VPRIV 400U powder infusion solution medication leaflet

VPRIV 400 Units powder for solution for infusion

Each vial contains 400 Units* of velaglucerase alfa**.

After reconstitution, one ml of the solution contains 100 Units of velaglucerase alfa.

*An enzyme unit is defined as the amount of enzyme that is required to convert one micromole ofp-nitrophenyl β-D-glucopyranoside to p-nitrophenol per minute at 37 ºC.

**produced in an HT-1080 human fibroblast cell line by recombinant DNA technology.

Each vial contains 12.15 mg sodium.

For the full list of excipients, see section 6.1.

Powder for solution for infusion.

White to off-white powder.

VPRIV is indicated for long-term enzyme replacement therapy (ERT) in patients with type 1 Gaucherdisease.

VPRIV treatment should be supervised by a physician experienced in the management of patients with

Gaucher disease.

The recommended dose is 60 Units/kg administered every other week.

Dose adjustments can be made on an individual basis based on achievement and maintenance oftherapeutic goals. Clinical studies have evaluated doses ranging from 15 to 60 Units/kg every otherweek. Doses higher than 60 Units/kg have not been studied.

Patients currently treated with imiglucerase enzyme replacement therapy for type 1 Gaucher diseasemay be switched to VPRIV, using the same dose and frequency.

Elderly patients may be treated within the same dose range (15 to 60 units/kg) as other adult patients(see section 5.1).

No dosing adjustment is recommended in patients with renal impairment based on current knowledgeof the pharmacokinetics and pharmacodynamics of velaglucerase alfa (see section 5.2).

No dosing adjustment is recommended in patients with hepatic impairment based on currentknowledge of the pharmacokinetics and pharmacodynamics of velaglucerase alfa (see section 5.2).

Twenty of the 94 patients (21%) who received velaglucerase alfa during clinical studies were in thepaediatric and adolescent age range (4 to 17 years). The safety and efficacy profiles were similarbetween paediatric and adult patients (see section 5.1 for further information).

The safety and efficacy of velaglucerase alfa in children below the age of 4 years have not yet beenestablished. No data are available.

For intravenous infusion use only.

To be administered as a 60-minute intravenous infusion.

Must be administered through a 0.2 or 0.22 µm filter.

Home administration under the supervision of a healthcare professional may be considered only forthose patients who have received at least three infusions and were tolerating their infusions well.

Appropriate medical support, including adequately trained personnel in emergency measures, shouldbe readily available when velaglucerase alfa is administered. If anaphylactic or other acute reactionsoccur, immediately discontinue the infusion and initiate appropriate medical treatment (seesection 4.4).

For instructions on reconstitution and dilution of the medicinal product before administration, seesection 6.6.

Severe allergic reaction to the active substance or to any of the excipients listed in section 6.1.

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

Hypersensitivity reactions, including symptoms consistent with anaphylaxis, have been reported inpatients in clinical studies and in post-marketing experience. The majority of hypersensitivityreactions usually occur up to 12 hours post infusion. The most frequently reported symptoms ofhypersensitivity include nausea, rash dyspnoea, back pain, chest discomfort (including chesttightness), urticaria, arthralgia, and headache.

An infusion-related reaction is defined as any adverse drug reaction occurring within 24 hours afterthe initiation of velaglucerase alfa infusion. Infusion-related reactions (IRR) were the most commonlyobserved adverse reactions in patients treated in clinical studies. An IRR often appears as ahypersensitivity reaction. The most frequently reported symptoms of hypersensitivity include nausea,rash, dyspnoea, back pain, chest discomfort (including chest tightness), urticaria, arthralgia, andheadache. Symptoms consistent with anaphylaxis have been reported in patients in clinical studies andin post-marketing experience. Apart from symptoms associated with hypersensitivity reactions IRRsmight show as fatigue, dizziness, pyrexia, blood pressure increase, pruritus, vision blurred, orvomiting. In treatment-naïve patients, the majority of infusion-related reactions occurred during thefirst 6 months of treatment.

Prevention and management of infusion related reactions including hypersensitivity reactions

The management of infusion-related reactions should be based on the severity of the reaction, andinclude slowing the infusion rate, treatment with medicinal products such as antihistamines,antipyretics and/or corticosteroids, and/or stopping and resuming treatment with increased infusiontime.

Due to the risk for hypersensitivity reactions including anaphylaxis, appropriate medical support,including adequately trained personnel in emergency measures, should be readily available whenvelaglucerase alfa is administered. If anaphylactic or other acute reactions occur, in the clinic or homesetting, immediately discontinue the infusion and initiate appropriate medical treatment. For patientsdeveloping anaphylaxis in a home setting it should be considered to continue treatment in a clinicalsetting.

Treatment should be approached with caution in patients who have exhibited symptoms ofhypersensitivity to velaglucerase alfa or other enzyme replacement therapy.

Pre-treatment with antihistamines and/or corticosteroids may prevent subsequent reactions in thosecases where symptomatic treatment was required.

Antibodies may play a role in treatment-related reactions found with the use of velaglucerase alfa. Tofurther evaluate the relationship, in cases of severe infusion-related reactions and in cases of lack orloss of effect, patients should be tested for the presence of antibodies and the results reported to thecompany.

In the clinical studies for Marketing Authorisation one of 94 (1%) patients developed IgG-classantibodies to velaglucerase alfa. In this one event, the antibodies were determined to be neutralising inan in vitro assay.

No patients developed IgE antibodies to velaglucerase alfa.

No infusion related reactions were reported.

Post-marketing phase

During a post marketing extension study, one patient developed IgG antibodies to VPRIV. In addition,a few events of positive neutralising antibodies and lack of effect were reported post marketing.

This medicinal product contains 12.15 mg sodium per vial. This is equivalent to 0.6% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

No interaction studies have been performed.

Patients who have Gaucher disease and become pregnant may experience a period of increased diseaseactivity during pregnancy and the puerperium. A risk-benefit assessment is required for women with

Gaucher disease who are considering pregnancy.

There are no or limited amount of data from the use of velaglucerase alfa in pregnant women. Animalstudies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetaldevelopment, parturition or postnatal development. Close monitoring of the pregnancy and clinicalmanifestations of Gaucher disease is necessary for the individualisation of therapy. Caution should beexercised when prescribing to pregnant women.

There is insufficient information on the excretion of velaglucerase alfa or its metabolites in humanmilk. Velaglucerase is a synthetic form of beta-glucocerebrosidase, which is a normal component ofhuman milk. Studies with other forms of the enzyme have found very low levels of the enzyme inbreastmilk. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom VPRIV taking into account the benefit of breast-feeding for the child and the benefit of therapyfor the woman.

Animal studies show no evidence of impaired fertility (see section 5.3).

VPRIV has no or negligible influence on the ability to drive or use machines.

The most serious adverse reactions in patients in clinical studies were hypersensitivity reactions(2.1%).

The most common adverse reactions were infusion-related reactions (39.4%). The most commonlyobserved symptoms of infusion-related reactions were: headache, dizziness, hypotension,hypertension, nausea, fatigue/asthenia, and pyrexia/body temperature increased (see section 4.4 forfurther information). The only adverse reaction leading to discontinuation of treatment was aninfusion-related reaction.

Adverse reactions reported in patients with type 1 Gaucher disease are listed in Table 1. Information ispresented by system organ class and frequency according to MedDRA convention. Frequency isdefined as very common (1/10), common (1/100 to <1/10), and uncommon (≥1/1,000 to <1/100).

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

Table 1: Adverse reactions reported with VPRIV in patients with type 1 Gaucher disease

System organ class Adverse reaction

Very common Common Uncommon

Immune system hypersensitivity reactionsdisorders (includes dermatitis allergicandanaphylactic*/anaphylactoidreactions)

Nervous system headache, dizzinessdisorders

Eye disorders vision blurred*

Cardiac disorders tachycardia

Respiratory, dyspnoea*thoracic andmediastinaldisorders

Vascular disorders hypertension, hypotension,flushing

Gastrointestinal abdominal nausea vomiting*disorders pain/abdominal painupper,

Skin and rash, urticaria, pruritus*subcutaneous tissuedisorders

Musculoskeletal bone pain, arthralgia,and connective back paintissue disorders

General disorders infusion-related chest discomfort*and administration reaction,site conditions asthenia/fatigue,pyrexia/bodytemperatureincreased

Investigations activated partialthromboplastin timeprolonged, neutralizingantibody positive

*Adverse reactions derived from post-marketing reports

In some cases vomiting can be serious and severe. Vomiting most often occurs during the infusion andup to 24 hours after the infusion.

Elderly population (≥65 years)

The safety profile of VPRIV in clinical studies involving patients aged 65 years and above was similarto that observed in other adult patients.

The safety profile of VPRIV in clinical studies involving children and adolescents aged 4 to 17 yearswas similar to that observed in adult patients.

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.

There is limited information available regarding overdose with velaglucerase alfa. In the majority ofthe cases reporting overdose, no additional adverse events were observed. However, in the event ofaccidental or intentional overdose, patients should be carefully observed and treatment should besymptomatic and supportive. There is no antidote available. The maximum dose of velaglucerase alfain clinical studies was 60 Units/kg (see section 4.4).

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code:

A16AB10.

Gaucher disease is an autosomal recessive disorder caused by mutations in the GBA gene whichresults in a deficiency of the lysosomal enzyme beta-glucocerebrosidase. This enzymatic deficiencycauses an accumulation of glucocerebroside primarily in macrophages, giving rise to foam cells or'Gaucher cells'. In this lysosomal storage disorder (LSD), clinical features are reflective of thedistribution of Gaucher cells in the liver, spleen, bone marrow, skeleton, and lungs. The accumulationof glucocerebroside in the liver and spleen leads to organomegaly. Bone involvement results inskeletal abnormalities and deformities as well as bone pain crises. Deposits in the bone marrow andsplenic sequestration lead to clinically significant anaemia and thrombocytopenia.

The active substance of VPRIV is velaglucerase alfa, which is produced by gene activation technologyin a human cell line. Velaglucerase alfa is a glycoprotein. The monomer is approximately 63 kDa, has497 amino acids, and the same amino acid sequence as the naturally occurring human enzyme,glucocerebrosidase. There are 5 potential N-linked glycosylation sites, four of which are occupied.

Velaglucerase alfa is manufactured to contain predominantly high-mannose-type glycans to facilitateinternalisation of the enzyme by the phagocytic target cells via the mannose receptor.

Velaglucerase alfa supplements or replaces beta-glucocerebrosidase, the enzyme that catalyses thehydrolysis of glucocerebroside to glucose and ceramide in the lysosome, reducing the amount ofaccumulated glucocerebroside and correcting the pathophysiology of Gaucher disease. Velaglucerasealfa increases haemoglobin concentration and platelet counts and reduces liver and spleen volumes inpatients with type 1 Gaucher disease.

In studies 025EXT and 034, patients were offered home therapy. In study 025EXT, 7 of 10 patientsreceived home therapy at least once during 60 months of treatment. In study 034, 25 of 40 patientsreceived home therapy at least once during the 12-month study.

Studies in treatment naïve patients

Study 025 was a 9 month, open-label study in 12 adult (≥18 years) patients who were naïve to ERT(defined as having not been treated with ERT for at least 12 months prior to study entry).

Velaglucerase alfa was initially administered in a dose-escalating fashion in the first 3 patients (15, 30,60 Units/kg) and the 9 remaining patients began treatment with 60 Units/kg.

Clinically meaningful improvements from baseline were observed in haemoglobin concentration andplatelet counts as early as 3 months and in liver and spleen volumes at both 6 months and 9 monthsfollowing the initiation of treatment with velaglucerase alfa.

Ten patients who completed Study 025 enrolled in an open-label extension study (025EXT), 8 ofwhom completed the study. After a minimum of 12 months of continuous treatment withvelaglucerase alfa, all patients qualified to have the dose of velaglucerase alfa reduced in a step-wisefashion from 60 to 30 Units/kg after achieving at least 2 of the 4 “Year 1” therapeutic goals of ERT fortype 1 Gaucher disease. Patients received doses ranging from 30 to 60 Units/kg (median dose35 Units/kg) every other week for up to 84 months (7 years). Sustained clinical activity continued tobe demonstrated during treatment as observed by improvements in haemoglobin concentrations andplatelet counts and reduced liver and spleen volumes.

By month 57, 8 out of the 8 patients had achieved a reduction of at least 2 points in the lumbar spine

Bone Marrow Burden (BMB) score as assessed by MRI scan. Improvement from baseline in meanlumbar spine and femoral neck bone mineral density (BMD) Z-scores were observed at month 24 (0.4;95% CI 0.1, 0.7) and month 33 (0.4; 95% CI 0.2, 0.6), respectively. After seven years of treatment, themean increase from baseline in Z-scores were 0.7 (95% CI 0.4, 1.0) for the lumbar spine and 0.5 (95%

CI 0.2, 0.7) for the femoral neck. No patients were classified at a more severe WHO classification ofbone density compared to baseline.

Study 032 was a 12-month, randomised, double-blind, parallel-group efficacy study that enrolled25 patients aged 4 years and older who were naïve to ERT (defined as having not been treated with

ERT for at least 30 months prior to study entry). Patients were required to have Gaucher disease-related anaemia and either thrombocytopenia or organomegaly. Patients were randomised to receivevelaglucerase alfa at a dose of either 45 Units/kg (N=13) or 60 Units/kg (N=12) every other week.

Velaglucerase alfa 60 Units/kg given intravenously every other week demonstrated clinicallymeaningful increases from baseline in mean haemoglobin concentration (+2.4 g/dl) and platelet count(+50.9 x 109/l), liver volume was reduced from 1.46 to 1.22 times normal (mean reduction of 17%)and spleen volume was reduced from 14.0 to 5.75 times normal (mean reduction of 50%). Meaningfulincreases from baseline were observed in the 45 Units/kg dose group in haemoglobin concentration(+2.4 g/dl) and platelet count (+40.9 x 109/l), liver volume was reduced from 1.40 to 1.24 timesnormal (mean reduction of 6%) and spleen volume was reduced from 14.5 to 9.50 times normal (meanreduction of 40%).

Study 039 was a 9-month, randomised, double-blind, non-inferiority, active-comparator (imiglucerase)controlled, parallel-group efficacy study that enrolled 34 patients aged 4 years and older who werenaïve to ERT (defined as having not been treated with ERT for at least 12 months prior to study entry).

Patients were required to have Gaucher disease-related anaemia and either thrombocytopenia ororganomegaly. Patients received either 60 Units/kg of velaglucerase alfa (N=17) or 60 Units/kg ofimiglucerase (N=17) every other week.

The mean absolute increase from baseline in haemoglobin concentrations was 1.624 g/dl (±0.223 SE)following 9 months of treatment with velaglucerase alfa. This increase in haemoglobin concentrationwas demonstrated to be clinically and statistically non-inferior to imiglucerase (mean treatmentdifference of change from baseline to 9 months [velaglucerase alfa - imiglucerase]: 0.135 g/dl). Therewere no statistically significant differences between velaglucerase alfa and imiglucerase in changes inplatelet counts and liver and spleen volumes after 9 months of velaglucerase alfa treatment, and in thetime to first haemoglobin response (defined as 1 g/dl increase from baseline).

Study in patients switching from imiglucerase treatment to VPRIV

Study 034 was a 12-month, open-label safety study that enrolled 40 patients aged 4 years and olderwho had been receiving treatment with imiglucerase at doses ranging from 15 to 60 Units/kg for aminimum of 30 consecutive months. Patients were required to have a stable dose of imiglucerase for atleast 6 months prior to study enrolment. Treatment with velaglucerase alfa was administered as thesame number of units and regimen as their imiglucerase dose. Haemoglobin concentration and plateletcounts were evaluated as changes from baseline, which was defined as the end of the patient’streatment with imiglucerase.

In patients who switched from imiglucerase to velaglucerase alfa, haemoglobin concentrations andplatelet counts were sustained at therapeutic levels through 12 months of treatment.

Study 058 was an open-label clinical safety study in 211 patients including 205 patients previouslytreated with imiglucerase 6 treatment-naïve patients and 57 patients aged 65 years or older (56/57 hadswitched from imiglucerase to velaglucerase alfa). Patients transferring from imiglucerase wereadministered velaglucerase alfa infusions every other week at the same number of units asimiglucerase within the range of 15 to 60 Units/kg. Patients transferring from a dose of <15 Units/kgimiglucerase were administered 15 Units/kg of velaglucerase alfa.

Patients previously treated with imiglucerase received a median of 8 velaglucerase alfa infusions withmedian duration of treatment of 15.1 weeks. The safety profile in these patients was similar to thatobserved in other clinical studies. Only 1 out of 163 patients assessed developed anti-velaglucerasealfa antibodies during the study.

The mean haemoglobin concentration and platelet count of patients previously treated withimiglucerase were maintained throughout the study and remained within the reference intervals.

Extension study 044

A total of 95 patients (73 adult and 22 paediatric) who participated in studies 032, 034, and 039enrolled in the open label extension study and were treated with velaglucerase alfa. 57 patients weretreatment naïve. All patients received at least 2 years of ERT and were followed for a mean of 4.5years (min. 2.3 years, max 5.8 years).

In this study, haemoglobin concentration, platelet count, liver volume and spleen volume wereassessed in treatment-naïve patients after 24 months of treatment. The results are presented in Table 2.

Table 2: Results at 24 months - change from baseline - study 044 ITT population

Clinical parameters Overall velaglucerase Patients treated Patients who switchedalfa group (N=39) with from long-termimiglucerase imiglucerasefor 9 months treatment to

- and then velaglucerase alfa

Mean change from velaglucerase (N=38)baseline (95% CI) alfa for 15 -months (N=16) Mean change from

- baseline (95% CI)

Mean changefrom baseline(95% CI)

Haemoglobin 2.75 2.00 -0.05concentration (g/dL) (2.28, 3.22) (1.25, 2.75) (-0.34, 0.25)

Platelet count (x109/L) 87.85 160.94 9.03(72.69, 103.00) (117.22, 204.66) (-2.60, 20.66)

Normalised liver volume* -1.21 -1.69 -0.03(%BW) (-1.50, -0.91) (-2.16, -1.21) (-0.10, 0.05)

Normalised spleen -2.66 -3.63 -0.11volume* (-3.50, -1.82) (-7.25, - 0.02) (-0.19, -0.03)(%BW)§§ Excludes patients with splenectomy. N=30, 6 and 34 for the 3 above groups.

*Liver and spleen volume are normalised as a percentage of body weight. Normal spleen isdefined as 0.2% of body weight; normal liver as 2.5% of body weight

Note: Imputation was applied to intermittent missing data.

In this study, BMD was assessed using dual x-ray absorptiometry of the lumbar spine and femoralneck. Among 31 treatment-naïve adult patients treated with velaglucerase alfa, the mean lumbar spine

BMD Z-score at baseline was -1.820 (95% CI: -2.21, -1.43) and increased by 0.62 (95% CI: 0.39,0.84) from baseline following 24 months of treatment with velaglucerase alfa. Similar results wereseen in treatment-naïve patients who received 9 months of imiglucerase followed by velaglucerase alfafor 15 months. In patients who switched from long-term imiglucerase to velaglucerase alfa, lumbarspine BMD was maintained at 24 months. In contrast, no significant change in femoral neck BMD wasobserved.

In the paediatric population (ages 4 to 17 years studied), increases in the mean height Z-score wereseen through 60 months of treatment in the overall treatment-naïve population, suggesting a beneficialtreatment effect with velaglucerase alfa on linear growth. Similar treatment effects were seen through48 months in the paediatric population who received 9 months of imiglucerase followed byvelaglucerase alfa. Paediatric subjects who switched from long-term imiglucerase to velaglucerase alfain study 034 had greater mean height Z-scores at baseline and their mean height Z-scores remainedstable over time.

These treatment effects on haemoglobin, platelet count, organ volumes, bone mineral density andheight were maintained through the end of the study.

Use in the age group 4 to 17 is supported by evidence from controlled studies in adults and paediatric[20 of 94 (21%)] patients. The safety and efficacy profiles were similar between paediatric and adultpatients. The studies allowed the inclusion of patients 2 years and older and the safety and efficacyprofiles are expected to be similar down to the age of 2 years. However, no data are available forchildren under the age of 4 years. The effect on height was assessed in the study 044 (see section 5.1,extension study 044).

Phase I/II study HGT-GCB-068 was conducted to explore the efficacy and safety of velaglucerase alfa

ERT in treatment naïve children and adolescents with type 3 Gaucher disease. This was a multicentre,open-label study in which 60 U/kg of velaglucerase alfa was administered by intravenous infusionevery other week (EOW) over 12 months in 6 patients (2 to 17 years of age at enrolment) with aconfirmed diagnosis of type 3 Gaucher disease.

In this small, exploratory study, the non-neurological efficacy findings and the safety profile ofintravenous velaglucerase alfa in type 3 Gaucher patients were consistent with those observed inpatients with type 1 Gaucher disease. There was no indication of significant improvements of theneurological manifestations of type 3 Gaucher disease except for one patient in this study.

The European Medicines Agency has waived the obligation to submit the results of studies with

VPRIV in all subsets of the paediatric population in type 2 Gaucher disease (see section 4.2 forinformation on paediatric use).

There were no apparent pharmacokinetic differences between male and female patients with type 1

Gaucher disease. None of the subjects in the pharmacokinetic studies were positive foranti-velaglucerase alfa antibodies on the days of pharmacokinetic evaluation. Therefore, it was notpossible to evaluate the effect of antibody response on the pharmacokinetic profile of velaglucerasealfa.

Velaglucerase alfa serum concentrations rose rapidly for the first 20 minutes of the 60-minute infusionbefore levelling off, and Cmax was typically attained between 40 and 60 minutes after the start of theinfusion. After the end of the infusion, velaglucerase alfa serum concentrations fell rapidly in amonophasic or biphasic fashion with a mean t1/2 ranging from 5 to 12 minutes at doses of 15, 30, 45,and 60 Units/kg.

Velaglucerase alfa exhibited an approximately linear (i.e. first-order) pharmacokinetic profile, and

Cmax and AUC increased approximately proportional to the dose over the dose range 15 to 60 Units/kg.

The steady state volume of distribution was approximately 10% of the body weight. The highclearance of velaglucerase alfa from serum (mean 6.7 to 7.6 ml/min/kg) is consistent with the rapiduptake of velaglucerase alfa into macrophages via mannose receptors.

The range of velaglucerase alfa clearance in paediatric patients (N=7, age range 4 to 17 years) wascontained within the range of clearance values in adult patients (N=15, age range 19 to 62 years).

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, and toxicity to reproduction and development (see section 4.6).

Sucrose

Sodium citrate dihydrate (E331)

Citric acid monohydrate (E330)

Polysorbate 20

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

3 years.

Chemical and physical in-use stability has been demonstrated for 24 hours at 2 °C to 8 °C underprotection from light.

From a microbiological point of view, the medicinal product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andmust not exceed 24 hours at 2 °C to 8 °C.

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 after reconstitution and dilution of the medicinal product, see section 6.3.

20 ml vial (type I glass) with a stopper (fluoro-resin coated butyl rubber), one-piece seal, and flip-offcap.

Pack sizes of 1, 5 and 25 vials. Each vial contains 400 Units powder for solution for infusion.

Not all pack sizes may be marketed.

VPRIV requires reconstitution and dilution, and is intended for intravenous infusion only. It is forsingle use only and is administered through a 0.2 or 0.22 µm filter.

Aseptic technique must be used.

VPRIV has to be prepared as follows:1. The number of vials to be reconstituted is determined based on the individual patient’s weightand the prescribed dose.2. The required vials are removed from the refrigerator. Each 400 Units vial is reconstituted with4.3 ml of sterile water for injections.

3. Upon reconstitution, vials should be mixed gently. Vials should not be shaken. Each vial willcontain an extractable volume of 4.0 ml (100 Units/ml).

4. Prior to further dilution, the solution in the vials should be visually inspected; the solutionshould be clear to slightly opalescent and colourless; the solution should not be used if it isdiscoloured or if foreign particulate matter is present.

5. The calculated volume of medicinal product is withdrawn from the appropriate number of vialsand the total volume required is diluted in 100 ml of sodium chloride 9 mg/ml (0.9%) solutionfor infusion. The diluted solution should be mixed gently. It should not be shaken. The infusionshould be initiated within 24 hours from the time of reconstitution.

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

Takeda Pharmaceuticals International AG Ireland Branch

Block 3 Miesian Plaza50 - 58 Baggot Street Lower

Dublin 2

Ireland

EU/1/10/646/002

EU/1/10/646/005

EU/1/10/646/006

Date of first authorisation: 26 August 2010

Date of latest renewal: 23 July 2020

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

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