TYSABRI 300 mg concentrate for solution for infusion

Each ml of concentrate contains 20 mg of natalizumab.

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

When diluted (see section 6.6), the solution for infusion contains approximately 2.6 mg/ml of natalizumab.

TYSABRI contains 2.3 mmol (or 52 mg) sodium per vial of medicinal product. When diluted in 100 ml sodium chloride 9 mg/ml (0.9%) the medicinal product contains 17.7 mmol (or 406 mg) sodium.

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion.

Colourless, clear to slightly opalescent solution.

TYSABRI is indicated as single disease modifying therapy in highly active relapsing remitting multiple sclerosis for the following patient groups:

• Adult patients aged 18 years and over with high disease activity despite treatment with a beta-interferon.

These patients may be defined as those who have failed to respond to a full and adequate course (normally at least one year of treatment) of beta-interferon. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2-hyperintense lesions in cranial Magnetic Resonance Image (MRI) or at least 1 Gadolinium-enhancing lesion. A “non-responder” could also be defined as a patient with an unchanged or increased relapse rate or ongoing severe relapses, as compared to the previous year.

or

• Adult patients aged 18 years and over with rapidly evolving severe relapsing remitting multiple sclerosis defined by 2 or more disabling relapses in one year, and with 1 or more Gadolinium enhancing lesions on brain MRI or a significant increase in T2 lesion load as compared to a previous recent MRI.

TYSABRI therapy is to be initiated and continuously supervised by specialised physicians experienced in the diagnosis and treatment of neurological conditions, in centres with timely access to MRI.

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

Patients can switch directly from beta interferon or glatiramer acetate to natalizumab providing there are no signs of relevant treatment-related abnormalities e.g. neutropenia. If there are signs of treatment-related abnormalities these must return to normal before treatment with natalizumab is started.

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

Posology

Adults

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

Continued therapy must be carefully reconsidered in patients who show no evidence of therapeutic benefit 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 of the potential for benefit and risk. Patients should be re-informed about the risk factors for PML, like duration of treatment, immunosuppressant use prior to receiving TYSABRI and the presence of anti-JCV antibodies (see Section 4.4.).

Readministration

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

Elderly

TYSABRI is not recommended for use in patients aged over 65 due to a lack of data in this population.

Renal and hepatic impairment

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 dose adjustment would not be necessary in patients with renal or hepatic impairment.

Paediatric Population

TYSABRI is contraindicated in children and adolescents below the age of 18 years (see section 4.3).

Method of Administration

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 and patients are to be observed during the infusion and for 1 hour after the completion of the infusion for signs and symptoms of hypersensitivity reactions.

TYSABRI must not be administered as a bolus injection.

Hypersensitivity to natalizumab or to any of the excipients.

Progressive multifocal leukoencephalopathy (PML).

Patients with increased risk for opportunistic infections, including immunocompromised patients (including those currently receiving immunosuppressive therapies or those immunocompromised by prior therapies, e.g. mitoxantrone or cyclophosphamide, see also sections 4.4 and 4.8).

Combination with beta-interferons or glatiramer acetate.

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

Children and adolescents below the age of 18 years.

Progressive Multifocal Leukoencephalopathy (PML)

Use of TYSABRI has been associated with an increased risk of PML, an opportunistic infection caused by JC virus, which may be fatal or result in severe disability. Due to this increased risk of developing PML, the benefits and risks of TYSABRI treatment should be individually reconsidered by the specialist physician and the patient.

Patients should be instructed together with their caregivers on early signs and symptoms of PML.

Each of the following independent risk factors is associated with an increased risk of PML.

• Treatment duration, especially beyond 2 years. There is limited experience in patients who have received more than 4 years of TYSABRI treatment therefore the risk of PML in these patients cannot currently be estimated.

• Immunosuppressant use prior to receiving TYSABRI.

• The presence of anti-JCV antibodies.

Anti-JCV antibody status identifies different levels of risk for PML in TYSABRI treated patients. Patients who are anti-JCV antibody positive are at an increased risk of developing PML compared to patients who are anti-JCV antibody negative. Patients who have all three risk factors for PML (i.e., have received more than 2 years of TYSABRI therapy, and have received prior immunosuppressant therapy and are anti-JCV antibody positive) have the highest risk of PML at approximately 9 in 1,000 patients treated. Patients should be informed about this increased risk for developing PML before continuation of treatment after 2 years.

For risk stratification prior or during the treatment with TYSABRI anti-JCV antibody testing may provide supportive information.

Before initiation of treatment with TYSABRI, a recent (usually within 3 months) MRI should be available as a reference, and be repeated on a yearly routine basis to update this reference. Patients must be monitored at regular intervals throughout. After 2 years the patient should be re-informed about the risk of PML with TYSABRI.

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

The clinician should eva luate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are typical of MS or possibly suggestive of PML. If any doubt exists, further eva luation, including MRI scan preferably with contrast (compared with pre-treatment MRI), CSF testing for JC Viral DNA and repeat neurological assessments, should be considered as described in the Physician Information and Management Guidelines (see educational guidance). Once the clinician has excluded PML (if necessary, by repeating clinical, imaging and/or laboratory investigations if clinical suspicion remains), dosing of natalizumab may resume.

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

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

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

PML and IRIS (Immune Reconstitution Inflammatory Syndrome)

IRIS occurs in almost all TYSABRI PML patients after withdrawal or removal of TYSABRI, e.g. by plasma exchange (see section 5.2). IRIS is thought to result from the restoration of immune function in patients with PML, which can lead to serious neurological complications and may be fatal. Monitoring for development of IRIS, which has occurred within days to several weeks after plasma exchange in TYSABRI treated patients with PML, and appropriate treatment of the associated inflammation during recovery from PML should be undertaken (see the Physician Information and Management Guidelines for further information).

Other Opportunistic Infections

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

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

If a patient receiving TYSABRI develops an opportunistic infection, dosing of TYSABRI must be permanently discontinued.

Educational guidance

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

Physicians must discuss the benefits and risks of TYSABRI therapy with the patient and provide them with a Patient Alert Card. Patients should be instructed that if they develop any infection then they should inform their physician that they are being treated with TYSABRI.

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

Hypersensitivity

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

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

Discontinue administration of TYSABRI and initiate appropriate therapy at the first symptoms or signs of hypersensitivity.

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

Concurrent or prior treatment with immunosuppressants

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

Patients with a treatment history of immunosuppressant medications are at increased risk for PML. Care should be taken with patients who have previously received immunosuppressants to allow sufficient time for immune function recovery to occur. Physicians must eva luate each individual case to determine whether there is evidence of an immunocompromised state prior to commencing treatment with TYSABRI (see section 4.3).

In Phase 3 MS clinical trials, concomitant treatment of relapses with a short course of corticosteroids was not associated with an increased rate of infection. Short courses of corticosteroids can be used in combination with TYSABRI.

Immunogenicity

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

Since patients who have received an initial short exposure to TYSABRI and then had an extended period without treatment are more at risk for hypersensitivity upon redosing, the presence of antibodies should be eva luated and if these remain positive in a confirmatory test after 6 weeks treatment should not be resumed.

Hepatic Events

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

Stopping TYSABRI therapy

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

Sodium content in TYSABRI

TYSABRI contains 2.3 mmol (or 52 mg) sodium per vial of medicinal product. When diluted in 100 ml sodium chloride 9 mg/ml (0.9%) this medicinal product contains 17.7 mmol (or 406 mg) sodium per dose. To be taken into consideration by patients on a controlled sodium diet.

TYSABRI is contraindicated in combination with beta-interferons or glatiramer acetate (see section 4.3).

Immunisations

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

Pregnancy

There are no adequate data from the use of natalizumab in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Natalizumab should not be used during pregnancy unless the clinical condition of the women requires treatment with TYSABRI.

If a woman becomes pregnant while taking TYSABRI, discontinuation of TYSABRI should be considered.

Breast-feeding

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

Fertility

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

It is considered unlikely that natalizumab will affect fertility performance in humans following the maximum recommended dose.

Based on the pharmacological mechanism of action of natalizumab, the use of TYSABRI has no or negligible influence on the ability to drive and use machines.

Summary of the safety profile

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

The highest incidence of adverse reactions identified from placebo-controlled trials in multiple sclerosis patients with natalizumab given at the recommended dose, are reported as dizziness, nausea, urticaria and rigors associated with infusions.

List of adverse reactions

Adverse reactions reported with natalizumab with an incidence of 0.5% greater than reported with placebo are shown below.

The reactions are reported as MedDRA preferred terms under the MedDRA primary system organ class. Frequencies were defined as follows:

Common ( 1/100 to < 1/10), uncommon ( 1/1,000 to < 1/100).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Description of selected adverse reactions

Infusion reactions

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

Hypersensitivity reactions

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

Immunogenicity

In 10% of patients antibodies against natalizumab were detected in 2-year controlled clinical trials in MS patients. Persistent anti-natalizumab antibodies (one positive test 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 antibodies were associated with a substantial decrease in the effectiveness of TYSABRI and an increased incidence of hypersensitivity reactions. Additional infusion-related reactions associated with persistent antibodies included rigors, nausea, vomiting and flushing (see section 4.4).

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

nfections, including PML and opportunistic infections

In 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per patient-year in both natalizumab- and placebo-treated patients. The nature of the infections was generally similar in natalizumab- and placebo-treated patients. A case of cryptosporidium diarrhoea was reported in MS clinical trials. In other clinical trials, cases of additional opportunistic infections have been reported, some of which were fatal. In clinical trials, herpes infections (Varicella-Zoster virus, Herpes-simplex virus) occurred slightly more frequently in natalizumab-treated patients than in placebo-treated patients. In post marketing experience, there have been reports of serious cases, including one fatal case of herpes encephalitis. See section 4.4.

The majority of patients did not interrupt natalizumab therapy during infections and recovery occurred with appropriate treatment.

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).

 Hepatic Events

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

 Malignancies

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 treatment periods is required before any effect of natalizumab on malignancies can be excluded. See section 4.3.

 Effects on laboratory tests

TYSABRI treatment was associated with increases in circulating lymphocytes, monocytes, eosinophils, basophils and nucleated red blood cells. Elevations in neutrophils were not seen. Increases from baseline for lymphocytes, monocytes, eosinophils and basophils ranged from 35% to 140% for individual cell types but mean cell counts remained within normal ranges. During treatment with TYSABRI, small reductions in haemoglobin (mean decrease 0.6 g/dl), haematocrit (mean decrease 2%) and red blood cell counts (mean decrease 0.1 x 10⁶/l) were seen. All changes in haematological variables returned to pre-treatment values, usually within 16 weeks of last dose of TYSABRI and the changes were not associated with clinical symptoms.

¹ An adverse event judged related to therapy by the investigating physician.

No case of overdose has been reported.

Pharmacotherapeutic group: Selective Immunosuppressive Agent, ATC code: L04AA23

 Pharmacodynamic effects

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 spliced domain of fibronectin, connecting segment-1 (CS-1). Natalizumab blocks the interaction of α4β7 integrin with the mucosal addressin cell adhesion molecule-1 (MadCAM-1). Disruption of these molecular interactions prevents transmigration of mononuclear leukocytes across the endothelium into inflamed parenchymal tissue. A further mechanism of action of natalizumab may be to suppress ongoing inflammatory reactions in diseased tissues by inhibiting the interaction of α4-expressing leukocytes 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 further recruitment 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 on inflammatory cells and endothelial cells of the vessel wall. The interaction between α4β1 and its targets is an important component of pathological inflammation in the brain and disruption of these interactions leads to reduced inflammation. Under normal conditions, VCAM-1 is not expressed in the brain parenchyma. However, in the presence of pro-inflammatory cytokines, VCAM-1 is upregulated on endothelial cells and possibly on glial cells near the sites of inflammation. In the setting of central nervous system (CNS) inflammation in MS, it is the interaction of α4β1 with VCAM-1, CS-1 and osteopontin that mediates the firm adhesion and transmigration of leukocytes into the brain parenchyma and may perpetuate the inflammatory cascade in CNS tissue. Blockade of the molecular interactions of α4β1 with its targets reduces inflammatory activity present in the brain in MS and inhibits further recruitment of immune cells into inflamed tissue, thus reducing the formation or enlargement of MS lesions.

 Clinical efficacy

Efficacy as monotherapy has been eva luated in one randomised, double-blind, placebo-controlled study lasting 2 years (AFFIRM study) in relapsing-remitting MS patients who had experienced at least 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 of 5 years. The patients were randomised with a 2:1 ratio to receive TYSABRI 300 mg (n = 627) or placebo (n = 315) every 4 weeks for up to 30 infusions. Neurological eva luations were performed every 12 weeks and at times of suspected relapse. MRI eva luations for T1-weighted gadolinium (Gd)-enhancing lesions and T2-hyperintense lesions were performed annually.

Study features and results are presented in the table below.

In the sub-group of patients indicated for treatment of rapidly evolving relapsing remitting MS (patients with 2 or more relapses and 1 or more Gd+ lesion), the annualised relapse rate was 0.282 in the TYSABRI treated group (n = 148) and 1.455 in the placebo group (n = 61) (p <0.001). Hazard ratio for disability progression was 0.36 (95% CI : 0.17, 0.76) p = 0.008. These results were obtained from a post hoc analysis and should be interpreted cautiously. No information on the severity of the relapses before inclusion of patients in the study is available.

Following the repeat intravenous administration of a 300 mg dose of natalizumab to MS patients, the mean maximum observed serum concentration was 110 ± 52 μg/ml. Mean average steady-state trough natalizumab concentrations over the dosing period ranged from 23 μg/ml to 29 μg/ml. The predicted time to steady-state was approximately 36 weeks.

A population pharmacokinetics analysis was conducted on samples from over 1,100 MS patients receiving doses ranging from 3 to 6 mg/kg natalizumab. Of these, 581 patients received a fixed 300 mg dose as monotherapy. The mean ± SD steady-state clearance was 13.1 ± 5.0 ml/h, with a mean ± SD half-life of 16 ± 4 days. The analysis explored the effects of selected covariates including body weight, age, gender, hepatic and renal function, and presence of anti-natalizumab antibodies upon pharmacokinetics. Only body weight and the presence of anti-natalizumab antibodies were found to influence natalizumab disposition. Body weight was found to influence clearance in a less-than-proportional manner, such that a 43% change in body weight resulted in a 31% to 34% change in clearance. The change in clearance was not clinically significant. The presence of persistent anti-natalizumab antibodies increased natalizumab clearance approximately 3-fold, consistent with reduced serum natalizumab concentrations observed in persistently antibody-positive patients, (see section 4.8).

The pharmacokinetics of natalizumab in paediatric MS patients or in patients with renal or hepatic insufficiency has not been studied.

The effect of plasma exchange on natalizumab clearance and pharmacodynamics was eva luated in a study of 12 MS patients. Estimates of the total natalizumab removal after 3 plasma exchanges (over a 5-8 day interval) was approximately 70-80%. This compares to approximately 40% seen in earlier studies in which measurements occurred after natalizumab discontinuation over a similar period of observation. The impact of plasma exchange on the restitution of lymphocyte migration and ultimately its clinical usefulness is unknown.

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

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

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

No clastogenic or mutagenic effects of natalizumab were observed in the Ames or human chromosomal 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 human dose; natalizumab did not affect male fertility.

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

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

Sodium phosphate, monobasic, monohydrate

Sodium phosphate, dibasic, heptahydrate

Sodium chloride

Polysorbate 80 (E433)

Water for injections.

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

4 years

Diluted solution

After dilution with 0.9 % sodium chloride, immediate use is recommended. If not used immediately, the diluted solution must be stored at 2˚C - 8˚C and infused within 8 hours of dilution. In-use storage times and conditions prior to use are the responsibility of the user.

Concentrate

Store in a refrigerator (2˚C - 8˚C).

Do not freeze.

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

For storage conditions of the diluted 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.

Instructions for use:

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

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

3. 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 TYSABRI solution to mix completely. Do not shake.

4. TYSABRI must not be mixed with other medicinal products or diluents.

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

6. The diluted medicinal product is to be used as soon as possible and within 8 hours of dilution. If the diluted medicinal product is stored at 2˚C - 8˚C (do not freeze), allow the solution to warm to room temperature prior to infusion.

7. The diluted solution is to be infused intravenously over 1 hour at a rate of approximately 2 ml/minute.

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

9. Each vial is for single–use only.

10. Any unused medicinal product or waste material must be disposed of in accordance with local requirements.

Elan Pharma International Ltd., Monksland, Athlone, County Westmeath, Ireland

EU/1/06/346/001

Date of first authorisation: 27^th June 2006

Date of first renewal: 17^th June 2011

06/2011

Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.