XAGRID 0.5mg capsules medication leaflet

Xagrid 0.5 mg hard capsules.

Each hard capsule contains 0.5 mg anagrelide (as anagrelide hydrochloride).

Each hard capsule contains lactose monohydrate (53.7 mg) and anhydrous lactose (65.8 mg).

For the full list of excipients, see section 6.1.

Hard capsule.

An opaque white hard capsule imprinted with S 063.

Xagrid is indicated for the reduction of elevated platelet counts in at risk essential thrombocythaemia(ET) patients who are intolerant to their current therapy or whose elevated platelet counts are notreduced to an acceptable level by their current therapy.

An at-risk essential thrombocythaemia patient is defined by one or more of the following features:

- >60 years of age or

- a platelet count >1000 x 109/l or

- a history of thrombo-haemorrhagic events.

Treatment with Xagrid should be initiated by a clinician with experience in the management ofessential thrombocythaemia.

The recommended starting dose of anagrelide is 1 mg/day, which should be administered orally in twodivided doses (0.5 mg/dose).

The starting dose should be maintained for at least one week. After one week the dose may be titrated,on an individual basis, to achieve the lowest effective dose required to reduce and/or maintain aplatelet count below 600 x 109/l and ideally at levels between 150 x 109/l and 400 x 109/l. The doseincrement must not exceed more than 0.5 mg/day in any one week and the recommended maximumsingle dose should not exceed 2.5 mg (see section 4.9). During clinical development, doses of10 mg/day have been used.

The effects of treatment with anagrelide must be monitored on a regular basis (see section 4.4). If thestarting dose is > 1 mg/day, platelet counts should be performed every two days during the first weekof treatment and at least weekly thereafter until a stable maintenance dose is reached. Typically, a fallin the platelet count will be observed within 14 to 21 days of starting treatment and in most patients anadequate therapeutic response will be observed and maintained at a dose of 1 to 3 mg/day (for furtherinformation on the clinical effects, refer to section 5.1).

The observed pharmacokinetic differences between elderly and young patients with ET (see section5.2) do not warrant using a different starting regimen or different dose titration step to achieve anindividual patient-optimised anagrelide regimen.

During clinical development, approximately 50% of the patients treated with anagrelide were over60 years of age and no age specific alterations in dose were required in these patients. However, asexpected, patients in this age group had twice the incidence of serious adverse events (mainly cardiac).

There are limited pharmacokinetic data for this patient population. The potential risks and benefits ofanagrelide therapy in a patient with impairment of renal function should be assessed before treatmentis commenced (see section 4.3).

There are limited pharmacokinetic data for this patient population. However, hepatic metabolismrepresents the major route of anagrelide clearance and liver function may therefore be expected toinfluence this process. Therefore, it is recommended that patients with moderate or severe hepaticimpairment are not treated with anagrelide. The potential risks and benefits of anagrelide therapy in apatient with mild impairment of hepatic function should be assessed before treatment is commenced(see sections 4.3 and 4.4).

The safety and efficacy of anagrelide in children have not been established. The experience in childrenand adolescents is very limited; anagrelide should be used in this patient group with caution. In theabsence of specific paediatric guidelines, WHO diagnostic criteria for adult diagnosis of ET areconsidered to be of relevance to the paediatric population. Diagnostic guidelines for essentialthrombocythemia should be followed carefully and diagnosis reassessed periodically in cases ofuncertainty, with effort made to distinguish from hereditary or secondary thrombocytosis, which mayinclude genetic analysis and bone marrow biopsy.

Typically, cytoreductive therapy is considered in high-risk paediatric patients.

Anagrelide treatment should only be initiated when the patient shows signs of disease progression orsuffers from thrombosis. If treatment is initiated, the benefits and risks of treatment with anagrelidemust be monitored regularly and the need for ongoing treatment evaluated periodically.

Platelet targets are assigned on an individual patient basis by the treating physician.

Discontinuation of treatment should be considered in paediatric patients who do not have a satisfactorytreatment response after approximately 3 months (see section 4.4).

Currently available data are described in sections 4.4, pct. 4.8, 5.1 and 5.2, but no recommendation on aposology can be made.

For oral use. The capsules must be swallowed whole. Do not crush or dilute the contents in a liquid.

Hypersensitivity to anagrelide or to any of the excipients listed in section 6.1.

Patients with moderate or severe hepatic impairment.

Patients with moderate or severe renal impairment (creatinine clearance <50 ml/min).

The potential risks and benefits of anagrelide therapy in a patient with mild impairment of hepaticfunction should be assessed before treatment is commenced. It is not recommended in patients withelevated transaminases (>5 times the upper limit of normal) (see sections 4.2 and 4.3).

The potential risks and benefits of anagrelide therapy in a patient with impairment of renal functionshould be assessed before treatment is commenced (see sections 4.2 and 4.3).

Thrombotic Risk

Abrupt treatment discontinuation should be avoided due to the risk of sudden increase in plateletcounts, which may lead to potentially fatal thrombotic complications, such as cerebral infarction.

Patients should be advised how to recognize early signs and symptoms suggestive of thromboticcomplications, such as cerebral infarction, and if symptoms occur to seek medical assistance.

In the event of dosage interruption or treatment withdrawal, the rebound in platelet count isvariable, but the platelet count will start to increase within 4 days of stopping treatment withanagrelide and will return to pre-treatment levels within 10 to 14 days, possibly rebounding abovebaseline values. Therefore, platelets should be monitored frequently (see section 4.2).

Therapy requires close clinical supervision of the patient which will include a full blood count(haemoglobin and white blood cell and platelet counts), assessment of liver function (ALT and AST),renal function (serum creatinine and urea) and electrolytes (potassium, magnesium and calcium).

Serious cardiovascular adverse events including cases of torsade de pointes, ventricular tachycardia,cardiomyopathy, cardiomegaly and congestive heart failure have been reported (see section 4.8).

Caution should be taken when using anagrelide in patients with known risk factors for prolongation ofthe QT interval, such as congenital long QT syndrome, a known history of acquired QTc prolongation,medicinal products that can prolong QTc interval and hypokalaemia.

Care should also be taken in populations that may have a higher maximum plasma concentration(Cmax) of anagrelide or its active metabolite, 3-hydroxy anagrelide, e.g., hepatic impairment or usewith CYP1A2 inhibitors (see section 4.5).

Close monitoring for an effect on the QTc interval is advisable.

A pre-treatment cardiovascular examination, including a baseline ECG and echocardiography isrecommended for all patients prior to initiating therapy with anagrelide. All patients should bemonitored regularly during treatment (e.g., ECG or echocardiography) for evidence of cardiovasculareffects that may require further cardiovascular examination and investigation. Hypokalaemia orhypomagnesaemia must be corrected prior to anagrelide administration and should be monitoredperiodically during therapy.

Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III and because of its positive inotropicand chronotropic effects, anagrelide should be used with caution in patients of any age with known orsuspected heart disease. Moreover, serious cardiovascular adverse events have also occurred inpatients without suspected heart disease and with normal pre-treatment cardiovascular examination.

Anagrelide should only be used if the potential benefits of therapy outweigh the potential risks.

Cases of pulmonary hypertension have been reported in patients treated with anagrelide. Patientsshould be evaluated for signs and symptoms of underlying cardiopulmonary disease prior to initiatingand during anagrelide therapy.

Very limited data are available on the use of anagrelide in the paediatric population and anagrelideshould be used in this patient group with caution (see sections 4.2, pct. 4.8, 5.1 and 5.2).

As with the adult population, a full blood count and assessment of cardiac, hepatic and renal functionshould be undertaken before treatment and regularly during treatment. The disease may progress tomyelofibrosis or AML. Although the rate of such progression is not known, children have a longerdisease course and may, therefore, be at increased risk for malignant transformation, relative to adults.

Children should be monitored regularly for disease progression according to standard clinicalpractices, such as physical examination, assessment of relevant disease markers and bone marrowbiopsy.

Any abnormalities should be evaluated promptly and appropriate measures taken, which may alsoinclude dose reduction, interruption or discontinuation.

Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III (PDE III). Concomitant use ofanagrelide with other PDE III inhibitors such as milrinone, amrinone, enoximone, olprinone andcilostazol is not recommended.

Use of concomitant anagrelide and acetylsalicylic acid has been associated with major haemorrhagicevents (see section 4.5).

Xagrid contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapplactase deficiency or glucose-galactose malabsorption should not take this medicinal product.

Limited pharmacokinetic and/or pharmacodynamic studies investigating possible interactions betweenanagrelide and other medicinal products have been conducted.

- In vivo interaction studies in humans have demonstrated that digoxin and warfarin do not affectthe pharmacokinetic properties of anagrelide.

- Anagrelide is primarily metabolised by CYP1A2. It is known that CYP1A2 is inhibited byseveral medicinal products, including fluvoxamine and enoxacin, and such medicinal productscould theoretically adversely influence the clearance of anagrelide.

- CYP1A2 inducers (such as omeprazole) could decrease the exposure of anagrelide (seesection 5.2). The consequences on the safety and efficacy profile of anagrelide are not established.

Therefore, clinical and biological monitoring is recommended in patients taking concomitant

CYP1A2 inducers. If needed, anagrelide dose adjustment could be made.

- Anagrelide demonstrates some limited inhibitory activity towards CYP1A2 which may present atheoretical potential for interaction with other co-administered medicinal products sharing thatclearance mechanism e.g., theophylline.

- Anagrelide is an inhibitor of PDE III. The effects of medicinal products with similar propertiessuch as the inotropes milrinone, enoximone, amrinone, olprinone and cilostazol may beexacerbated by anagrelide.

- In vivo interaction studies in humans have demonstrated that anagrelide does not affect thepharmacokinetic properties of digoxin or warfarin.

- At the doses recommended for use in the treatment of essential thrombocythaemia, anagrelidemay potentiate the effects of other medicinal products that inhibit or modify platelet functione.g., acetylsalicylic acid.

- A clinical interaction study performed in healthy subjects showed that co-administration ofrepeat-dose anagrelide 1 mg once daily and acetylsalicylic acid 75 mg once daily may enhancethe anti-platelet aggregation effects of each active substance compared with administration ofacetylsalicylic acid alone. In some patients with ET concomitantly treated by acetylsalicylic acidand anagrelide, major haemorrhages occurred. Therefore, the potential risks of the concomitantuse of anagrelide with acetylsalicylic acid should be assessed, particularly in patients with ahigh-risk profile for haemorrhage before treatment is initiated.

- Anagrelide may cause intestinal disturbance in some patients and compromise the absorption ofhormonal oral contraceptives.

- Food delays the absorption of anagrelide, but does not significantly alter systemic exposure.

- The effects of food on bioavailability are not considered clinically relevant to the use ofanagrelide.

Interaction studies have only been performed in adults.

Women of child-bearing potential should use adequate birth-control measures during treatment withanagrelide.

There are no adequate data from the use of anagrelide in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Therefore,

Xagrid is not recommended during pregnancy.

If anagrelide is used during pregnancy, or if the patient becomes pregnant while using the medicinalproduct, she should be advised of the potential risk to the foetus.

It is unknown whether anagrelide/metabolites are excreted in human milk. Available data in animalshave shown excretion of anagrelide/metabolites in milk. A risk to the newborn/infant cannot beexcluded. Breast-feeding should be discontinued during treatment with anagrelide.

No human data on the effect of anagrelide on fertility are available. In male rats, there was no effecton fertility or reproductive performance with anagrelide. In female rats, using doses in excess of thetherapeutic range, anagrelide disrupted implantation (see section 5.3).

In clinical development, dizziness was commonly reported. Patients are advised not to drive or operatemachinery while taking anagrelide if dizziness is experienced.

The safety of anagrelide has been examined in 4 open label clinical studies. In 3 of the studies 942patients who received anagrelide at a mean dose of approximately 2 mg/day were assessed for safety.

In these studies, 22 patients received anagrelide for up to 4 years.

In the later study 3660 patients who received anagrelide at a mean dose of approximately 2 mg/daywere assessed for safety. In this study 34 patients received anagrelide for up to 5 years.

The most commonly reported adverse reactions associated with anagrelide were headache occurring atapproximately 14%, palpitations occurring at approximately 9%, fluid retention and nausea bothoccurring at approximately 6% and diarrhoea occurring at 5%. These adverse drug reactions areexpected based on the pharmacology of anagrelide (inhibition of PDE III). Gradual dose titration mayhelp diminish these effects (see section 4.2).

Adverse reactions arising from clinical studies, post-authorisation safety studies and spontaneousreports are presented in the table below. Within the system organ classes they are listed under thefollowing headings: 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), not known (cannot be estimated fromthe available data). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

MedDRA Frequency of adverse reactions

System Organ Very Common Uncommon Rare Not known

Class common

Blood and Anaemia Pancytopenialymphatic Thrombocytopeniasystem Haemorrhagedisorders Ecchymosis

Metabolism and Fluid Oedema Weight gainnutrition retention Weight lossdisorders

Nervous system Headache Dizziness Depression Migraine Cerebraldisorders Amnesia Dysarthria infarction*

Confusion Somnolence

Insomnia Abnormal

Paraesthesia coordination

Hypoaesthesia

Nervousness

Dry mouth

Eye disorders Diplopia

Vision abnormal

Ear and Tinnituslabyrinthdisorders

Cardiac Tachycardia Ventricular Myocardial Torsade dedisorders Palpitations tachycardia infarction pointes

Congestive heart Cardiomyopathyfailure Cardiomegaly

Atrial fibrillation Pericardial

Supraventricular effusiontachycardia Angina pectoris

Arrhythmia Postural

Hypertension hypotension

Syncope Vasodilatation

MedDRA Frequency of adverse reactions

System Organ Very Common Uncommon Rare Not known

Class common

Prinzmetalangina

Respiratory, Pulmonary Pulmonary Interstitial lungthoracic and hypertension infiltrates disease includingmediastinal Pneumonia pneumonitis anddisorders Pleural effusion allergic alveolitis

Epistaxis

Gastrointestinal Diarrhoea Gastrointestinal Colitisdisorders Vomiting haemorrhage Gastritis

Abdominal Pancreatitis Gingivalpain Anorexia bleeding

Nausea Dyspepsia

Flatulence Constipation

Gastrointestinaldisorder

Hepatobiliary Hepatic enzymes Hepatitisdisorders increased

Skin and Rash Alopecia Dry skinsubcutaneous Pruritustissue disorders Skin discoloration

Musculoskeletal Arthralgiaand connective Myalgiatissue disorders Back pain

Renal and Impotence Renal failure Tubulointerstitialurinary Nocturia nephritisdisorders

General Fatigue Chest pain Flu-likedisorders and Fever syndromeadministration Chills Painsite conditions Malaise Asthenia

Weakness

Investigations Blood creatinineincreased

* Cerebral infarction (see section 4.4 Thrombotic Risk)

Paediatric population48 patients aged 6 through17 years (19 children and 29 adolescents) have received anagrelide for up to6.5 years either in clinical studies or as part of a disease registry (see section 5.1).

The majority of adverse events observed were among those listed in the SmPC. However, safety dataare limited and do not allow a meaningful comparison between adult and paediatric patients to bemade (see section 4.4).

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.

Post-marketing case reports of intentional overdose with anagrelide have been received. Reportedsymptoms include sinus tachycardia and vomiting. Symptoms resolved with conservativemanagement.

Anagrelide, at higher than recommended doses, has been shown to produce reductions in bloodpressure with occasional instances of hypotension. A single 5-mg dose of anagrelide can lead to a fallin blood pressure usually accompanied by dizziness.

A specific antidote for anagrelide has not been identified. In case of overdose, close clinicalsupervision of the patient is required; this includes monitoring of the platelet count forthrombocytopenia. Dose should be decreased or stopped, as appropriate, until the platelet count returnsto within the normal range (see section 4.4).

Pharmacotherapeutic group: Other antineoplastic agents, ATC Code: L01XX35.

The precise mechanism by which anagrelide reduces blood platelet count is unknown. In cell culturestudies, anagrelide suppressed expression of transcription factors including GATA-1 and FOG-1required for megakaryocytopoiesis, ultimately leading to reduced platelet production.

In vitro studies of human megakaryocytopoiesis established that anagrelide’s inhibitory actions onplatelet formation in man are mediated via retardation of maturation of megakaryocytes, and reducingtheir size and ploidy. Evidence of similar in vivo actions was observed in bone marrow biopsy samplesfrom treated patients.

Anagrelide is an inhibitor of cyclic AMP phosphodiesterase III.

The safety and efficacy of anagrelide as a platelet lowering agent have been evaluated in four open-label, non-controlled clinical trials (study numbers 700-012, 700-014, 700-999 and 13970-301)including more than 4000 patients with myeloproliferative neoplasms (MPNs). In patients withessential thrombocythaemia complete response was defined as a decrease in platelet count to 600 x109/l or a 50% reduction from baseline and maintenance of the reduction for at least 4 weeks. Instudies 700-012, 700-014, 700-999 and study 13970-301 the time to complete response ranged from 4to 12 weeks. Clinical benefit in terms of thrombohaemorrhagic events has not been convincinglydemonstrated.

The effect of two dose levels of anagrelide (0.5 mg and 2.5 mg single doses) on the heart rate and QTcinterval was evaluated in a double-blind, randomised, placebo- and active-controlled, cross-over studyin healthy adult men and women.

A dose-related increase in heart rate was observed during the first 12 hours, with the maximumincrease occurring around the time of maximal concentrations. The maximum change in mean heartrate occurred at 2 hours after administration and was +7.8 beats per minute (bpm) for 0.5 mg and+29.1 bpm for 2.5 mg.

A transient increase in mean QTc was observed for both doses during periods of increasing heart rateand the maximum change in mean QTcF (Fridericia correction) was +5.0 msec occurring at 2 hoursfor 0.5 mg and +10.0 msec occurring at 1 hour for 2.5 mg.

In an open-label clinical study in 8 children and 10 adolescents (including patients who wereanagrelide treatment naïve or who had been receiving anagrelide for up to 5 years pre-study), medianplatelet counts were decreased to controlled levels after 12 weeks of treatment. The average daily dosetended to be higher in adolescents.

In a paediatric registry study, median platelet counts were reduced from diagnosis and maintained forup to 18 months in 14 paediatric patients with ET (4 children, 10 adolescents) with anagrelidetreatment. In earlier, open-label studies, median platelet count reductions were observed in 7 childrenand 9 adolescents treated for between 3 months and 6.5 years.

The average total daily dose of anagrelide across all studies in paediatric patients with ET was highlyvariable, but overall the data suggest that adolescents could follow similar starting and maintenancedoses to adults and that a lower starting dose of 0.5 mg/day would be more appropriate for childrenover 6 years (see sections 4.2, pct. 4.4, pct. 4.8, pct. 5.2). In all paediatric patients, careful titration to a patient-specific daily dose is needed.

Following oral administration of anagrelide in man, at least 70% is absorbed from the gastrointestinaltract. In fasted subjects, peak plasma levels occur about 1 hour after administration. Pharmacokineticdata from healthy subjects established that food decreases the Cmax of anagrelide by 14%, but increasesthe AUC by 20%. Food also decreased the Cmax of the active metabolite, 3-hydroxy anagrelide, by29%, although it had no effect on the AUC.

Anagrelide is primarily metabolised by CYP1A2 to form, 3-hydroxy anagrelide, which is furthermetabolised via CYP1A2 to the inactive metabolite, 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline.

The effect of omeprazole, a CYP1A2 inducer, on the pharmacokinetics of anagrelide was investigatedin 20 healthy adult subjects following multiple, once daily 40-mg doses. The results showed that in thepresence of omeprazole, AUC(0-∞), AUC(0-t), and Cmax of anagrelide were reduced by 27%, 26%, and36%, respectively; and the corresponding values for 3-hydroxy anagrelide, a metabolite of anagrelide,were reduced by 13%, 14%, and 18%, respectively.

The plasma half-life of anagrelide is short, approximately 1.3 hours and as expected from its half-life,there is no evidence for anagrelide accumulation in the plasma. Less than 1% is recovered in the urineas anagrelide. The mean recovery of 2-amino-5, 6-dichloro-3, 4-dihydroquinazoline in urine isapproximately 18-35% of the administered dose.

Additionally these results show no evidence of auto-induction of the anagrelide clearance.

Dose proportionality has been found in the dose range 0.5 mg to 2 mg.

Pharmacokinetic data from exposed fasting children and adolescents (age range 7 through 16 years)with essential thrombocythaemia indicate that dose normalised exposure, Cmax and AUC, of anagrelidetended to be higher in children/adolescents compared with adults. There was also a trend to higherdose-normalised exposure to the active metabolite.

Pharmacokinetic data from fasting elderly patients with ET (age range 65 through 75 years) comparedto fasting adult patients (age range 22 through 50 years) indicate that the Cmax and AUC of anagrelidewere 36% and 61% higher respectively in elderly patients, but that the Cmax and AUC of the activemetabolite, 3-hydroxy anagrelide, were 42% and 37% lower respectively in the elderly patients. Thesedifferences were likely to be caused by lower presystemic metabolism of anagrelide to 3-hydroxyanagrelide in the elderly patients.

Following repeated oral administration of anagrelide in dogs, subendocardial haemorrhage and focalmyocardial necrosis was observed at 1mg/kg/day or higher in males and females with males beingmore sensitive. The no observed effect level (NOEL) for male dogs (0.3 mg/kg/day) corresponds to0.1-, 0.1-, and 1.6-fold the AUC in humans for anagrelide at 2 mg/day, and the metabolites BCH24426and RL603, respectively.

In male rats, anagrelide at oral doses up to 240 mg/kg/day (>1000 times a 2-mg/day dose, based onbody surface area) was found to have no effect on fertility and reproductive performance. In femalerats increases in pre- and post-implantation losses and a decrease in the mean number of live embryoswas observed at 30 mg/kg/day. The NOEL (10 mg/kg/day) to this effect was 143-, 12- and 11-foldhigher than the AUC in humans administered a dose of anagrelide 2 mg/day, and the metabolites

BCH24426 and RL603, respectively.

Maternally toxic doses of anagrelide in rats and rabbits were associated with increased embryoresorption and foetal mortality.

In a pre- and post-natal development study in female rats, anagrelide at oral doses of ≥10 mg/kgproduced a non-adverse increase in gestational duration. At the NOEL dose (3 mg/kg/day), the AUCsfor anagrelide and the metabolites BCH24426 and RL603 were 14-, 2- and 2-fold higher than the

AUC in humans administered an oral dose of anagrelide 2 mg/day.

Anagrelide at ≥60 mg/kg increased parturition time and mortality in the dam and foetus, respectively.

At the NOEL dose (30 mg/kg/day), the AUCs for anagrelide and the metabolites BCH24426 and

RL603 were 425-, 31- and 13-fold higher than the AUC in humans administered an oral dose ofanagrelide 2 mg/day, respectively.

Studies on the genotoxic potential of anagrelide did not identify any mutagenic or clastogenic effects.

In a two-year rat carcinogenicity study, non-neoplastic and neoplastic findings were observed andrelated or attributed to an exaggerated pharmacological effect. Among them, the incidence of adrenalphaeochromocytomas was increased relative to control in males at all dose levels (3 mg/kg/day) andin females receiving 10 mg/kg/day and above. The lowest dose in males (3 mg/kg/day) corresponds to37 times the human AUC exposure after a 1 mg twice daily dose. Uterine adenocarcinomas, ofepigenetic origin, could be related to an enzyme induction of CYP1 family. They were observed infemales receiving 30 mg/kg/day, corresponding to 572 times the human AUC exposure after a 1-mgtwice daily dose.

Povidone (E1201)

Lactose, anhydrous

Lactose monohydrate

Cellulose, microcrystalline (E460)

Crospovidone

Magnesium stearate

Gelatin

Titanium dioxide (E171)

Shellac

Strong ammonium solution

Potassium hydroxide (E525)

Black iron oxide (E172)

Not applicable

4 years

This medicinal product does not require any special storage conditions.

High-density polyethylene (HDPE) bottles with child-resistant closures and desiccant containing 100capsules.

No special requirements.

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50 - 58 Baggot Street Lower

Dublin 2

D02 HW68

Ireland

EU/1/04/295/001

Date of first authorisation: 16 November 2004

Date of latest renewal: 18 July 2014

Detailed information on this product is available on the website of the European Medicines Agencyhttp://www.ema.europa.eu.