ALDURAZYME 100UI / ml concentrate for solution for infusion medication leaflet

Aldurazyme 100 U/ml concentrate for solution for infusion

1 ml contains 100 U (approximately 0.58 mg) of laronidase.

Each vial of 5 ml contains 500 U of laronidase.

The activity unit (U) is defined as the hydrolysis of one micromole of substrate (4-MUI) per minute.

Laronidase is a recombinant form of human α-L-iduronidase and is produced by recombinant DNAtechnology using mammalian Chinese Hamster Ovary (CHO) cell culture.

Each vial of 5 ml contains 1.29 mmol sodium.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

A clear to slightly opalescent, and colourless to pale yellow solution.

Aldurazyme is indicated for long-term enzyme replacement therapy in patients with a confirmeddiagnosis of Mucopolysaccharidosis I (MPS I; α-L-iduronidase deficiency) to treat the non-neurological manifestations of the disease (see section 5.1).

Aldurazyme treatment should be supervised by a physician experienced in the management of patientswith MPS I or other inherited metabolic diseases. Administration of Aldurazyme should be carried outin an appropriate clinical setting where resuscitation equipment to manage medical emergencies wouldbe readily available.

The recommended dosage regimen of Aldurazyme is 100 U/kg body weight administered once everyweek.

No dose adjustment is necessary for the paediatric population.

The safety and efficacy of Aldurazyme in patients older than 65 years have not been established andno dosage regimen can be recommended in these patients.

The safety and efficacy of Aldurazyme in patients with renal or hepatic insufficiency have not beenevaluated and no dosage regimen can be recommended in these patients.

Aldurazyme is to be administered as an intravenous infusion.

The initial infusion rate of 2 U/kg/h may be incrementally increased every fifteen minutes, if tolerated,to a maximum of 43 U/kg/h. The total volume of the administration should be delivered inapproximately 3-4 hours. For information on pre-treatment, see section 4.4.

For instruction on dilution of the medicinal product before administration, see section 6.6.

Home Infusion

Infusion of Aldurazyme at home may be considered for patients who are tolerating their infusions welland have no history of moderate or severe IARs for a few months. The decision to have a patient moveto home infusion should be made after evaluation and upon recommendation by the treating physician.

Home infusion infrastructure, resources, and procedures, including training, must be established andavailable to the healthcare professional. Home infusion should be supervised by a healthcareprofessional who should be always available during the home infusion and for a specified time afterinfusion. Appropriate information should be given by the treating physician and/or nurse to the patientand/or caregiver prior to initiation of home infusion.

Dose and infusion rate should remain constant while at home, and not be changed without supervisionof a healthcare professional.

If the patient experiences adverse reactions during the home infusion, the infusion process should bestopped immediately, and appropriate medical treatment should be initiated (see section 4.4).

Subsequent infusions may need to occur in a hospital or in an appropriate setting of outpatient careuntil no such adverse reaction is present.

Severe hypersensitivity (e.g. anaphylactic reaction) to the active substance or to any of the excipientslisted in section 6.1 (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.

Hypersensitivity reactions (including anaphylaxis)

Hypersensitivity reactions, including anaphylaxis have been reported in patients treated with

Aldurazyme (see section 4.8). Some of these reactions were life threatening and included respiratoryfailure/distress, stridor, obstructive airways disorder, hypoxia, hypotension, bradycardia, and urticaria.

Appropriate medical support measures, including cardiopulmonary resuscitation equipment should bereadily available when Aldurazyme is administered.

If anaphylaxis or other severe hypersensitivity reactions occur, the infusion of Aldurazyme should bediscontinued immediately. Caution should be exercised if epinephrine is being considered for use inpatients with MPS I due to the increased prevalence of coronary artery disease in these patients. Inpatients with severe hypersensitivity, desensitization procedure to Aldurazyme may be considered. Ifthe decision is made to re-administer the product, extreme care should be exercised, with appropriateresuscitation measures available.

If mild or moderate hypersensitivity reactions occur, the infusion rate may be slowed or temporarilystopped.

Once a patient tolerates the infusion, the dose may be increased to reach the approved dose.

Infusion-associated reactions (IARs)

IARs, defined as any related adverse event occurring during the infusion or until the end of theinfusion day were reported in patients treated with Aldurazyme (see section 4.8).

Patients with an acute underlying illness at the time of Aldurazyme infusion appear to be at greaterrisk for IARs. Careful consideration should be given to the patient’s clinical status prior toadministration of Aldurazyme.

With initial administration of Aldurazyme or upon re-administration following interruption oftreatment, it is recommended that patients be administered pre-treatment medicines (antihistaminesand/or antipyretics) approximately 60 minutes prior to the start of the infusion, to minimise thepotential occurrence of IARs. If clinically indicated, administration of pre-treatment medications withsubsequent infusions of Aldurazyme should be considered. As there is little experience on resumptionof treatment following prolonged interruption, use caution due to the theoretical increased risk ofhypersensitivity reaction after treatment interruption.

Severe IARs have been reported in patients with pre-existent severe underlying upper airwayinvolvement and therefore specifically these patients should continue to be closely monitored and onlybe infused with Aldurazyme in an appropriate clinical setting where resuscitation equipment tomanage medical emergencies would be readily available.

In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved andsymptomatic treatment (e.g. with antihistamines and antipyretics/ anti-inflammatories) should beconsidered. The benefits and risk of re-administering Aldurazyme following severe IARs should beconsidered. The infusion can be restarted with a reduction of the infusion rate to 1/2 - 1/4 the rate ofthe infusion at which the reaction occurred.

In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pre-treatment should beconsidered (antihistamines and antipyretics/anti-inflammatories and/or corticosteroids) and a reductionof the infusion rate to 1/2 - 1/4 the rate of the infusion at which the previous reaction occurred.

In case of a mild or moderate IAR, symptomatic treatment (e.g. with antihistamines andantipyretics/anti-inflammatories) should be considered and/or a reduction in the infusion rate to halfthe infusion rate at which the reaction occurred.

Once a patient tolerates the infusion, the dose may be increased to reach the approved dose.

Based on the randomized, double-blind, placebo-controlled Phase 3 clinical trial, almost all patientsare expected to develop IgG antibodies to laronidase, mostly within 3 months of initiation oftreatment.

As with any intravenous protein medicinal product, severe allergic-type hypersensitivity reactions arepossible. IARs and hypersensitivity reactions may occur independently of the development of anti-drug antibodies (ADAs). Patients who have developed antibodies or symptoms of IARs should betreated with caution when administering Aldurazyme (see sections 4.3 and 4.8).

Patients treated with Aldurazyme should be closely monitored and all cases of infusion-associatedreactions, delayed reactions and possible immunological reactions reported. Antibody status, including

IgG, IgE, neutralizing antibodies for enzyme activity or enzyme reuptake, should be regularlymonitored and reported.

In clinical studies IARs were usually manageable by slowing the rate of infusion and by (pre-) treatingthe patient with antihistamines and/or antipyretics (paracetamol or ibuprofen), thus enabling thepatient to continue treatment.

This medicinal product contains 30 mg sodium per vial, equivalent to 1.5% of the WHO recommendedmaximum daily intake of 2 g sodium for an adult, and is administered in 0.9% sodium chlorideintravenous solution (see section 6.6).

No interaction studies have been performed. Based on its metabolism, laronidase is an unlikelycandidate for Cytochrome P450 mediated interactions.

Aldurazyme should not be administered simultaneously with chloroquine or procaine due to apotential risk of interference with the intracellular uptake of laronidase.

There are inadequate data on the use of Aldurazyme in pregnant women. Animal studies do notindicate direct or indirect harmful effects on pregnancy, embryonal/foetal development, parturition andpostnatal development (see section 5.3). The potential risk for humans is unknown. Therefore

Aldurazyme should not be used during pregnancy unless clearly necessary.

Laronidase may be excreted in milk. Because there are no data available in neonates exposed tolaronidase via breast milk, it is recommended to stop breast-feeding during Aldurazyme treatment.

There are no clinical data on the effects of laronidase on fertility. Preclinical data did not reveal anysignificant adverse finding (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed.

The majority of the related adverse events in the clinical trials were classified as infusion-associatedreactions (IARs), experienced by 53% of the patients in the Phase 3 study (treated for up to 4 years)and 35% of the patients in the under 5 study (up to 1 year of treatment). Some of the IARs weresevere. Over time the number of these reactions decreased. The most frequent adverse drug reactions(ADRs) were: headache, nausea, abdominal pain, rash, arthralgia, backpain, pain at extremity,flushing, pyrexia, infusion site reactions, blood pressure increased, oxygen saturation decreased,tachycardia and chills. Post-marketing experience of infusion-associated reactions revealed reportingof cyanosis, hypoxia, tachypnoea, pyrexia, vomiting, chills and erythema, in which some of thesereactions were severe.

ADRs to Aldurazyme reported during the Phase 3 study and its extension in a total of 45 patients age5 years and older and treated up to 4 years are listed below using the following categories offrequency: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare(≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the availabledata). Due to the small patient population, an ADR reported in a single patient is classified ascommon.

MedDRA Very common Common Not known

System Organ Class

Immune system Anaphylactic reaction Hypersensitivitydisorders

Psychiatric disorders Restlessness

Nervous system Headache Paraesthesia, dizzinessdisorders

Cardiac disorders Tachycardia Bradycardia

Vascular disorders Flushing Hypotension, pallor, Hypertensionperipheral coldness

Respiratory, thoracic Respiratory distress, Cyanosis, hypoxia,and mediastinal dyspnoea, cough tachypnoea,disorders bronchospasm,respiratory arrest,laryngeal oedema,respiratory failure,pharyngeal swelling,stridor, obstructiveairways disorder

Gastrointestinal Nausea, abdominal pain Vomiting, diarrhoea Lip swelling, swollendisorders tongue

Skin and subcutaneous Rash Angioedema, swelling Erythema, facial edema,tissue disorders face, urticaria, pruritus,cold sweat, alopecia,hyperhidrosis

Musculoskeletal and Arthropathy, arthralgia, Musculoskeletal painconnective tissue back pain, pain indisorders extremity

General disorders and Pyrexia, infusion site Chills, feeling hot, Extravasation, oedemaadministration site reaction* feeling cold, fatigue, peripheralconditions influenza like illness,injection site pain

Investigations Body temperature Drug specific antibody,increased, oxygen neutralizing antibodies,saturation decreased blood pressure increased

* During clinical trials and post-marketing experience, infusion/injection site reactions notablyincluded: swelling, erythema, oedema, discomfort, urticaria, pallor, macule, and warmth.

A single patient with pre-existing airway compromise developed a severe reaction three hours fromthe start of the infusion (at week 62 of treatment) consisting of urticaria and airway obstruction,requiring tracheostomy. This patient tested positive for IgE.

Additionally, a few patients who had a prior history of severe MPS I- related upper airway andpulmonary involvement, experienced severe reactions including bronchospasm, respiratory arrest, andfacial oedema (see section 4.4).

ADRs to Aldurazyme reported during a Phase 2 study in a total of 20 patients, under 5 years of ageand mainly of the severe phenotype, treated up to 12 months are listed below. ADRs were all mild tomoderate in severity.

MedDRA MedDRA

System Organ Class Preferred term Frequency

Cardiac disorders tachycardia Very common

General disorders and administration site pyrexia Very commonconditions chills Very commonblood pressure increased Very common

Investigations oxygen saturationdecreased Very common

In a phase 4 study 33 MPS I patients received 1 of 4 dose regimens: 100 U/kg IV every week(recommended dose), 200 U/kg IV every week, 200 U/kg IV every 2 weeks or 300 U/kg IV every2 weeks. The recommended dose group had the fewest number of patients who experienced ADRs and

IARs. The type of IARs was similar to those seen in other clinical studies.

Almost all patients developed IgG antibodies to laronidase. Most patients seroconverted within3 months of initiation of treatment; although seroconversion in patients under 5 years old with a moresevere phenotype occurred mostly within 1 month (mean 26 days versus 45 days in patients 5 yearsand older). By the end of the Phase 3 study (or at time of early study withdrawal), 13/45 patients hadno detectable antibodies by radioimmunoprecipitation (RIP) assay, including 3 patients that had neverseroconverted. Patients with absent to low antibody levels showed a robust reduction in urinary GAGlevel, whereas patients with high antibody titres showed variable reduction in urinary GAG. Inaddition, higher ADA titres were also observed in MPS I Registry patients with severe disease.

Patients with persistently high ADA titres tended to have less reduction in urinary GAG.

In the Phase 2 and 3 studies, 60 patients were tested for in-vitro neutralising effects. Four patients(three in the Phase 3 study and one in the Phase 2 study) showed marginal to low level in vitroinhibition of laronidase enzymatic activity, which did not appear to impact clinical efficacy and/orurinary GAG reduction.

In patients with clinical decline, assessing urinary GAGs, ADA and neutralising antibodies should beconsidered.

The presence of antibodies was not consistently related to the incidence of IARs, although the onset of

IARs typically coincided with the formation of IgG antibodies. Clinical trials and observational studiesshow only a small number of patients have tested positive for IgE antibodies. The development of IgEantibodies may be associated with hypersensitivity or anaphylactic reactions.

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.

Inappropriate administration of laronidase (overdose and/or infusion rate higher than recommended)may be associated with adverse drug reactions. An excessively fast administration of laronidase mayresult in nausea, abdominal pain, headache, dizziness and dyspnoea.

In such situations and according to the patient's clinical status, the infusion should be stopped or theinfusion rate slowed down immediately. If medically appropriate, further intervention may beindicated.

Pharmacotherapeutic group: Enzymes.

ATC code: A16AB05.

MPS I disease

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymesrequired for the catabolism of glycosaminoglycans (GAGs). MPS I is a heterogeneous andmultisystemic disorder characterised by the deficiency of α-L-iduronidase, a lysosomal hydrolasewhich catalyses the hydrolysis of terminal α-L-iduronic residues of dermatan sulfate and heparansulfate. Reduced or absent α-L-iduronidase activity results in the accumulation of the GAGs, dermatansulfate and heparan sulfate in many cell types and tissues.

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient tohydrolyse the accumulated substrate and to prevent further accumulation. After intravenous infusion,laronidase is rapidly removed from the circulation and taken up by cells into lysosomes, most likelyvia mannose-6 phosphate receptors.

Purified laronidase is a glycoprotein with a molecular weight of approximately 83 kDa. Laronidase iscomprised of 628 amino acids after cleavage of the N-terminus. The molecule contains 6 N-linkedoligosaccharide modifications sites.

Three clinical trials were performed with Aldurazyme to assess its efficacy and safety. One clinicalstudy focussed mainly on assessing the effect of Aldurazyme on the systemic manifestations of MPS Isuch as poor endurance, restrictive lung disease, upper airway obstruction, reduced joint range ofmotion, hepatomegaly and visual impairment. One study mainly assessed the safety andpharmacokinetics of Aldurazyme in patients less than 5 years old, but some efficacy measurementswere included as well. The third study was conducted to evaluate the pharmacodynamics and safety ofdifferent dose regimens of Aldurazyme.

To date there are no clinical data that demonstrate any benefit on the neurological manifestations ofthe disorder.

The safety and efficacy of Aldurazyme was assessed in a randomised, double-blind, placebocontrolled, Phase 3 Study of 45 patients, ranging in age from 6 to 43 years. Although patientsrepresenting the full range of the disease spectrum were enrolled, the majority of the patients were ofthe intermediate phenotype, with only one patient exhibiting the severe phenotype. Patients wereenrolled with a Forced Vital Capacity (FVC) less than 80% of the predicted value and had to be able tostand for 6 minutes and to walk 5 meters. Patients received either 100 U/kg of Aldurazyme or placeboevery week for a total of 26 weeks. The primary efficacy endpoints were changes in percent ofpredicted normal FVC and absolute distance travelled in the six-minute walk test (6MWT). Allpatients subsequently enrolled in an open label extension study where they all received 100 U/kg of

Aldurazyme every week for an additional 3.5 years (182 weeks).

Following 26 weeks of therapy, Aldurazyme-treated patients showed improved respiratory functionand walking ability as compared to placebo as indicated below.

Phase 3, 26 weeks of treatmentcompared to placebop value Confidence interval(95%)

Percent Predicted mean 5.6 -

Phase 3, 26 weeks of treatmentcompared to placebo

FVC median 3.0 0.009 0.9 - 8.6(percentage point)6MWT mean 38.1 -(meters) median 38.5 0.066 -2.0 - 79.0

The open label extension study showed improvement and/or maintenance of these effects up to208 weeks in the Aldurazyme/Aldurazyme group and 182 weeks in the Placebo/Aldurazyme group asindicated in the table below.

Aldurazyme/Aldurazyme Placebo/Aldurazyme

At 208 weeks At 182 weeks

Mean change from pre-treatment baseline

Percent predicted FVC (%)1 - 1.2 - 3.36MWT (meters) + 39.2 + 19.4

Apnea/Hypopnea Index (AHI) - 4.0 - 4.8

Shoulder flexion Range Of Motion (degrees) + 13.1 + 18.3

CHAQ/HAQ Disability Index 2 - 0.43 - 0.261 The decrease in percent predicted FVC is not clinically significant over this timeframe, and absolutelung volumes continued to increase commensurate with changes in height in growing paediatricpatients.2 Both groups exceeded the minimal clinically important difference (-0.24)

Of the 26 patients with abnormal liver volumes at pre-treatment baseline, 22 (85%) achieved a normalliver size by the end of the study. There was a rapid reduction in the excretion of urinary GAG (µg/mgcreatinine) within the first 4 weeks, which was maintained through the remainder of the study. Urinary

GAG levels decreased by 77% and 66% in the Placebo/Aldurazyme and Aldurazyme/Aldurazymegroups, respectively; at the end of the study one-third of the patients (15 of 45) had reached normalurinary GAG levels.

To address the heterogeneity in disease manifestation across patients, using a composite endpoint thatsummed up clinically significant changes across five efficacy variables (percent predicted normal

FVC, 6MWT distance, shoulder flexion range of motion, AHI, and visual acuity) the global responsewas an improvement in 26 patients (58%), no change in 10 patients (22%), and a deterioration in9 patients (20%).

A Phase 2 open-label, 1-year study was conducted that mainly assessed the safety andpharmacokinetics of Aldurazyme in 20 patients less than 5 years of age at the time of enrolment(16 patients with the severe phenotype and 4 with the intermediate phenotype). The patients werescheduled to receive Aldurazyme 100 U/kg weekly infusions for a total duration of 52 weeks. Fourpatients underwent dosage increases to 200 U/kg for the last 26 weeks because of elevated urinary

GAG levels at Week 22.

Eighteen patients completed the study. Aldurazyme was well tolerated at both dosages. The meanurinary GAG level declined by 50% at Week 13 and was reduced by 61% at the end of the study.

Upon study completion, all patients showed reductions in liver size and 50% (9/18) had normal liversize. The proportion of patients with mild left ventricular hypertrophy decreased from 53% (10/19) to17% (3/18), and mean left ventricular mass normalized for body surface area decreased by 0.9 Z-Score(n=17). Several patients showed an increase in height (n=7) and weight (n=3) for age Z-score. Theyounger patients with the severe phenotype (< 2.5 years) and all 4 patients with the intermediatephenotype exhibited a normal rate of mental development, whereas the older patients with a severephenotype made limited or no gains in cognition.

A phase 4 study was conducted to evaluate the pharmacodynamic effects on urinary GAGs, livervolume, and 6MWT, of different Aldurazyme dose regimens. In this 26-week open label study,33 MPS I patients received 1 of 4 dose regimens of Aldurazyme: 100 U/kg IV every week(recommended dose), 200 U/kg IV every week, 200 U/kg IV every 2 weeks; or 300 U/kg IV every2 weeks. No definite benefit was shown with the higher doses over the recommended dose. The200 U/kg IV every 2 weeks regimen may be an acceptable alternative for patients with difficultyreceiving weekly infusions; however, there is no evidence that the long term clinical efficacy of thesetwo dose regimens is equivalent.

After intravenous administration of laronidase with an infusion time of 240 minutes and at a dose of100 U/kg body weight pharmacokinetic properties were measured at Weeks 1, 12 and 26.

Parameter Infusion 1 Infusion 12 Infusion 26

Mean ± SD Mean ± SD Mean± SD

Cmax (U/ml) 0.197 ± 0.052 0.210 ± 0.079 0.302 ± 0.089

AUC∞ (h*U/ml) 0.930 ± 0.214 0.913 ± 0.445 1.191 ± 0.451

CL (ml/min/kg) 1.96 ± 0.495 2.31 ± 1.13 1.68 ± 0.763

Vz (l/kg) 0.604 ± 0.172 0.307 ± 0.143 0.239 ± 0.128

Vss (l/kg) 0.440 ± 0.125 0.252 ± 0.079 0.217 ± 0.081t1/2 (h) 3.61 ± 0.894 2.02 ± 1.26 1.94 ± 1.09

Cmax showed an increase over time. The volume of distribution decreased with continued treatment,possibly related to antibody formation and/or decreased liver volume.

The pharmacokinetic profile in patients less than 5 years old was similar to that of older and lessseverely affected patients.

Laronidase is a protein and is expected to be metabolically degraded through peptide hydrolysis.

Consequently, impaired liver function is not expected to affect the pharmacokinetics of laronidase in aclinically significant way. Renal elimination of laronidase is considered to be a minor pathway forclearance (see section 4.2).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single dose toxicity, repeated dose toxicity and toxicity to reproduction. Genotoxic andcarcinogenic potential are not expected.

Sodium chloride

Sodium phosphate monobasic, monohydrate

Sodium phosphate dibasic, heptahydrate

Polysorbate 80

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts except those mentioned in section 6.6.

Unopened vials:3 years

Diluted solutions:

From a microbiological safety point of view, the product should be used immediately. If not usedimmediately, in-use storage should not be longer than 24 hours at 2°C - 8°C provided that dilution hastaken place under controlled and validated aseptic conditions.

Store in a refrigerator (2°C - 8°C).

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

5 ml concentrate for solution in a vial (type I glass) with a stopper (siliconised chlorobutyl rubber) anda seal (aluminium) with a flip-off cap (polypropylene).

Pack sizes: 1, 10 and 25 vials.

Not all pack sizes may be marketed.

Each vial of Aldurazyme is intended for single use only. The concentrate for solution for infusion hasto be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It isrecommended that the diluted Aldurazyme solution be administered to patients using an infusion setequipped with a 0.2 µm in-line filter.

Aldurazyme 100 U/ml concentrate for solution for infusion reconstituted in 0.9% sodium chloride hasan osmolality of 415 - 505 mOsm/kg and a pH of 5.2 - 5.9.

Preparation of the Aldurazyme Infusion (Use Aseptic Technique) Determine the number of vials to be diluted based on the individual patient's weight. Removethe required vials from the refrigerator approximately 20 minutes in advance in order to allowthem to reach room temperature (below 30˚C).

 Before dilution, visually inspect each vial for particulate matter and discoloration. The clear toslightly opalescent and colourless to pale yellow solution should be free of visible particles. Donot use vials exhibiting particles or discoloration.

 Determine the total volume of infusion based on the individual patient's weight, either 100 ml (ifbody weight is less or equal than 20 kg) or 250 ml (if body weight is more than 20 kg) ofsodium chloride 9 mg/ml (0.9%) solution for infusion.

 Withdraw and discard a volume of the sodium chloride 9 mg/ml (0.9%) solution for infusionfrom the infusion bag equal to the total volume of Aldurazyme to be added.

 Withdraw the required volume from the Aldurazyme vials and combine the withdrawn volumes. Add the combined volumes of Aldurazyme to the sodium chloride 9 mg/ml (0.9%) solution forinfusion. Mix the solution for infusion gently. Prior to use visually inspect the solution for particulate matter. Only clear and colourlesssolutions without visible particles should be used.

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

Sanofi B.V., Paasheuvelweg 25, 1105 BP Amsterdam, The Netherlands.

EU/1/03/253/001-003

Date of first authorisation: 10 June 2003

Date of latest renewal: 10 June 2008

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

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