ELAPRASE 2mg / ml perfusive solution concentrate medication leaflet

Elaprase 2 mg/ml concentrate for solution for infusion

Each vial contains 6 mg of idursulfase. Each ml contains 2 mg of idursulfase*.

Each vial contains 0.482 mmol of sodium.

For the full list of excipients, see section 6.1.

* idursulfase is produced by recombinant DNA technology in a continuous human cell line.

Concentrate for solution for infusion (sterile concentrate).

A clear to slightly opalescent, colourless solution.

Elaprase is indicated for the long-term treatment of patients with Hunter syndrome(Mucopolysaccharidosis II, MPS II).

Heterozygous females were not studied in the clinical trials.

This treatment should be supervised by a physician or other healthcare professional experienced in themanagement of patients with MPS II disease or other inherited metabolic disorders.

Elaprase is administered at a dose of 0.5 mg/kg body weight every week by intravenous infusion overa 3 hour period, which may be gradually reduced to 1 hour if no infusion-associated reactions areobserved (see section 4.4).

For instructions for use, see section 6.6.

Infusion at home may be considered for patients who have received several months of treatment in theclinic and who are tolerating their infusions well. Home infusions should be performed under thesurveillance of a physician or other healthcare professional.

There is no clinical experience in patients over 65 years of age.

There is no clinical experience in patients with renal or hepatic insufficiency. (see section 5.2).

The dose for children and adolescents is the same as for adults, 0.5 mg/kg body weight weekly.

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

Severe or life-threatening hypersensitivity to the active substance or to any of the excipients listed insection 6.1 if hypersensitivity is not controllable.

Patients treated with idursulfase may develop infusion-related reactions (see section 4.8). Duringclinical trials, the most common infusion-related reactions included cutaneous reactions (rash, pruritus,urticaria), pyrexia, headache, hypertension, and flushing. Infusion-related reactions were treated orameliorated by slowing the infusion rate, interrupting the infusion, or by administration of medicinalproducts, such as antihistamines, antipyretics, low-dose corticosteroids (prednisone andmethylprednisolone), or beta-agonist nebulisation.

Special care should be taken when administering an infusion in patients with severe underlying airwaydisease. These patients should be closely monitored and infused in an appropriate clinical setting.

Caution must be exercised in the management and treatment of such patients by limitation or carefulmonitoring of antihistamine and other sedative medicinal product use. Institution of positive-airwaypressure may be necessary in some cases.

Delaying the infusion in patients who present with an acute febrile respiratory illness should beconsidered. Patients using supplemental oxygen should have this treatment readily available duringinfusion in the event of an infusion-related reaction.

Anaphylactoid/anaphylactic reactions

Anaphylactoid/anaphylactic reactions, which have the potential to be life threatening, have beenobserved in some patients treated with idursulfase up to several years after initiating treatment. Lateemergent symptoms and signs of anaphylactoid/anaphylactic reactions have been observed as long as24 hours after an initial reaction. If an anaphylactoid/anaphylactic reaction occurs the infusion shouldbe immediately suspended and appropriate treatment and observation initiated. The current medicalstandards for emergency treatment are to be observed. Patients experiencing severe or refractoryanaphylactoid/anaphylactic reactions may require prolonged clinical monitoring. Patients who haveexperienced anaphylactoid/anaphylactic reactions should be treated with caution when re-administering idursulfase, appropriately trained personnel and equipment for emergency resuscitation(including epinephrine) should be available during infusions. Severe or potentially life-threateninghypersensitivity is a contraindication to rechallenge, if hypersensitivity is not controllable (seesection 4.3).

Patients with the complete deletion/large rearrangement genotype

Paediatric patients with the complete deletion/large rearrangement genotype have a high probability ofdeveloping antibodies, including neutralizing antibodies, in response to exposure to idursulfase.

Patients with this genotype have a higher probability of developing infusion-related adverse eventsand tend to show a muted response as assessed by decrease in urinary output of glycosaminoglycans,liver size and spleen volume compared to patients with the missense genotype. Management ofpatients must be decided on an individual basis (see section 4.8).

This medicinal product contains 0.482 mmol sodium (or 11.1 mg) per vial. This is equivalent to 0.6%of the WHO recommended maximum daily intake of 2 g sodium for an adult.

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

No formal medicinal product interaction studies have been conducted with idursulfase.

Based on its metabolism in cellular lysosomes, idursulfase would not be a candidate for cytochrome

P450 mediated interactions.

There are no data or limited amount of data from the use of idursulfase in pregnant women. Animalstudies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (seesection 5.3). As a precautionary measure, it is preferable to avoid the use of idursulfase duringpregnancy.

It is not known whether idursulfase is excreted in human breast milk. Available data in animals haveshown excretion of idursulfase in milk (see section 5.3). A risk to the newborns/infants cannot beexcluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstainfrom idursulfase therapy taking into account the benefit of breast feeding for the child and the benefitof therapy for the woman.

No effects on male fertility were seen in reproductive studies in male rats.

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

Adverse reactions that were reported for the 32 patients treated with 0.5 mg/kg idursulfase weekly inthe TKT024 phase II/III 52-week placebo-controlled study were almost all mild to moderate inseverity. The most common were infusion-related reactions, 202 of which were reported in 22 out of32 patients following administration of a total of 1580 infusions. In the placebo treatment group128 infusion-related reactions were reported in 21 out of 32 patients following administration of a totalof 1612 infusions. Since more than one infusion-related reaction may have occurred during any singleinfusion, the above numbers are likely to overestimate the true incidence of infusion reactions. Relatedreactions in the placebo group were similar in nature and severity to those in the treated group. Themost common of these infusion-related reactions included cutaneous reactions (rash, pruritus,urticaria, and erythema), pyrexia, flushing, wheezing, dyspnoea, headache, vomiting, abdominal pain,nausea, and chest pain. The frequency of infusion-related reactions decreased over time withcontinued treatment.

Adverse reactions are listed in table 1 with information presented by system organ class andfrequency. Frequency is given as very common (≥1/10), common (≥1/100 to <1/10) or uncommon(≥1/1,000 to <1/100). The occurrence of an adverse reaction in a single patient is defined as commonin view of the number of patients treated. Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness. Adverse reactions only reported during the postmarketing period are also included in the table with a frequency “not known” (cannot be estimatedfrom the available data).

Table 1: Adverse reactions from clinical trials and post-marketing experience in patients treatedwith Elaprase.

System organ Adverse reaction (preferred term)class

Very common Common Uncommon Not known

Anaphylactoid/anaphylacticreaction

Headache Dizziness, tremor

Cyanosis,arrhythmia,tachycardia

Flushing Hypertension,

Wheezing, Hypoxia, Tachypnoeadyspnoea bronchospasm,cough

Abdominal pain, Swollen tongue,nausea, diarrhoea, dyspepsiavomiting

Urticaria, rash,pruritus, erythema

Musculoskeletal and connective disorders

Arthralgia

Pyrexia, chest Infusion-sitepain swelling, faceoedema, oedemaperipheral

Infusion-relatedreaction

Across clinical studies, serious adverse reactions were reported in a total of 5 patients who received0.5 mg/kg weekly or every other week. Four patients experienced a hypoxic episode during one orseveral infusions, which necessitated oxygen therapy in 3 patients with severe underlying obstructiveairway disease (2 with a pre-existing tracheostomy). The most severe episode occurred in a patientwith a febrile respiratory illness and was associated with hypoxia during the infusion, resulting in ashort seizure. In the fourth patient, who had less severe underlying disease, spontaneous resolutionoccurred shortly after the infusion was interrupted. These events did not recur with subsequentinfusions using a slower infusion rate and administration of pre-infusion medicinal products, usuallylow-dose steroids, antihistamine, and beta-agonist nebulisation. The fifth patient, who had pre-existingcardiopathy, was diagnosed with ventricular premature complexes and pulmonary embolism duringthe study.

There have been post-marketing reports of anaphylactoid/anaphylactic reactions (see section 4.4).

Patients with complete deletion/large rearrangement genotype have a higher probability of developinginfusion related adverse events (see section 4.4).

Across 4 clinical studies (TKT008, TKT018, TKT024 and TKT024EXT), 53/107 patients (50%)developed anti-idursulfase IgG antibodies at some point. The overall neutralizing antibody rate was26/107 patients (24%).

In the post-hoc immunogenicity analysis of data from TKT024/024EXT studies, 51% (32/63) patientstreated with 0.5mg/kg weekly idursulfase had at least 1 blood sample that tested positive for anti-idursulfase antibodies, and 37 % (23/63) tested positive for antibodies on at least 3 consecutive studyvisits. Twenty-one percent (13/63) tested positive for neutralizing antibodies at least once and 13 %(8/63) tested positive for neutralizing antibodies on at least 3 consecutive study visits.

Clinical study HGT-ELA-038 evaluated immunogenicity in children 16 months to 7.5 years of age.

During the 53-week study, 67.9% (19 of 28) of patients had at least one blood sample that testedpositive for anti-idursulfase antibodies, and 57.1% (16 of 28) tested positive for antibodies on at leastthree consecutive study visits. Fifty-four percent of patients tested positive for neutralizing antibodiesat least once and half of the patients tested positive for neutralizing antibodies on at least threeconsecutive study visits.

All patients with the complete deletion/large rearrangement genotype developed antibodies, and themajority of them (7/8) also tested positive for neutralizing antibodies on at least 3 consecutiveoccasions. All patients with the frameshift/splice site mutation genotype developed antibodies and 4/6also tested positive for neutralizing antibodies on at least 3 consecutive study visits. Antibody-negativepatients were found exclusively in the missense mutation genotype group (see sections 4.4 and 5.1).

Adverse reactions reported in the paediatric population were, in general, similar to those reported inadults.

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 regarding overdose with Elaprase. Evidence suggests that some patientsmay experience an anaphylactoid reaction due to overdose (see sections 4.3 and 4.4).

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

A16AB09.

Hunter syndrome is an X-linked disease caused by insufficient levels of the lysosomal enzymeiduronate-2-sulfatase. Iduronate-2-sulfatase functions to catabolize the glycosaminoglycans (GAG)dermatan sulfate and heparan sulfate by cleavage of oligosaccharide-linked sulfate moieties. Due tothe missing or defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome,glycosaminoglycans progressively accumulate in the cells, leading to cellular engorgement,organomegaly, tissue destruction, and organ system dysfunction.

Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase, produced in a human cellline providing a human glycosylation profile, which is analogous to the naturally occurring enzyme.

Idursulfase is secreted as a 525 amino acid glycoprotein and contains 8 N-linked glycosylation sitesthat are occupied by complex, hybrid, and high-mannose type oligosaccharide chains. Idursulfase hasa molecular weight of approximately 76 kD.

Treatment of Hunter syndrome patients with intravenous idursulfase provides exogenous enzyme foruptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chainsallow specific binding of the enzyme to the M6P receptors on the cell surface, leading to cellularinternalization of the enzyme, targeting to intracellular lysosomes and subsequent catabolism ofaccumulated GAG.

The safety and efficacy of Elaprase has been shown in three clinical studies: two randomised, placebo-controlled clinical studies (TKT008 and TKT024) in adults and children above the age of 5 years andone open-label, safety study (HGT-ELA-038) in children between the age of 16 months and 7.5 years.

A total of 108 male Hunter syndrome patients with a broad spectrum of symptoms were enrolled in thetwo randomized, placebo-controlled clinical studies, 106 continued treatment in two open-label,extension studies.

Study TKT024

In a 52-week, randomized, double-blind, placebo-controlled clinical study, 96 patients between theages of 5 and 31 years received Elaprase 0.5 mg/kg every week (n=32) or 0.5 mg/kg every other week(n=32), or placebo (n=32). The study included patients with a documented deficiency in iduronate-2-sulfatase enzyme activity, a percent predicted FVC <80%, and a broad spectrum of disease severity.

The primary efficacy endpoint was a two-component composite score based on the sum of the ranks ofthe change from baseline to the end of the study in the distance walked during six minutes (6-minutewalk test or 6MWT) as a measure of endurance, and % predicted forced vital capacity (FVC) as ameasure of pulmonary function. This endpoint differed significantly from placebo for patients treatedweekly (p=0.0049).

Additional clinical benefit analyses were performed on individual components of the primary endpointcomposite score, absolute changes in FVC, changes in urine GAG levels, liver and spleen volumes,measurement of forced expiratory volume in 1 second (FEV1), and changes in left ventricular mass(LVM). The results are presented in Table 2.

Table 2. Results from pivotal clinical study at 0.5 mg/kg per week (Study TKT024).

52 weeks of treatment0.5 mg/kg weekly

Marginally weighted (OM) Mean treatment P-valuemean (SE) difference (compared with

Idursulfase Placebo compared with placebo)

Endpoint placebo (SE)

Composite 74.5 (4.5) 55.5 (4.5) 19.0 (6.5) 0.0049(6MWT and%FVC)6MWT (m) 43.3 (9.6) 8.2 (9.6) 35.1 (13.7) 0.0131% Predicted FVC 4.2 (1.6) -0.04 (1.6) 4.3 (2.3) 0.0650

FVC absolute 0.23 (0.04) 0.05 (0.04) 0.19 (0.06) 0.0011volume (L)

Urine GAG levels -223.3 (20.7) 52.23 (20.7) -275.5 (30.1) <0.0001(μg GAG/mgcreatinine)% Change in liver -25.7 (1.5) -0.5 (1.6) -25.2 (2.2) <0.0001volume% Change in -25.5 (3.3) 7.7 (3.4) -33.2 (4.8) <0.0001spleen volume

A total of 11 of 31 (36%) patients in the weekly treatment group versus 5 of 31 (16%) patients in theplacebo group had an increase in FEV1 of at least 0.2 l at or before the end of the study, indicating adose-related improvement in airway obstruction. The patients in the weekly treatment groupexperienced a clinically significant 15% mean improvement in FEV1 at the end of the study.

Urine GAG levels were normalized below the upper limit of normal (defined as 126.6 µg GAG/mgcreatinine) in 50% of the patients receiving weekly treatment.

Of the 25 patients with abnormally large livers at baseline in the weekly treatment group, 80% (20patients) had reductions in liver volume to within the normal range by the end of the study.

Of the 9 patients in the weekly treatment group with abnormally large spleens at baseline, 3 had spleenvolumes that normalized by the end of the study.

Approximately half of the patients in the weekly treatment group (15 of 32; 47%) had left ventricularhypertrophy at baseline, defined as LVM index 103 g/m2. Of these 6 (40%) had normalised LVM bythe end of the study.

All patients received weekly idursulfase up to 3.2 years in an extension to this study (TKT024EXT).

Among patients who were originally randomised to weekly idursulfase in TKT024, mean maximumimprovement in distance walked during six minutes occurred at Month 20 and mean percent predicted

FVC peaked at Month 16.

Among all patients, statistically significant mean increases from treatment baseline (TKT024 baselinefor TKT024 idursulfase patients and Week 53 baseline for TKT024 placebo patients) were seen in thedistance walked 6MWT at the majority of time points tested, with significant mean and percentincreases ranging from 13.7m to 41.5m (maximum at Month 20) and from 6.4% to 13.3% (maximumat Month 24) respectively. At most time points tested, patients who were from the original TKT024weekly treatment group improved their walking distance to a greater extent that patients in the other 2treatment groups.

Among all patients, mean % predicted FVC was significantly increased at Month 16, although by

Month 36, it was similar to the baseline. Patients with the most severe pulmonary impairment atbaseline (as measured by % predicted FVC) tended to show the least improvement.

Statistically significant increases from treatment baseline in absolute FVC volume were seen at mostvisits for all treatment groups combined and for each of the prior TKT024 treatment groups. Meanchanges from 0.07 l to 0.31 l and percent ranged from 6.3% to 25.5% (maximum at Month 30). Themean and percent changes from treatment baseline were greatest in the group of patients from the

TKT024 study who had received the weekly dosing, across all time points.

At their final visit 21/31 patients in the TKT024 Weekly group, 24/32 in the TKT024 EOW group and18/31 patients in the TKT024 placebo group had final normalised urine GAG levels that were belowthe upper limit of normal. Changes in urinary GAG levels were the earliest signs of clinicalimprovement with idursulfase treatment and the greatest decreases in urinary GAG were seen withinthe first 4 months of treatment in all treatment groups; changes from Month 4 to 36 were small. Thehigher the urinary GAG levels at baseline, the greater the magnitude of decreases in urinary GAG withidursulfase treatment.

The decreases in liver and spleen volumes observed at the end of study TKT024 (week 53) weremaintained during the extension study (TKT024EXT) in all patients regardless of the prior treatmentthey had been assigned. Liver volume normalised by Month 24 for 73% (52 out of 71) of patients withhepatomegaly at baseline. In addition, mean liver volume decreased to a near maximum extent by

Month 8 in all patients previously treated, with a slight increase observed at Month 36. The decreasesin mean liver volume were seen regardless of age, disease severity, IgG antibody status or neutralisingantibody status. Spleen volume normalised by Months 12 and 24 for 9.7% of patients in the TKT024

Weekly group with splenomegaly.

Mean cardiac LVMI remained stable over 36 months of idursulfase treatment within each TKT024treatment group.

In a post-hoc analysis of immunogenicity in studies TKT024 and TKT024EXT (see section 4.8),patients were shown to have either the mis-sense mutation or the frameshift/nonsense mutation. After105 weeks of exposure to idursulfase, neither antibody status nor genotype affected reductions in liverand spleen size or distance walked in the 6-minute walk test or forced vital capacity measurements.

Patients who tested antibody-positive displayed less reduction in urinary output ofglycosaminoglycans than antibody-negative patients. The longer-term effects of antibody developmenton clinical outcomes have not been established.

Study HGT-ELA-038

This was an open-label, multicenter, single-arm study of idursulfase infusions in male Huntersyndrome patients between the age of 16 months and 7.5 years.

Idursulfase treatment resulted in up to 60% reduction in urine output of glycosaminoglycans and inreductions of liver and spleen size: results were comparable to those found in study TKT024.

Reductions were evident by week 18 and were maintained to week 53. Patients who developed a hightitre of antibodies displayed less response to idursulfase as assessed by urine output ofglycosaminoglycans and by liver and spleen size.

Analyses of genotypes of patients in study HGT-ELA-038

Patients were classified into the following groups: missense (13), complete deletion/largerearrangement (8), and frameshift/ splice site mutations (5). One patient was unclassified /unclassifiable.

The complete deletion/ large rearrangement genotype was most commonly associated withdevelopment of high titre of antibodies and neutralising antibodies to idursulfase and was most likelyto display a muted response to the medicinal product. It was not possible, however, to accuratelypredict individual clinical outcome based on antibody response or genotype.

No clinical data exist demonstrating a benefit on the neurological manifestations of the disorder.

This medicinal product has been authorised under “exceptional circumstances”.

This means that due to the rarity of the disease it has not been possible to obtain complete informationon this medicinal product.

The European Medicines Agency will review any new information which may become available everyyear and this SmPC will be updated as necessary.

Idursulfase is taken up by selective receptor-mediated mechanisms involving binding to mannose 6-phosphate receptors. Upon internalization by cells, it is localized within cellular lysosomes, therebylimiting distribution of the protein. Degradation of idursulfase is achieved by generally wellunderstood protein hydrolysis mechanisms to produce small peptides and amino acids, consequentlyrenal and liver function impairment is not expected to affect the pharmacokinetics of idursulfase.

Pharmacokinetic parameters measured during the first infusion at week 1 of studies TKT024 (0.5mg/kg weekly arm) and HGT-ELA-038 are displayed in table 3 and table 4 below as a function of ageand body weight, respectively.

Table 3. Pharmacokinetic parameters at week 1 as a function of age in Studies TKT024 and

HGT-ELA-038

Study

HGT-ELA-038 TKT024

Age (years) 1.4 to 7.5 5 to 11 12 to 18 > 18(n=27) (n=11) (n=8) (n=9)

Cmax (μg/mL) 1.3 ± 0.8 1.6 ± 0.7 1.4 ± 0.3 1.9 ± 0.5

Mean ± SD

AUC0-∞ 224.3 ± 76.9 238 ± 103.7 196 ± 40.5 262 ± 74.5(min*μg/mL)

Mean ± SD

CL 2.4 ± 0.7 2.7 ± 1.3 2.8 ± 0.7 2.2 ± 0.7(mL/min/kg)

Mean ± SD

Vss (mL/kg) 394 ± 423 217 ± 109 184 ± 38 169 ± 32

Mean ± SD

Patients in the TKT024 and HGT-ELA-038 studies were also stratified across five weight categories;as shown in the following table:

Table 4. Pharmacokinetic parameters at week 1 as a function of body weight in studies TKT024and HGT-ELA-038

Weight (kg) <20 ≥ 20 and < 30 ≥ 30 and < 40 ≥ 40 and < 50 ≥ 50(n=17) (n=18) (n=9) (n=5) (n=6)

Cmax (μg/mL) 1.2 ± 0.3 1.5 ± 1.0 1.7 ± 0.4 1.7 ± 0.7 1.7 ± 0.7

Mean ± SD

AUC0-∞ 206.2 ± 33.9 234.3 ± 103.0 231.1 ± 681.0 260.2 ± 113.8 251.3 ± 86.2(min*μg/mL)

CL 2.5 ± 0.5 2.6 ± 1.1 2.4 ± 0.6 2.4 ± 1.0 2.4 ± 1.1(mL/min/kg)

Mean ± SD

Vss 321 ± 105 397 ± 528 171 ± 52 160 ± 59 181 ± 34(mL/kg)

A higher volume of distribution at steady state (Vss) was observed in the lowest weight groups.

Overall, there was no apparent trend in either systemic exposure or clearance rate of idursulfase withrespect to either age or body weight.

Nonclinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, single dose toxicity, repeated dose toxicity, toxicity to reproduction and developmentand to male fertility.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development.

Animal studies have shown excretion of idursulfase in breast milk.

Polysorbate 20

Sodium chloride

Dibasic sodium phosphate heptahydrate

Monobasic sodium phosphate monohydrate

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

3 years.

Chemical and physical in-use stability has been demonstrated for 8 hours at 25°C.

From a microbiological safety point of view, the diluted product should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand should not be longer than 24 hours at 2 to 8°C.

Store in a refrigerator (2°C - 8°C).

Do not freeze.

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

5 ml vial (type I glass) with a stopper (fluoro-resin coated butyl rubber), one piece seal and blue flip-off cap. Each vial contains 3 ml of concentrate for solution for infusion.

Pack sizes of 1, 4 and 10 vials. Not all pack sizes may be marketed.

Each vial of Elaprase is intended for single use only and contains 6 mg of idursulfase in 3 ml ofsolution. Elaprase is for intravenous infusion and must be diluted in sodium chloride 9 mg/ml (0.9%)solution for infusion prior to use. It is recommended to deliver the total volume of infusion using a 0.2µm in line filter. Elaprase should not be infused with other medicinal products in the infusion tubing.

- The number of vials to be diluted should be determined based on the individual patient’s weightand the recommended dose of 0.5 mg/kg.

- The solution in the vials should not be used if it is discoloured or if particulate matter is present.

The solution should not be shaken.

- The calculated volume of Elaprase should be withdrawn from the appropriate number of vials.

- The total volume required of Elaprase should be diluted in 100 ml of 9 mg/ml (0.9%) sodiumchloride solution for infusion. Care must be taken to ensure the sterility of the preparedsolutions since Elaprase does not contain any preservative or bacteriostatic agent; aseptictechnique must be observed. Once diluted, the solution should be mixed gently, but not shaken.

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

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50-58 Baggot Street Lower

Dublin 2

D02 HW68

IrelandmedinfoEMEA@takeda.com

EU/1/06/365/001-003

Date of first authorisation: 08 January 2007

Date of latest renewal: 09 September 2016

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

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