REPLAGAL 1mg / ml concentrate for solution for infusion medication leaflet

Replagal 1 mg/ml concentrate for solution for infusion.

1 ml of concentrate for solution for infusion contains 1 mg of agalsidase alfa*.

Each vial of 3.5 ml of concentrate contains 3.5 mg of agalsidase alfa.

*agalsidase alfa is the human protein α-galactosidase A produced in a human cell line by geneticengineering technology.

This medicinal product contains 14.2 mg sodium per vial.

For the full list of excipients, see section 6.1.

Concentrate for solution for infusion.

A clear and colourless solution.

Replagal is indicated for long-term enzyme replacement therapy in patients with a confirmeddiagnosis of Fabry Disease (α-galactosidase A deficiency).

Replagal treatment should be supervised by a physician experienced in the management of patientswith Fabry Disease or other inherited metabolic diseases.

Replagal is administered at a dose of 0.2 mg/kg body weight every other week by intravenous infusionover 40 minutes.

Studies in patients over the age of 65 years have not been performed and no dosage regimen canpresently be recommended in these patients as safety and efficacy have not yet been established.

No studies have been performed in patients with hepatic impairment.

No dose adjustment is necessary in patients with renal impairment.

The presence of extensive renal damage (eGFR < 60mL/min) may limit the renal response to enzymereplacement therapy. Limited data are available in patients on dialysis or post-kidney transplantation,no dose adjustment is recommended.

The safety and efficacy of Replagal in children aged 0-6 years has not yet been established. Currentlyavailable data are described in section 5.1 but no recommendation on posology can be made.

In clinical studies of children (7-18 years) who received Replagal 0.2 mg/kg every other week, nounexpected safety issues were encountered (see section 5.1).

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

Administer the infusion solution over a period of 40 minutes using an intravenous line with an integralfilter.

Do not infuse Replagal concomitantly in the same intravenous line with other agents.

Replagal home infusion, and administration by the patient in presence of a responsible adult oradministration by the patient’s caregiver (self-administration), may be considered for patients who aretolerating their infusions well. The decision to have a patient move to home infusion and/orself-administration should be made after evaluation and recommendation by the treating physician.

Appropriate training should be given by the treating physician and/or nurse to the patient and/orcaregiver prior to initiation of self-administration. Dose and infusion rate should remain constantwhile at home, and not be changed without supervision of a healthcare professional.

Self-administration should be closely followed by the treating physician.

Any patients experiencing adverse events during the home infusion/self-administration need toimmediately stop the infusion process and seek the attention of a healthcare professional. Subsequentinfusions may need to occur in a clinical setting.

Hypersensitivity 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 product should be clearly recorded.

Idiosyncratic infusion related reactions13.7% of adult patients treated with Replagal in clinical trials have experienced idiosyncratic infusionrelated reactions. Four of 17 (23.5%) paediatric patients ≥ 7 years of age enrolled in clinical trialsexperienced at least one infusion reaction over a period of 4.5 years of treatment (mean duration ofapprox. 4 years). Three of 8 (37.5%) paediatric patients < 7 years of age experienced at least oneinfusion related reaction over a mean observation time of 4.2 years. The most common symptomshave been rigors, headache, nausea, pyrexia, flushing and fatigue. Serious infusion reactions have beenreported uncommonly; symptoms reported include pyrexia, rigors, tachycardia, urticaria,nausea/vomiting, angioneurotic oedema with throat tightness, stridor, and swollen tongue. Otherinfusion-related symptoms may include dizziness and hyperhidrosis. A review of cardiac eventsshowed that infusion reactions may be associated with hemodynamic stress triggering cardiac eventsin patients with pre-existing cardiac manifestations of Fabry disease.

The onset of infusion related reactions has generally occurred within the first 2-4 months afterinitiation of treatment with Replagal although later onset (after 1 year) has been reported as well.

These effects have decreased with time. If mild or moderate acute infusion reactions occur, medicalattention must be sought immediately, and appropriate actions instituted. The infusion can betemporarily interrupted (5 to 10 minutes) until symptoms subside and the infusion may then berestarted. Mild and transient effects may not require medical treatment or discontinuation of theinfusion. In addition, oral or intravenous pre-treatment with antihistamines and/or corticosteroids,from 1 to 24 hours prior to infusion may prevent subsequent reactions in those cases wheresymptomatic treatment was required.

Hypersensitivity reactions have been reported. If severe hypersensitivity or anaphylactic reactionsoccur, the administration of Replagal should be discontinued immediately and appropriate treatmentinitiated. The current medical standards for emergency treatment are to be observed.

Antibodies to the protein

As with all protein pharmaceutical products, patients may develop antibodies to the protein. A lowtitre IgG antibody response has been observed in approximately 24% of the male patients treated with

Replagal. Based on limited data this percentage has been found to be lower (7%) in the male paediatricpopulation. These IgG antibodies appeared to develop following approximately 3-12 months oftreatment. After 12 to 54 months of therapy, 17% of Replagal treated patients were still antibodypositive whereas 7% showed evidence for the development of immunologic tolerance, based on thedisappearance of IgG antibodies over time. The remaining 76% were antibody negative throughout. Inpaediatric patients > 7 years of age, 1/16 male patients tested positive for IgG anti-agalsidase alfaantibodies during the study. No increase in the incidence of adverse events was detected for thispatient. In paediatric patients < 7 years of age, 0/7 male patients tested positive for IgG anti-agalsidasealfa antibodies. IgE antibody positivity not associated with anaphylaxis has been reported in clinicaltrials in a very limited number of patients.

The presence of extensive renal damage may limit the renal response to enzyme replacement therapy,possibly due to underlying irreversible pathological changes. In such cases, the loss of renal functionremains within the expected range of the natural progression of disease.

This medicinal product contains 14.2 mg sodium per vial, equivalent to 0.7% of the WHOrecommended maximum daily intake of 2 g sodium for an adult.

Replagal should not be co-administered with chloroquine, amiodarone, benoquin or gentamicin sincethese substances have the potential to inhibit intra-cellular α-galactosidase activity.

As α-galactosidase A is itself an enzyme, it would be an unlikely candidate for cytochrome P450mediated drug-drug interactions. In clinical studies, neuropathic pain medicinal products (such ascarbamazepine, phenytoin, and gabapentin) were administered concurrently to most patients withoutany evidence of interaction.

There is very limited data on pregnancies exposed to Replagal. Animal studies do not indicate director indirect harmful effects with respect to pregnancy or embryonic/foetal development when exposedduring organogenesis (see section 5.3). Caution should be exercised when prescribing to pregnantwomen.

It is not known whether Replagal is excreted in human milk. Caution should be exercised whenprescribing to breast-feeding women.

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

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

The most commonly reported adverse reactions were infusion associated reactions, which occurred in13.7% of adult patients treated with Replagal in clinical trials. Most undesirable effects were mild tomoderate in severity.

Table 1 lists adverse reactions reported for the 344 patients treated with Replagal in clinical trials,including 21 patients with history of end stage renal disease, 30 paediatric patients (≤ 18 years of age)and 17 female patients, and from post-marketing spontaneous reports. Information is presented bysystem organ class and frequency (very common ≥ 1/10; common ≥ 1/100 to < 1/10; uncommon≥ 1/1,000 to < 1/100). The adverse reactions categorized as incidence “not known (cannot beestimated from the available data)” are derived from post-marketing spontaneous reports. Within eachfrequency grouping, undesirable effects are presented in order of decreasing seriousness. Theoccurrence of an event in a single patient is defined as uncommon in view of the number of patientstreated. A single patient could be affected by several adverse reactions.

The following adverse reactions have been identified for agalsidase alfa:

Table 1

System organ class Adverse reaction

Very common Common Uncommon Not known

Metabolism and peripheralnutrition disorders oedema

Nervous system headache, dysgeusia, parosmiadisorders dizziness, hypersomnia,neuropathicpain, tremor,hypoesthesia,paraesthesia

Eye disorders lacrimation corneal reflexincreased decreased,

Table 1

System organ class Adverse reaction

Very common Common Uncommon Not known

Ear and labyrinth tinnitus tinnitusdisorders aggravated

Cardiac disorders palpitations tachycardia, tachyarrhythmia myocardialatrial fibrillation ischaemia,heart failure,ventricularextrasystoles,

Vascular disorders hypertension,hypotension,flushing

Respiratory, thoracic, dyspnoea, hoarseness, oxygen saturationand mediastinal cough, throat tightness, decreased, throatdisorders nasopharyngitis, rhinorrhoea secretionpharyngitis increased

Gastrointestinal vomiting, abdominaldisorders nausea, discomfortabdominal pain,diarrhoea

Skin and subcutaneous rash urticaria, angioneurotictissue disorders erythema, oedema, livedopruritus, acne, reticularishyperhidrosis

Musculoskeletal, arthralgia, pain musculoskeletal sensation ofconnective tissue and in limb, myalgia, discomfort, heavinessbone disorders back pain peripheralswelling, jointswelling

Immune system hypersensitivity anaphylacticdisorders reaction,

General disorders and chest pain, chest tightness, injection site rashadministration site rigors, pyrexia, fatigueconditions pain, asthenia, aggravated,fatigue feeling hot,feeling cold,influenza likeillness,discomfort,malaise

See also section 4.4.

Infusion related reactions reported in the post-marketing setting (also see section 4.4) may includecardiac events such as cardiac arrhythmias (atrial fibrillation, ventricular extrasystoles,tachyarrhythmia), myocardial ischemia, and heart failure in patients with Fabry disease involving theheart structures. The most common infusion related reactions were mild and include rigors, pyrexia,flushing, headache, nausea, dyspnoea, tremor, and pruritus. Infusion-related symptoms may alsoinclude dizziness, hyperhidrosis, hypotension, cough, vomiting and fatigue. Hypersensitivity,including anaphylaxis, has been reported.

Adverse drug reactions reported in the paediatric population (children and adolescents) were, ingeneral, similar to those reported in adults. However, infusion related reactions (pyrexia, dyspnoea,chest pain) and pain exacerbation occurred more frequently.

Patients with renal disease

Adverse drug reactions reported in patients with history of end stage renal disease were similar tothose reported in the general patient population.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical trials doses up to 0.4 mg/kg weekly were used, and their safety profile was not differentfrom the recommended dose of 0.2 mg/kg biweekly.

Pharmacotherapeutic group: Other alimentary tract and metabolism products - Enzymes. ATC code:

A16AB03.

Fabry Disease is a glycosphingolipid storage disorder that is caused by deficient activity of thelysosomal enzyme α-galactosidase A, resulting in accumulation of globotriaosylceramide (Gb3 or

GL-3, also known as ceramidetrihexoside (CTH)), the glycosphingolipid substrate for this enzyme.

Agalsidase alfa catalyses the hydrolysis of Gb3, cleaving a terminal galactose residue from themolecule. Treatment with the enzyme has been shown to reduce accumulation of Gb3 in many celltypes including endothelial and parenchymal cells. Agalsidase alfa has been produced in a human cellline to provide for a human glycosylation profile that can influence uptake by mannose-6-phosphatereceptors on the surface of target cells. The selection of 0.2 mg/kg dose (infused over 40 minutes) forthe registration clinical studies was intended to temporarily saturate the ability of themannose-6-phosphate receptors to internalize the agalsidase alfa in the liver and allow distribution ofenzyme to other relevant organ tissues. Data with patients indicates that at least 0.1 mg/kg is requiredto achieve a pharmacodynamics response.

The safety and efficacy of Replagal was assessed in two randomised, double-blind, placebo-controlledstudies and open label extension studies, in a total of forty patients with a diagnosis of Fabry Diseasebased on clinical and biochemical evidence. Patients received the recommended dosage of 0.2 mg/kgof Replagal. Twenty-five patients completed the first study and entered an extension study. After6 months of therapy there was a significant reduction in pain in the Replagal treated patients comparedwith placebo (p=0.021), as measured by the Brief Pain Inventory (a validated pain measurementscale). This was associated with a significant reduction in chronic neuropathic pain medication use andnumber of days on pain medication. In subsequent studies, in male paediatric patients above the ageof 7, a reduction in pain was observed after 9 and 12 months of Replagal therapy compared topre-treatment baseline. This pain reduction persisted through 4 years of Replagal therapy in 9 patients(in patients 7 - 18 years of age).

Twelve to 18 months of treatment with Replagal resulted in improvement in quality of life (QoL), asmeasured by validated instruments.

After 6 months of therapy, Replagal stabilised renal function compared with a decline in placebotreated patients. Kidney biopsy specimens revealed a significant increase in the fraction of normalglomeruli and a significant decrease in the fraction of glomeruli with mesangial widening in patientstreated with Replagal in contrast to the patients treated with placebo. After 12 to 18 months ofmaintenance therapy, Replagal improved renal function as measured by inulin based glomerularfiltration rate by 8.7 ± 3.7 ml/min. (p=0.030). Longer term therapy (48-54 months) resulted instabilisation of GFR in male patients with normal baseline GFR (≥ 90 mL/min/1.73 m2) and with mildto moderate renal dysfunction (GFR 60 to < 90 mL/min/1.73 m2), and in slowing of the rate of declinein renal function and progression to end-stage renal disease in male Fabry patients with more severerenal dysfunction (GFR 30 to < 60 mL/min/1.73 m2).

In a second study, fifteen patients with left ventricular hypertrophy completed a 6 monthplacebo-controlled study and entered an extension study. Treatment with Replagal resulted in an11.5 g decrease in left ventricular mass as measured by magnetic resonance imaging (MRI) in thecontrolled study, while patients receiving placebo exhibited an increase in left ventricular mass of21.8 g. In addition, in the first study involving 25 patients, Replagal effected a significant reduction incardiac mass after 12 to 18 months of maintenance therapy (p<0.001). Replagal was also associatedwith improved myocardial contractility, a decrease in mean QRS duration and a concomitant decreasein septal thickness on echocardiography. Two patients with right bundle branch block in the studiesconducted reverted to normal following therapy with Replagal. Subsequent open label studiesdemonstrated significant reduction from baseline in left ventricular mass by echocardiography in bothmale and female Fabry patients over 24 to 36 months of Replagal treatment. The reductions in LVmass observed by echocardiography in both male and female Fabry patients over 24 to 36 months of

Replagal treatment were associated with meaningful symptom improvement as measured using the

NYHA and CCS in Fabry patients with severe heart failure or anginal symptoms at baseline.

Compared with placebo, treatment with Replagal also reduced accumulation of Gb3. After the first 6months of therapy mean decreases of approximately 20 - 50 % were observed in plasma, urinesediment, liver, kidney, and heart biopsy samples. After 12 to 18 months treatment a reduction of50 - 80% was observed in plasma and urine sediment. The metabolic effects were also associated withclinically significant weight gain, increased sweating, and increased energy. Consistent with theclinical effects of Replagal, treatment with the enzyme reduced accumulation of Gb3 in many celltypes, including renal glomerular and tubular epithelial cells, renal capillary endothelial cells (cardiacand dermal capillary endothelial cells were not examined) and cardiac myocytes. In male paediatric

Fabry patients plasma Gb3 decreased 40 - 50% after 6 months of Replagal therapy 0.2 mg/kg and thisreduction persisted after a total 4 years of treatment in 11 patients.

Infusion of Replagal at home may be considered for patients who are tolerating their infusions well.

In male paediatric Fabry patients ≥ 7 years of age, hyperfiltration can be the earliest manifestation ofrenal involvement in the disease. Reduction in their hypernormal eGFRs was observed within6 months of initiating Replagal therapy. After one year of treatment with agalsidase alfa 0.2 mg/kgevery other week, the abnormally high eGFR decreased from 143.4 ± 6.8 to121.3 ± 5.6 mL/min/1.73 m2 in this subgroup and these eGFRs stabilized in the normal range during4 years of Replagal 0.2 mg/kg therapy, as did the eGFRs of the non-hyperfiltrators.

In male paediatric patients ≥ 7 years of age, heart rate variability was abnormal at baseline andimproved after 6 months of Replagal therapy in 15 boys and the improvement was sustained through6.5 years of Replagal 0.2 mg/kg therapy in an open-label long-term extension study in 9 boys. Among9 boys with left ventricular mass (LVMI) indexed to height2.7 within the normal range for children(< 39 g/m2.7 in boys) at baseline, LVMI remained stable at levels below the left ventricularhypertrophy (LVH) threshold throughout the 6.5 years of treatment. In a second study, in 14 patients≥ 7 years of age, the results regarding heart rate variability were consistent with previous findings. Inthis study, only one patient had LVH at baseline and remained stable over time.

For patients between 0 and 7 years of age, limited data indicate no specific safety issues.

Study in patients switching from agalsidase beta to Replagal (agalsidase alfa)100 patients [(naïve (n=29); or previously treated with agalsidase beta who switched to Replagal(n=71)) were treated for up to 30 months in an open label, uncontrolled study. An analysis showed thatserious adverse events were reported in 39.4% of those patients who switched from agalsidase betacompared to 31.0% in those who were naïve to therapy prior to study entry. Patients switched fromagalsidase beta to Replagal had a safety profile consistent with that observed in other clinicalexperience. Infusion related reactions have been experienced by 9 patients of the naïve population(31.0%) compared to 27 patients of the switched population (38.0%).

Study with various dosing regimen

In an open-label randomised study, there were no statistically significant differences between adultpatients treated for 52 weeks with 0.2 mg/kg intravenously every other week (n=20) and those treatedwith 0.2 mg/kg weekly (n=19) in mean change from baseline LVMI or other endpoints (cardiacfunctional status, renal function, and pharmacodynamic activity). In each treatment group, LVMIremained stable over the treatment period of the study. The overall incidence of SAEs by treatmentgroup did not show any obvious effect of treatment regimen on the SAE profile of the differenttreatment groups.

Antibodies to agalsidase alfa have not been shown to be associated with any clinically significanteffects on safety (e.g., infusion reactions) or efficacy.

Single doses ranging from 0.007 - 0.2 mg enzyme per kg body weight were administered to adult malepatients as 20 - 40 minute intravenous infusions while female patients received 0.2 mg enzyme per kgbody weight as 40 minute infusions. The pharmacokinetic properties were essentially unaffected bythe dose of the enzyme. Following a single intravenous dose of 0.2 mg/kg, agalsidase alfa had abiphasic distribution and elimination profile from the circulation. Pharmacokinetic parameters werenot significantly different between male and female patients. Elimination half-lives were 108  17minutes in males compared to 89  28 minutes in females and volume of distribution wasapproximately 17% body weight in both sexes. Clearance normalised for body weight was 2.66 and2.10 ml/min/kg for males and females, respectively. Based on the similarity of pharmacokineticproperties of agalsidase alfa in both males and females, tissue distribution in major tissues and organsis also expected to be comparable in male and female patients.

Following six months of Replagal treatment 12 of 28 male patients showed altered pharmacokineticsincluding an apparent increase in clearance. These changes were associated with the development oflow titre antibodies to agalsidase alfa but no clinically significant effects on safety or efficacy wereobserved in the patients studied.

Based on the analysis of pre- and post-dose liver biopsies in males with Fabry Disease, the tissuehalf-life has been estimated to be in excess of 24 hours and hepatic uptake of the enzyme estimated tobe 10% of administered dose.

Agalsidase alfa is a protein. It is not expected to bind to proteins. It is expected that its metabolicdegradation will follow the pathways of other proteins, i.e., peptide hydrolysis. Agalsidase alfa isunlikely to be a candidate for drug-drug interactions.

Renal elimination of agalsidase alfa is considered to be a minor clearance pathway sincepharmacokinetic parameters are not altered by impaired renal function.

As metabolism is expected to occur by peptide hydrolysis, impaired liver function is not expected toaffect the pharmacokinetics of agalsidase alfa in a clinically significant manner.

In children (aged 7-18 years), Replagal administered at 0.2 mg/kg was cleared faster from thecirculation than in adults. Mean clearance of Replagal in children aged (7-11 years), in adolescents(aged 12-18 years), and adults was 4.2 ml/min/kg, 3.1 ml/min/kg, and 2.3 ml/min/kg, respectively.

Pharmacodynamic data suggest that at a dose of 0.2 mg/kg Replagal, the reductions in plasma Gb3 aremore or less comparable between adolescents and young children (see section 5.1).

Non-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity.

Genotoxic and carcinogenic potential are not expected. Reproduction toxicity studies in female ratsand rabbits have shown no effect on pregnancy or the developing foetus. No studies have beenconducted with respect to parturition or peri/post-natal development. It is not known whether Replagalcrosses the placenta.

Sodium phosphate monobasic, monohydrate

Polysorbate 20

Sodium chloride

Sodium hydroxide

Water for injections

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

2 years.

Chemical and physical in use stability has been demonstrated for 24 hours at 25 °C.

From a microbiological point of view, the product should be used immediately. If not usedimmediately, in-use storage times and conditions prior to use are the responsibility of the user andwould normally not be longer than 24 hours at 2 to 8 °C, unless dilution has taken place in controlledand validated aseptic conditions.

Store in a refrigerator (2 °C - 8 °C).

3.5 ml of concentrate for solution for infusion in a 5 ml vial (Type I glass) with a stopper (fluoro-resincoated butyl rubber), a one piece seal (aluminium) and flip-off cap. Pack sizes of 1, 4 or 10 vials.

Not all pack sizes may be marketed.

- Calculate the dose and number of Replagal vials needed.

- Any dose change should occur only at the direction of the treating physician.

- Dilute the total volume of Replagal concentrate required 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 Replagal does not contain any preservative or bacteriostatic agent; aseptictechnique must be observed. Once diluted, the solution should be mixed gently but not shaken.

- Since no preservative is present, it is recommended that administration is started as soon aspossible after dilution (see section 6.3).

- The solution should be inspected visually for particulate matter and discolouration prior toadministration.

- For single use only. Any unused product or waste material should be disposed of in accordancewith local requirements.

Takeda Pharmaceuticals International AG Ireland Branch

Block 2 Miesian Plaza50-58 Baggot Street Lower

Dublin 2

D02 HW68

Ireland

EU/1/01/189/001-003

Date of first authorisation: 03/08/2001

Date of last renewal: 28/07/2006

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

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