physician.

Patients or caregivers must administer at least two doses via SC route (two injections each) under theguidance of a healthcare professional. They must be instructed to read the patient alert card and reviewthe Pre-Administration Checklist prior to each dose. Patients or caregivers must be advised to remainvigilant for the early signs and symptoms of PML (see section 4.4 for further information on PML andeducational guidance) and, if a hypersensitivity reaction occurs, to stop administration and seekmedical attention immediately.

After a treatment gap of 3 months or more, the six subsequent doses must be administered under thesupervision of a healthcare professional because of the concern for hypersensitivity reaction.

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 batch number ofthe administered product should be clearly recorded.

Use of this medicinal product has been associated with an increased risk of PML, an opportunisticinfection caused by JC virus, which may be fatal or result in severe disability. Due to this increasedrisk of developing PML, the benefits and risks of treatment should be individually reconsidered by thespecialised 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 with thismedicinal product. Symptoms of JCV GCN are similar to symptoms of PML (i.e. cerebellarsyndrome).

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 this medicinalproduct 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 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). The decrease in PML risk is based on data from intravenous route ofadministration. No clinical data are available on either the safety or efficacy of this extended intervaldosing with subcutaneous route of administration. For further information, refer to the Physician

Information and Management Guidelines.

Patients considered at high risk with this treatment should only continue the treatment 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 every 6months 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 within 6months of IVIg (i.e. 6 months = 5x half-life for immunoglobulins).

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 an index equal to or below 0.9 and increasessubstantially above 1.5 for patients who have been on treatment with this medicinal product for longerthan 2 years (see the Physician Information and Management Guidelines for further information).

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

PML should be considered as a differential diagnosis in any MS patient taking natalizumab presentingwith 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 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 physician 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 this medicinal product in patients who did nothave findings suggestive of PML at the time of discontinuation. Patients and physicians shouldcontinue to follow the same monitoring protocol and be alert for any new signs or symptoms that maybe suggestive of PML for approximately 6 months following discontinuation of natalizumab.

If a patient develops PML the dosing of this medicinal product 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, no difference was observed on2-year survival after PML diagnosis between patients who received PLEX and those who did not. Forother considerations on the management of PML, see the Physician Information and Management

Guidelines.

IRIS occurs in almost all PML patients treated with this medicinal product after withdrawal orremoval of the medicinal product. IRIS is thought to result from the restoration of immune function inpatients with PML, which can lead to serious neurological complications and may be fatal. Monitoringfor development of IRIS and appropriate treatment of the associated inflammation during recoveryfrom PML should be undertaken (see the Physician Information and Management Guidelines forfurther information).

Other opportunistic infections have been reported with use of this medicinal product, primarily inpatients with Crohn’s disease who were immunocompromised or where significant comorbidityexisted, however increased risk of other opportunistic infections with use of the medicinal product inpatients without these co-morbidities cannot currently be excluded. Opportunistic infections were alsodetected 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 simplexand varicella zoster viruses. Serious, life-threatening, and sometimes fatal cases have been reported inthe postmarketing 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 administered thismedicinal product and can be potentially blinding. Patients presenting with eye symptoms such asdecreased 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 consideredin these patients.

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 Tysabri-treatedpatients. If an opportunistic infection is suspected, dosing is to be suspended until such infections canbe 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).

Healthcare professionals administering natalizumab subcutaneous injection outside a clinical setting,e.g. at home, must review the Pre-Administration Checklist for each patient prior to eachadministration. In case of administration by the patient or by a caregiver, they must be instructed toreview the Pre-Administration Checklist prior to each dose.

Hypersensitivity reactions have been associated with this medicinal product, including, for theintravenous infusion, serious systemic reactions (see section 4.8).

These reactions usually occurred within one hour after administration. The risk for hypersensitivitywas greatest with early infusions and in patients re-exposed to treatment following an initial shortexposure (one or two infusions) and extended period (3 months or more) without treatment. However,the risk of hypersensitivity reactions should be considered for every administration.

Patients are to be observed during the subcutaneous injections and for 1 hour after, for signs andsymptoms of injection reactions including hypersensitivity (see sections 4.2 and 4.8). Resources forthe management of hypersensitivity reactions should be available. In case of administration by thepatient or a caregiver, they should be informed of the signs and symptoms of hypersensitivityreactions. If a hypersensitivity reaction occurs, patients or caregivers should be advised to stopadministration and seek medical attention immediately.

This medicinal product should be discontinued and appropriate therapy initiated at the first symptomsor signs of hypersensitivity.

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

There are limited data for the subcutaneous formulation in the Tysabri naïve patient population (seesection 5.1).

The safety and efficacy of this medicinal product 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.

No studies 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 injection 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 this medicinal product and an increasedincidence of hypersensitivity reactions (see section 4.8).

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

This medicinal product contains less than 1 mmol sodium (23 mg) per dose (300 mg natalizumab),that is to say essentially ‘sodium-free’.

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 this medicinal product for 6 months compared to an untreated controlgroup. Live vaccines have not been studied.

If a woman becomes pregnant while taking this medicinal product, discontinuation of treatment shouldbe considered. 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 this medicinal product exposure on pregnancy outcomes.

The completed prospective Tysabri 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 this medicinal product.

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 postmarketing setting. Monitoring of platelet counts, haemoglobin, andhaematocrit is recommended in neonates born to women exposed to natalizumab during pregnancy.

This drug should be used during pregnancy only if clearly needed. If a woman becomes pregnantwhile taking natalizumab, discontinuation of natalizumab should be considered.

Natalizumab is excreted in human milk. The effect of natalizumab on newborn/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.

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

The safety profile observed for natalizumab administered subcutaneously was consistent with theknown safety profile of natalizumab administered intravenously, with the exception of injection sitepain. The overall frequency of injection site pain was common 4% (3/71) for subjects receivingnatalizumab 300 mg, every 4 weeks, by subcutaneous administration.

In placebo-controlled trials in 1,617 MS patients treated with natalizumab (intravenous infusion), forup 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% ofpatients treated with natalizumab reported adverse reactions (placebo: 39.6%).

In clinical trials in 6786 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

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

Hypersensitivity reactions usually occurred within one hour after completion of the subcutaneousinjections. The number of patients analysed in the DELIVER and REFINE studies was low (see section5.1).

In 2-year controlled clinical trials in MS patients receiving natalizumab intravenously, hypersensitivityreactions occurred in up to 4% of patients. Anaphylactic/anaphylactoid reactions occurred in less than1% of patients receiving this medicinal product. Hypersensitivity reactions usually occurred during theinfusion 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 withone or more of the following associated symptoms: hypotension, hypertension, chest pain, chestdiscomfort, dyspnoea, angioedema, in addition to more usual symptoms such as rash and urticaria.

In 10% of patients antibodies against natalizumab were detected in 2-year controlled clinical trials in

MS patients receiving natalizumab intravenously. Persistent anti-natalizumab antibodies (one positivetest reproducible on retesting at least 6 weeks later) developed in approximately 6% of patients.

Antibodies were detected on only one occasion in an additional 4% of patients. Persistent antibodieswere associated with a substantial decrease in the effectiveness of natalizumab and an increasedincidence of hypersensitivity reactions. Additional infusion-related reactions associated with persistentantibodies included rigors, nausea, vomiting and flushing (see section 4.4). In the 32-week DELIVERstudy in MS patients with no prior exposure to natalizumab, persistent anti-natalizumab antibodiesdeveloped in 1 subject (4%) from 26 subjects who received natalizumab subcutaneously. Antibodieswere detected on only one occasion in another 5 subjects (19%). In the 60-week REFINE study in MSpatients, no subjects (136 subjects) who switched from natalizumab intravenous administration tosubcutaneous administration had detectable ADA during the study (see section 5.1).

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 (intravenously)- and placebo-treated patients. The nature of theinfections was generally similar in natalizumab- and placebo-treated patients. A case ofcryptosporidium diarrhoea was reported in MS clinical trials. In other clinical trials, cases of additionalopportunistic infections have been reported, some of which were fatal. The majority of patients did notinterrupt natalizumab therapy during infections and recovery occurred with appropriate treatment.

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

In postmarketing experience, rare cases of ARN have been observed in patients receiving thismedicinal product. 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 postmarketing use of this medicinal product

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- andplacebo-treated patients were observed over 2 years of treatment. However, observation over longertreatment periods is required before any effect of natalizumab on malignancies can be excluded (seesection 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 intravenous infusion administration. During treatment with thismedicinal product, small reductions in haemoglobin (mean decrease 0.6 g/dL), haematocrit (meandecrease 2%) and red blood cell counts (mean decrease 0.1 x 106/L) were seen. All changes inhaematological variables returned to pre-treatment values, usually within 16 weeks of last dose of themedicinal product and the changes were not associated with clinical symptoms. In post-marketingexperience, there have also been reports of eosinophilia (eosinophil count >1,500/mm3) withoutclinical symptoms. In such cases where therapy was discontinued the elevated eosinophil levelsresolved.

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

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.

The EC50 of natalizumab binding to α4β1 integrin is estimated to be 2.04 mg/L based on a populationpharmacokinetic/pharmacodynamic model. There was no difference in α4β1integrin binding afternatalizumab 300 mg every 4 weeks was administered subcutaneously or intravenously. Mean PD(alpha-4 saturation on mononuclear lymphocyte cells) was similar between the intravenousadministration Q6W and Q4W regimens, with the difference in mean % alpha-4 saturation rangingfrom 9 to 16%.

Based on similarities in pharmacokinetics and pharmacodynamics between intravenous andsubcutaneous administration, the efficacy data from intravenous infusion is provided as well as thosefrom patients receiving the subcutaneous injection.

Efficacy as monotherapy for intravenous infusion has been evaluated in one randomised, double-blind,placebo-controlled study lasting 2 years (AFFIRM study) in RRMS patients who had experienced atleast 1 clinical relapse 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 of5 years. The patients were randomised with a 2:1 ratio to receive natalizumab 300 mg (n = 627) orplacebo (n = 315) every 4 weeks for up to 30 infusions. Neurological evaluations were performedevery 12 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(range) 2.0 (0-23) 2.0 (0-24)

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

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

Table 2. AFFIRM study: Main features and results

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

Proportion progressed1(24-weekconfirmation) 23% 11%

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

MRI (0-2 years)

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

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

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

Mean number of Gd-enhancinglesions 1.2 0.1(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.

Interim analysis of results (as of May 2015) from the ongoing Tysabri Observational Program (TOP),a phase 4, multicentre, single-arm study (n = 5,770) demonstrated that patients switching from betainterferon (n= 3,255) or glatiramer acetate (n = 1,384) to Tysabri 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 Tysabri, for patients switching from fingolimod (n = 147) to this medicinal product, asignificant decrease in annualised relapse rate (ARR) was observed, which remained stable over 2years, and mean EDSS scores remained similar from baseline to Year 2. The limited sample size andshorter duration of natalizumab exposure for this subgroup of patients should be considered wheninterpreting these 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 Tysabri patientsintravenously administered (TOUCH Prescribing Program), the risk of PML was compared betweenpatients treated with the approved dosing interval and patients treated with extended interval dosing asidentified in the last 18 months of exposure (EID, average dosing intervals of approximately 6 weeks).

The majority (85%) of patients dosed with EID had received the approved dosing for ≥1 year prior toswitching to EID. The analysis showed a lower risk of PML in patients treated with EID (hazard ratio= 0.06, 95% CI of hazard ratio = 0.01 to 0.22). The efficacy of this medicinal product whenadministered with EID has not been established, and therefore the benefit/risk balance of EID isunknown (see section 4.4).

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.

No clinical data are available on either the safety or efficacy of this extended interval dosing with thesubcutaneous route of administration.

REFINE clinical study (subcutaneous formulation, population pre-treated with natalizumab[intravenous infusion] for a minimum of 12 months)

Subcutaneous administration was assessed in a randomised, blinded, parallel-group, phase 2 study(REFINE) exploring the safety, tolerability, and efficacy of multiple regimens of natalizumab (300 mgintravenous every 4 weeks, 300 mg subcutaneous every 4 weeks, 300 mg intravenous every 12 weeks,300 mg subcutaneous every 12 weeks, 150 mg intravenous every 12 weeks and 150 mg subcutaneousevery 12 weeks) in adult subjects (n=290) with relapsing remitting multiple sclerosis conducted over a60 week period. Subjects had received natalizumab for at least 12 months and were free from relapsefor 12 months prior to randomisation. The primary objective of this study was to explore the effects ofmultiple regimens of natalizumab on disease activity and safety in subjects with RRMS. The primaryendpoint of this study was the cumulative number of combined unique active (CUA) MRI lesions(sum of new Gd+ lesions on brain MRI and new or newly enlarging T2 hyperintense lesions notassociated with Gd+ on T1 weighted scans). The mean CUA for the 300 mg subcutaneous every4 week arm was low (0.02) and comparable to the 300 mg intravenous every 4 weeks arm (0.23). The

CUA in the every 12 week treatment arms was significantly higher than the every 4 week treatmentarms resulting in the early discontinuation of the every 12 week arms. Due to the exploratory nature ofthis study, no formal efficacy comparisons were made.

The efficacy and safety of natalizumab for subcutaneous administration in the natalizumab naïve MSpopulation was evaluated in a phase 1 randomised, open-label, dose-ranging study (DELIVER). 12subjects with RRMS and 14 subjects with secondary progressive MS were enrolled in thesubcutaneous treatment arms. The study’s primary objective was to compare the pharmacokinetics(PK) and pharmacodynamics (PD) of single subcutaneous or intramuscular 300-mg doses ofnatalizumab with intravenous infusion 300-mg doses of natalizumab in patients with multiple sclerosis(MS). Secondary objectives included investigation of the safety, tolerability, and immunogenicity ofrepeated subcutaneous and intramuscular natalizumab doses. An exploratory endpoint of this studyincluded the number of new Gd+ lesions on brain MRI from baseline to Week 32. None of thesubjects treated with natalizumab had any Gd+ lesions post-baseline, regardless of their disease stage(RRMS or secondary progressive MS), assigned route of administration, or the presence of Gd+lesions at baseline. Across the RRMS and secondary progressive MS populations, 2 patients in thenatalizumab 300 mg subcutaneous group experienced relapses compared to 3 patients in thenatalizumab 300 mg intravenous infusion group. Small sample sizes and inter- and intra-patientvariability prevent meaningful comparisons of efficacy data between groups.

The pharmacokinetics of natalizumab after subcutaneous administration was evaluated in 2 studies.

DELIVER was a phase 1, randomised, open-label, dose-ranging study to evaluate thepharmacokinetics of subcutaneous and intramuscular natalizumab in subjects with MS (RRMS orsecondary progressive MS) (n = 76). (see section 5.1 for a description of the REFINE study).

An updated population pharmacokinetic analysis was conducted consisting of 11 studies (conductedwith subcutaneously and intravenously administered natalizumab) and data with serial PK sampling asmeasured by an industry standard assay. It included over 1,286 subjects receiving doses ranging from1 to 6 mg/kg and fixed doses of 150/ 300 mg.

The absorption from the injection site to systemic circulation following SC administration wascharacterised by first order absorption with a model estimated delay of 3 hours. No covariates wereidentified.

The bioavailability of natalizumab after subcutaneous administration was 84% as estimated using theupdated population pharmacokinetic analysis. After SC administration of 300 mg natalizumab, peakvalues (Cmax) were reached by approximately 1 week (tmax: 5.8 days, range from 2 to 7.9 days).

The mean Cmax for RRMS participants was 35.44 μg/mL (range 22.0 to 47.8 μg/mL) being 33% ofthe peak values achieved following IV administration.

Multiple subcutaneous doses of 300 mg administered every 4 weeks resulted in comparable Ctrough to300 mg administered intravenously every 4 weeks. The predicted time to steady-state wasapproximately 24 weeks. In both intravenous and subcutaneous administration of natalizumab (every4 weeks) Ctrough values resulted in comparable α4β1 integrin binding.

Both intravenous and subcutaneous routes of administration shared the same disposition PKparameters (CL, Vss and t½) and same sets of covariates as described in the updated populationpharmacokinetic analysis.

Median steady-state volume of distribution was 5.58 L (5.27-5.92 L, 95% confidence interval).

Population median estimate for linear clearance was 6.21 mL/h (5.60-6.70 mL/h, 95% confidenceinterval) and the estimated median half-life was 26.8 days. The 95th percentile interval of the terminalhalf-life is from 11.6 to 46.2 days.

The population analysis of 1,286 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 only a

- 38% to 36% change in clearance. The presence of persistent anti-natalizumab antibodies increasednatalizumab clearance approximately 2.54-fold, consistent with reduced serum natalizumabconcentrations observed in persistently antibody-positive patients.

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 ofα4-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 phosphate, monobasic, monohydrate

Sodium phosphate, dibasic, heptahydrate

Sodium chloride

Polysorbate 80 (E 433)

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years

Store in a refrigerator (2 °C - 8 °C).

Do not freeze.

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

The pre-filled syringes can be kept at room temperature (up to 30 °C) for a maximum of a combinedperiod of up to 24 hours, including the time to allow warming to room temperature for administration.

The syringes can be returned to the refrigerator and used before the expiry date stated on the label andcarton. Date and time of removal of the pack from the refrigerator must be recorded on the carton.

Discard the syringes if left out of the refrigerator for more than 24 hours. Do not use external heatsources such as hot water to warm the pre-filled syringes.

Each PFS consists of a pre-filled syringe made of glass (Type 1A) with a rubber stopper andthermoplastic rigid needle shield, containing 1 mL of solution. A 27 gauge needle is pre-affixed to thesyringe. Each PFS has a needle guard system that will automatically cover the exposed needle whenthe plunger is fully depressed.

Pack size of two PFS per carton.

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

Biogen Netherlands B.V.

Prins Mauritslaan 131171 LP Badhoevedorp

The Netherlands

EU/1/06/346/002

Date of first authorisation: 27th June 2006

Date of latest renewal: 18th April 2016

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

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