REBIF 44mcg / 0.5ml injection solution in the cartridge medication leaflet

Rebif 44 micrograms/0.5 mL solution for injection in cartridge

Each pre-filled cartridge contains 132 micrograms (36 MIU*) of interferon beta-1a** in 1.5 mLsolution, corresponding to 88 micrograms/mL.

* Million International Units, measured by cytopathic effect (CPE) bioassay against the in-houseinterferon beta-1a standard which is calibrated against the current international NIH standard(GB-23-902-531).

** produced in Chinese hamster ovary Cells (CHO-K1) by recombinant DNA technology.

Excipient with known effect: Contains 2.5 mg benzyl alcohol per dose of 0.5 mL.

For the full list of excipients, see section 6.1.

Solution for injection in cartridge.

Clear to opalescent solution, with pH 3.7 to 4.1 and osmolarity 250 to 450 mOsm/L.

Rebif is indicated for the treatment of

* patients with a single demyelinating event with an active inflammatory process, if alternativediagnoses have been excluded, and if they are determined to be at high risk of developingclinically definite multiple sclerosis (see section 5.1)

* patients with relapsing multiple sclerosis. In clinical trials, this was characterised by two ormore acute exacerbations in the previous two years (see section 5.1).

Efficacy has not been demonstrated in patients with secondary progressive multiple sclerosis withoutongoing relapse activity (see section 5.1).

Treatment should be initiated under supervision of a physician experienced in the treatment of thedisease.

For patients initiating treatment with Rebif, Rebif 8.8 micrograms and Rebif 22 micrograms areavailable in a pack that corresponds to the patient needs for the first month of therapy.

When first starting treatment with Rebif, in order to allow tachyphylaxis to develop thus reducingadverse reactions it is recommended that patients be started at 8.8 micrograms dose subcutaneouslyand the dose be increased over a 4 week period to the targeted dose, according to the followingschedule:

Recommended Titration dose for Rebif

Titration 44 micrograms(% of final dose) three times per week (tiw)

Weeks 1-2 20% 8.8 micrograms tiw

Weeks 3-4 50% 22 micrograms tiw

Weeks 5+ 100% 44 micrograms tiw

First demyelinating event

The posology for patients who have experienced a first demyelinating event is 44 micrograms of Rebifgiven three times per week by subcutaneous injection.

Relapsing multiple sclerosis

The recommended posology of Rebif is 44 micrograms given three times per week by subcutaneousinjection. A lower dose of 22 micrograms, also given three times per week by subcutaneous injection,is recommended for patients who cannot tolerate the higher dose in view of the treating specialist.

No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents.

However, a paediatric retrospective cohort study collected safety data with Rebif from medical recordsin children (n=52) and adolescents (n=255). The results of this study suggest that the safety profile inchildren (2 to 11 years old) and in adolescents (12 to 17 years old) receiving Rebif 22 micrograms or44 micrograms subcutaneous three times per week is similar to that seen in adults.

The safety and efficacy of Rebif in children below 2 years of age have not yet been established. Rebifshould not be used in this age group.

Rebif solution for subcutaneous injection in a cartridge is intended for multidose use with the

RebiSmart electronic injection device following adequate training of the patient and/or carer.

For administration, the instructions provided in the package leaflet and in the instruction manual(Instructions for Use) provided with RebiSmart should be followed.

Prior to injection and for an additional 24 hours after each injection, an antipyretic analgesic is advisedto decrease flu-like symptoms associated with Rebif administration.

At the present time, it is not known for how long patients should be treated. Safety and efficacy with

Rebif have not been demonstrated beyond 4 years of treatment. It is recommended that patients shouldbe evaluated at least every second year in the 4-year period after initiation of treatment with Rebif anda decision for longer term treatment should then be made on an individual basis by the treatingphysician.

* Hypersensitivity to natural or recombinant interferon beta or to any of the excipients listed insection 6.1.

* Current severe depression and/or suicidal ideation (see sections 4.4 and 4.8).

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

Patients should be informed of the most frequent adverse reactions associated with interferon betaadministration, including symptoms of the flu-like syndrome (see section 4.8). These symptoms tendto be most prominent at the initiation of therapy and decrease in frequency and severity with continuedtreatment.

Cases of thrombotic microangiopathy, manifested as thrombotic thrombocytopenic purpura (TTP) orhaemolytic uraemic syndrome (HUS), including fatal cases, have been reported with interferon betaproducts. Events were reported at various time points during treatment and may occur several weeks toseveral years after starting treatment with interferon beta. Early clinical features includethrombocytopenia, new onset hypertension, fever, central nervous system symptoms (e.g. confusion,paresis) and impaired renal function. Laboratory findings suggestive of TMA include decreasedplatelet counts, increased serum lactate dehydrogenase (LDH) due to haemolysis and schistocytes(erythrocyte fragmentation) on a blood film. Therefore if clinical features of TMA are observed,further testing of blood platelet levels, serum LDH, blood films and renal function is recommended. If

TMA is diagnosed, prompt treatment is required (considering plasma exchange) and immediatediscontinuation of Rebif is recommended.

Depression and suicidal ideation

Rebif should be administered with caution to patients with previous or current depressive disorders inparticular to those with antecedents of suicidal ideation (see section 4.3). Depression and suicidalideation are known to occur in increased frequency in the multiple sclerosis population and inassociation with interferon use. Patients treated with Rebif should be advised to immediately reportany symptoms of depression and/or suicidal ideation to their prescribing physician. Patients exhibitingdepression should be monitored closely during therapy with Rebif and treated appropriately. Cessationof therapy with Rebif should be considered (see sections 4.3 and 4.8).

Seizure disorders

Rebif should be administered with caution to patients with a history of seizures, to those receivingtreatment with anti-epileptics, particularly if their epilepsy is not adequately controlled withantiepileptics (see sections 4.5 and 4.8).

Cardiac disease

Patients with cardiac disease, such as angina, congestive heart failure or arrhythmia, should be closelymonitored for worsening of their clinical condition during initiation of therapy with interferon beta-1a.

Symptoms of the flu-like syndrome associated with interferon beta-1a therapy may prove stressful topatients with cardiac conditions.

Injection site necrosis

Injection site necrosis (ISN) has been reported in patients using Rebif (see section 4.8). To minimisethe risk of injection site necrosis patients should be advised to:

* use an aseptic injection technique,

* rotate the injection sites with each dose.

The procedure for the self-administration by the patient should be reviewed periodically especially ifinjection site reactions have occurred.

If the patient experiences any break in the skin, which may be associated with swelling or drainage offluid from the injection site, the patient should be advised to consult with their physician beforecontinuing injections with Rebif. If the patient has multiple lesions, Rebif should be discontinued untilhealing has occurred. Patients with single lesions may continue provided that the necrosis is not tooextensive.

Hepatic dysfunction

In clinical trials with Rebif, asymptomatic elevations of hepatic transaminases (particularly alanineaminotransferase (ALT)) were common and 1-3% of patients developed elevations of hepatictransaminases above 5 times the upper limit of normal (ULN). In the absence of clinical symptoms,serum ALT levels should be monitored prior to the start of therapy, at months 1, 3 and 6 on therapyand periodically thereafter. Dose reduction of Rebif should be considered if ALT rises above 5 timesthe ULN, and gradually re-escalated when enzyme levels have normalized. Rebif should be initiatedwith caution in patients with a history of significant liver disease, clinical evidence of active liverdisease, alcohol abuse or increased serum ALT (>2.5 times ULN). Treatment with Rebif should bestopped if icterus or other clinical symptoms of liver dysfunction appear.

Rebif, like other interferons beta, has a potential for causing severe liver injury including acute hepaticfailure (see section 4.8). The majority of the cases of severe liver injury occurred within the first sixmonths of treatment. The mechanism for the rare symptomatic hepatic dysfunction is not known. Nospecific risk factors have been identified.

Nephrotic syndrome

Cases of nephrotic syndrome with different underlying nephropathies including collapsing focalsegmental glomerulosclerosis (FSGS), minimal change disease (MCD), membranoproliferativeglomerulonephritis (MPGN) and membranous glomerulopathy (MGN) have been reported duringtreatment with interferon-beta products. Events were reported at various time points during treatmentand may occur after several years of treatment with interferon-beta. Periodic monitoring of early signsor symptoms, e.g. oedema, proteinuria and impaired renal function is recommended, especially inpatients at higher risk of renal disease. Prompt treatment of nephrotic syndrome is required anddiscontinuation of treatment with Rebif should be considered.

Laboratory abnormalities are associated with the use of interferons. The overall incidence of these isslightly higher with Rebif 44 than Rebif 22 micrograms. Therefore, in addition to those laboratorytests normally required for monitoring patients with multiple sclerosis, liver enzyme monitoring andcomplete and differential blood cell counts and platelet counts are recommended at regular intervals(1, 3 and 6 months) following introduction of Rebif therapy and then periodically thereafter in theabsence of clinical symptoms. These should be more frequent when initiating Rebif 44 micrograms.

Thyroid disorders

Patients being treated with Rebif may occasionally develop new or worsening thyroid abnormalities.

Thyroid function testing is recommended at baseline and if abnormal, every 6-12 months followinginitiation of therapy. If tests are normal at baseline, routine testing is not needed but should beperformed if clinical findings of thyroid dysfunction appear (see section 4.8).

Severe renal or hepatic failure and severe myelosuppression

Caution should be used, and close monitoring considered when administering interferon beta-1a topatients with severe renal and hepatic failure and to patients with severe myelosuppression.

Neutralising antibodies

Serum neutralising antibodies against interferon beta-1a may develop. The precise incidence ofantibodies is as yet uncertain. Clinical data suggest that after 24 to 48 months of treatment with

Rebif 44 micrograms, approximately 13 to 14% of patients develop persistent serum antibodies tointerferon beta-1a. The presence of antibodies has been shown to attenuate the pharmacodynamicresponse to interferon beta-1a (beta-2 microglobulin and neopterin). Although the clinical significanceof the induction of antibodies has not been fully elucidated, the development of neutralising antibodiesis associated with reduced efficacy on clinical and MRI variables. If a patient responds poorly totherapy with Rebif, and has neutralising antibodies, the treating physician should reassess thebenefit/risk ratio of continued Rebif therapy.

The use of various assays to detect serum antibodies and differing definitions of antibody positivitylimits the ability to compare antigenicity among different products.

Other forms of multiple sclerosis

Only sparse safety and efficacy data are available from non-ambulatory patients with multiplesclerosis. Rebif has not yet been investigated in patients with primary progressive multiple sclerosisand should not be used in these patients.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. it is essentially‘sodium-free’.

Benzyl alcohol

This medicinal product contains benzyl alcohol. Benzyl alcohol may cause allergic reactions.

Monitor patients less than 3 years of age for respiratory symptoms.

Advise patients who are pregnant or breastfeeding of the potential risk from excipient benzyl alcohol,which might accumulate over time and cause metabolic acidosis. Use with caution in patients withhepatic or renal impairment, because of the potential risk from excipient benzyl alcohol which mightaccumulate over time and cause metabolic acidosis.

No interaction studies have been performed with interferon beta-1a in humans.

Interferons have been reported to reduce the activity of hepatic cytochrome P450-dependent enzymesin humans and animals. Caution should be exercised when administering Rebif in combination withmedicinal products that have a narrow therapeutic index and are largely dependent on the hepaticcytochrome P450 system for clearance, e.g. antiepileptics and some classes of antidepressants.

The interaction of Rebif with corticosteroids or adrenocorticotropic hormone (ACTH) has not beenstudied systematically. Clinical studies indicate that multiple sclerosis patients can receive Rebif andcorticosteroids or ACTH during relapses.

A large amount of data (more than 1,000 pregnancy outcomes) from registries and post-marketingexperience indicates no increased risk of major congenital anomalies after pre-conception exposure tointerferon beta or such exposure during the first trimester of pregnancy. However, the duration ofexposure during the first trimester is uncertain, because data were collected when interferon beta usewas contraindicated during pregnancy, and treatment likely interrupted when the pregnancy wasdetected and/or confirmed. Experience with exposure during the second and third trimester is verylimited.

Based on animal data (see section 5.3), there is a possibly increased risk for spontaneous abortion. Therisk of spontaneous abortions in pregnant women exposed to interferon beta cannot adequately beevaluated based on the currently available data, but the data do not suggest an increased risk so far.

If clinically needed, the use of Rebif may be considered during pregnancy

Limited information available on the transfer of interferon beta-1a into breast milk, together with thechemical/physiological characteristics of interferon beta, suggests that levels of interferon beta-1aexcreted in human milk are negligible. No harmful effects on the breastfed newborn/infant areanticipated.

Rebif can be used during breast-feeding.

The effects of Rebif on fertility have not been investigated.

Central nervous system-related adverse events associated with the use of interferon beta(e.g. dizziness) might influence the patient's ability to drive or use machines (see section 4.8).

The highest incidence of adverse reactions associated with Rebif therapy is related to flu-likesyndrome. Flu-like symptoms tend to be most prominent at the initiation of therapy and decrease infrequency with continued treatment. Approximately 70 % of patients treated with Rebif can expect toexperience the typical interferon flu-like syndrome within the first six months after starting treatment.

Approximately 30 % of patients will also experience reactions at the injection site, predominantly mildinflammation or erythema. Asymptomatic increases in laboratory parameters of hepatic function anddecreases in white blood cells are also common.

The majority of adverse reactions observed with interferon beta-1a are usually mild and reversible,and respond well to dose reductions. In case of severe or persistent undesirable effects, the dose of

Rebif may be temporarily lowered or interrupted, at the discretion of the physician.

List of adverse reactions

The adverse reactions presented have been identified from clinical studies as well as from post-marketing reports (an asterisk [*] indicates adverse reactions identified during post-marketingsurveillance). The following definitions apply to the frequency terminology used hereafter: verycommon (≥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), frequency not known (cannot be estimated from the available data).

Blood and the lymphatic system disorders

Very common: Neutropenia, lymphopenia, leukopenia, thrombocytopenia, anaemia

Rare: Thrombotic microangiopathy including thrombotic thrombocytopenicpurpura/haemolytic uraemic syndrome* (class label for interferon betaproducts, see section 4.4), pancytopenia*

Uncommon: Thyroid dysfunction, most often presenting as hypothyroidism orhyperthyroidism

Rare: Anaphylactic reactions*

Very common: Asymptomatic transaminase increase

Common: Severe elevations in transaminases

Uncommon: Hepatitis with or without icterus*

Rare: Hepatic failure* (see section 4.4), autoimmune hepatitis*

Common: Depression, insomnia

Rare: Suicide attempt*

Very common: Headache

Uncommon: Seizures*

Frequency not known: Transient neurological symptoms (i.e. hypoesthesia, muscle spasm,paraesthesia, difficulty in walking, musculoskeletal stiffness) that maymimic multiple sclerosis exacerbations*

Uncommon: Retinal vascular disorders (i.e. retinopathy, cotton wool spots, obstruction ofretinal artery or vein)*

Uncommon: Thromboembolic events*

Uncommon: Dyspnoea*

Frequency not known: Pulmonary arterial hypertension* (class label for interferon products, seebelow Pulmonary arterial hypertension)

Common: Diarrhoea, vomiting, nausea

Common: Pruritus, rash, erythematous rash, maculo-papular rash, alopecia*

Uncommon: Urticaria*

Rare: Quincke’s oedema (angio-oedema)*, erythema multiforme*, erythemamultiforme-like skin reactions*, Stevens Johnson syndrome*

Musculoskeletal and connective disorders

Common: Myalgia, arthralgia

Rare: Drug-induced lupus erythematosus*

Rare: Nephrotic syndrome*, glomerulosclerosis* (see section 4.4)

Very common: Injection site inflammation, injection site reaction, influenza-like symptoms

Common: Injection site pain, fatigue, rigors, fever

Uncommon: Injection site necrosis, injection site mass, injection site abscess, injectionsite infections*, increased sweating*

Rare: Injection site cellulitis*

Frequency not known: Panniculitis (occurred in the injection site)

No formal clinical trials or pharmacokinetic studies have been conducted in children or adolescents.

Limited safety data suggest that the safety profile in children and adolescents (2 to 17 years old)receiving Rebif 22 micrograms or 44 micrograms three times weekly is similar to that seen in adults.

The administration of interferons has been associated with anorexia, dizziness, anxiety, arrhythmias,vasodilation and palpitation, menorrhagia and metrorrhagia.

An increased formation of auto-antibodies may occur during treatment with interferon beta.

Cases of pulmonary arterial hypertension (PAH) have been reported with interferon beta products.

Events were reported at various time points including up to several years after starting treatment withinterferon beta.

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.

In case of overdose, patients should be hospitalised for observation and appropriate supportivetreatment should be given.

Pharmacotherapeutic group: Immunostimulants, Interferons, ATC code: L03AB07

Interferons are a group of endogenous glycoproteins endowed with immunomodulatory, antiviral andantiproliferative properties.

Rebif (interferon beta-1a) shares the same amino acid sequence with endogenous humaninterferon beta. It is produced in mammalian cells (Chinese hamster ovary) and is thereforeglycosylated like the natural protein.

Regardless of the route of dosing, pronounced pharmacodynamic changes are associated with theadministration of Rebif. After a single dose, intracellular and serum activity of 2’5’OAS synthetaseand serum concentrations of beta-2 microglobulin and neopterin increase within 24 hours, and start todecline within 2 days. Intramuscular and subcutaneous administrations produce fully superimposableresponses. After repeated subcutaneous administration every 48 hours for 4 doses, these biologicalresponses remain elevated, with no signs of tolerance development.

Biological response markers (e.g., 2’,5’-OAS activity, neopterin and beta 2-microglobulin) areinduced by interferon beta-1a following subcutaneous doses administered to healthy volunteersubjects. Time to peak concentrations following a single subcutaneous injection were 24 to 48 hoursfor neopterin, beta-2-microglobulin and 2’5’OAS, 12 hours for MX1 and 24 hours for OAS1 and

OAS2 gene expression. Peaks of similar height and time were observed for most of these markers afterfirst and sixth administration.

The precise mechanism of action of Rebif in multiple sclerosis is still under investigation.

Single clinical event suggestive of multiple sclerosis

One 2-year controlled clinical trial with Rebif was performed in patients with a single clinical eventsuggestive of demyelination due to multiple sclerosis. The patients enrolled into the trial had at leasttwo clinically silent lesions on the T2-weighted MRI scan, with a size of at least 3 mm, at least one ofwhich is ovoid or periventricular or infratentorial. Any disease other than multiple sclerosis that couldbetter explain signs and symptoms of the patient had to be excluded.

Patients were randomised in a double-blind manner to either Rebif 44 micrograms given three timesper week, Rebif 44 micrograms once weekly, or placebo. If a second clinical demyelinating eventoccurred confirming definite multiple sclerosis, patients switched to the recommended posology of

Rebif 44 micrograms three times per week in an open label manner, while maintaining blinding as toinitial randomisation.

Efficacy results of Rebif 44 micrograms given three times per week compared to placebo from thisstudy are as follows:

Parameter Treatment Treatment Comparison

Statistics Rebif 44 mcg tiw versus Placebo

Placebo Rebif 44 Risk Cox’s Log-Rank(n=171) mcg tiw Reduction Proportional p-value(n=171) Hazard Ratio[95% CI]

McDonald (2005) Conversion

Number of events 144 106

KM Estimate 85.8% 62.5% 51% 0.49 [0.38;0.64] <0.001

CDMS Conversion

Number of events 60 33

KM Estimate 37.5% 20.6% 52% 0.48 [0.31;0.73] <0.001

Mean CUA Lesions per Subject per Scan During the Double Blind Period

Least Square Means(SE) 2.59 (0.30) 0.50 (0.06) 81% 0.19 [0.14;0.26]* <0.001tiw: three times per week, CI: confidence interval, CUA: combined unique active

* Least Squared Mean Ratio [95% CI]

For the time being there is no well established definition of a high risk patient, although a moreconservative approach is to accept at least nine T2 hyperintense lesions on the initial scan and at leastone new T2 or one new Gd-enhancing lesion on a follow-up scan taken at least 1 month after theinitial scan. In any case, treatment should only be considered for patients classified as high risk.

Relapsing-remitting multiple sclerosis

The safety and efficacy of Rebif has been evaluated in patients with relapsing-remitting multiplesclerosis at doses ranging from 11 to 44 micrograms (3-12 million IU), administered subcutaneouslythree times per week. At licensed posology, Rebif 44 micrograms has been demonstrated to decreasethe incidence (approximately 30% over 2 years) and severity of clinical relapses in patients with atleast 2 exacerbations in the previous 2 years and with an EDSS of 0-5.0 at entry. The proportion ofpatients with disability progression, as defined by at least one point increase in EDSS confirmedthree months later, was reduced from 39% (placebo) to 27% (Rebif 44 micrograms). Over 4 years, thereduction in the mean exacerbation rate was 22% in patients treated with Rebif 22 micrograms, and29% in patients treated with Rebif 44 micrograms group compared with a group of patients treatedwith placebo for 2 years and then either Rebif 22 or Rebif 44 micrograms for 2 years.

Secondary progressive multiple sclerosis

In a 3-year study in patients with secondary progressive multiple sclerosis (EDSS 3-6.5) with evidenceof clinical progression in the preceding two years and who had not experienced relapses in thepreceding 8 weeks, Rebif had no significant effect on progression of disability, but relapse rate wasreduced by approximately 30%. If the patient population was divided into 2 subgroups (those with andthose without relapses in the 2-year period prior to study entry), there was no effect on disability inpatients without relapses, but in patients with relapses, the proportion with progression in disability atthe end of the study was reduced from 70% (placebo) to 57% (Rebif 22 micrograms and44 micrograms combined). These results obtained in a subgroup of patients a posteriori should beinterpreted cautiously.

Primary progressive multiple sclerosis

Rebif has not yet been investigated in patients with primary progressive multiple sclerosis, and shouldnot be used in these patients.

In healthy volunteers after intravenous administration, interferon beta-1a exhibits a sharpmulti-exponential decline, with serum levels proportional to the dose. Subcutaneous and intramuscularadministrations of Rebif produce equivalent exposure to interferon beta.

Following repeated subcutaneous injections of 22 and 44 micrograms doses of Rebif maximumconcentrations were typically observed after 8 hours, but this was highly variable.

After repeated subcutaneous doses in healthy volunteers, the main PK parameters (AUCtau and Cmax)increased proportional to the increased in dose from 22 micrograms to 44 micrograms. The estimatedapparent half-life is 50 to 60 hours, which is in line with the accumulation observed after multipledosing.

Interferon beta-1a is mainly metabolised and excreted by the liver and the kidneys.

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

Rebif has not been investigated for carcinogenicity.

A study on embryo/foetal toxicity in monkeys showed no evidence of reproductive disturbances. Anincreased risk of abortions has been reported in animal studies of other alpha and beta interferons. Noinformation is available on the effects of the interferon beta-1a on male fertility.

Mannitol

Poloxamer 188

L-methionine

Benzyl alcohol

Sodium acetate

Acetic acid for pH adjustment

Sodium hydroxide for pH adjustment

Water for injections

Not applicable.

18 months.

After first injection use within 28 days.

Store in a refrigerator (2°C - 8°C) away from the cooling element. Do not freeze. Store the cartridge inthe original package in order to protect from light.

The device (RebiSmart) containing a pre-filled cartridge of Rebif must be stored in the device storagebox in a refrigerator (2°C - 8°C).

For the purpose of ambulatory use, the patient may remove Rebif from the refrigerator and store it notabove 25°C for one single period of up to 14 days. Rebif must then be returned to the refrigerator andused before the expiry date.

Cartridges (type 1 glass) with a plunger stopper (rubber) and crimp cap (aluminium and halobutyl rubber)containing 1.5 mL solution for injection.

Pack size of 4 or 12 cartridges.

Not all pack sizes may be marketed.

The solution for injection in a pre-filled cartridge is ready for use with the RebiSmart electronicinjection device. For storage of the device with the cartridge, see section 6.4.

For multidose use. Only clear to opalescent solution without particles and without visible signs ofdeterioration should be used.

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

Merck Europe B.V.

Gustav Mahlerplein 1021082 MA Amsterdam

The Netherlands

EU/1/98/063/009

EU/1/98/063/019

Date of first authorisation: 04 May 1998

Date of latest renewal: 04 May 2008

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

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