TYSABRI 300 mg concentrate for solution for infusion.

Concentrate: Each ml of concentrate contains 20 mg of natalizumab.

Natalizumab is a recombinant humanised antiα4integrin 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.

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:

• Patients with high disease activity despite treatment with a beta-interferon (see section 5.1);

or

• Patients with rapidly evolving severe relapsing remitting multiple sclerosis (see section 5.1).

TYSABRI therapy is to be initiated and 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.

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

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.

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

Some patients may have been exposed to immunosuppressive medications (e.g. mitoxantrone, cyclophosphamide, azathioprine). These drugs 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.

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 beyond 2 years are not available. Continued therapy beyond this time should be considered only following a reassessment of the potential for benefit and risk.

Adults

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

Elderly

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

Children and adolescents

TYSABRI is contraindicated in children and adolescents (see section 4.3).

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.

Readministration

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

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.

Progressive Multifocal Leukoencephalopathy (PML)

Use of TYSABRI has been associated with an increased risk of PML.

Before initiation of treatment with TYSABRI, a recent (usually within 3 months) Magnetic Resonance Image should be available. Patients must be monitored at regular intervals for any new or worsening neurological symptoms or signs that may be suggestive of PML.

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

The clinician should evaluate the patient to determine if the symptoms are indicative of neurological dysfunction, and if so, whether these symptoms are typical of MS or possibly suggestive of PML. If any doubt exists, further evaluation, 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, stabilisation or improved outcome has been seen (see section 5.2). It remains unknown if early detection of PML and suspension of TYSABRI therapy may lead to similar stabilisation or improved outcome.

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 comorbidity 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 TYSABRItreated patients. If an opportunistic infection is suspected, dosing with TYSABRI is to be suspended until such infections can be excluded through further evaluations.

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, including cyclophosphamide and mitoxantrone, may experience prolonged immunosuppression and therefore may be 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 evaluate 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 evaluated 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 evaluated 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 drugs 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 medicines soon after the discontinuation of natalizumab may lead to an additive immunosuppressive effect. This should be carefully considered on a casebycase 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.

See section 4.3.

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

It is not known whether TYSABRI is excreted in human milk, but it has been observed in animal studies (see section 5.3). Patients receiving TYSABRI should not breastfeed their infants.

No studies on the effects on the ability to drive and use machines have been performed. Based on the pharmacological mechanism of action of natalizumab, the use of TYSABRI is not expected to affect patient's ability to drive and use machines.

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 2year duration of the studies, 43.5% of patients treated with natalizumab reported adverse drug reactions (placebo: 39.6%)^[1]. Adverse drug 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, undesirable effects are presented in order of decreasing seriousness.

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

Infusion reactions

In 2-year controlled clinical trials in MS patients, an infusionrelated 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 1hour 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.

Infections, including PML and opportunistic infections

In 2-year controlled clinical trials in MS patients, the rate of infection was approximately 1.5 per patientyear in both natalizumab- and placebotreated patients. The nature of the infections was generally similar in natalizumab- and placebotreated 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.

In clinical trials, cases of PML have been reported. PML usually leads to severe disability or death (see section 4.4). In pivotal clinical trials, two cases, including one fatality, occurred in MS patients who were being treated with concomitant interferon beta1a therapy for more than 2 years. In another trial, one patient with Crohn's disease, who had a long history of treatment with immunosuppressants and associated lymphopenia also developed PML and died.

PML has been reported in post-marketing experience in patients treated with TYSABRI monotherapy.

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 placebotreated patients were observed over 2 years of treatment. However, observation over longer treatment periods is required before any effect of natalizumab on malignancies can be excluded. See section 4.3.

Effects on laboratory tests

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 pretreatment values, usually within 16 weeks of last dose of TYSABRI and the changes were not associated with clinical symptoms.

No case of overdose has been reported.

Pharmacotherapeutic group: Selective Immunosuppressive Agent, ATC code: L04AA23.

Pharmacodynamic properties

Natalizumab is a selective adhesion-molecule inhibitor and binds to the α4subunit 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 molecule1 (VCAM1), and ligands osteopontin, and an alternatively spliced domain of fibronectin, connecting segment1 (CS1). Natalizumab blocks the interaction of α4β7 integrin with the mucosal addressin cell adhesion molecule1 (MadCAM1). 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 α4expressing 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 Tlymphocytes cross the bloodbrain 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, VCAM1 is not expressed in the brain parenchyma. However, in the presence of proinflammatory cytokines, VCAM1 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 VCAM1, CS1 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

TYSABRI is indicated as a single disease modifying therapy in relapsing remitting multiple sclerosis to prevent relapses and delay progression of disability. Due to safety concerns (see sections 4.4 and 4.8) treatment is restricted to the following patient groups:

• Patients who have failed to respond to a full and adequate course of a beta-interferon. Patients should have had at least 1 relapse in the previous year while on therapy, and have at least 9 T2hyperintense lesions in cranial MRI or at least 1 Gadoliniumenhancing lesion.

or

• Patients 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.

Efficacy as monotherapy has been evaluated in one randomised, doubleblind, placebocontrolled study lasting 2 years (AFFIRM study)in relapsingremitting 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 evaluations were performed every 12 weeks and at times of suspected relapse. MRI evaluations for T1weighted gadolinium (Gd)enhancing lesions and T2hyperintense 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 steadystate 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 steadystate clearance was 13.1 ± 5.0 ml/h, with a mean ± SD halflife 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 antinatalizumab 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 3fold, 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 evaluated in a study of 12 MS patients. Estimates of the total drug 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 drug 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 α4integrinpositive 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 evaluated 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 natalizumabrelated 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, indicating the possibility for transfer of natalizumab into breast milk in humans (see section 4.6).

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.

Concentrate

4 years

Diluted solution

After dilution, 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. Inuse 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 TYSABRI in a vial (type I glass) with a stopper (bromobutyl rubber) and a seal (aluminium) with a flipoff 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 flipoff 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 product for particles or discolouration prior to administration. Do not use if it is discoloured or if foreign particles are seen.

6. The diluted product is to be used as soon as possible and within 8 hours of dilution. If the diluted 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 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

27^th June 2006

01/2009

Detailed information on this product is available on the website of the European Medicines Agency (EMEA) http://www.emea.europa.eu/.