Replagal

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Replagal 1 mg/ml concentrate for solution for infusion. 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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 genetic 
engineering technology. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Concentrate for solution for infusion. 
A clear and colourless solution. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
Replagal is indicated for long-term enzyme replacement therapy in patients with a confirmed 
diagnosis of Fabry Disease (α-galactosidase A deficiency).  
 
4.2 Posology and method of administration 
 
Replagal treatment should be supervised by a physician experienced in the management of patients 
with Fabry Disease or other inherited metabolic diseases.   
 
Posology 
Replagal is administered at a dose of 0.2 mg/kg body weight every other week by intravenous infusion 
over 40 minutes.  
 
Special populations 
Elderly patients 
Studies in patients over the age of 65 have not been performed and no dosage regimen can presently 
be recommended in these patients as safety and efficacy have not yet been established. 
 
Patients with hepatic impairment 
No studies have been performed in patients with hepatic impairment. 
 
Patients with renal 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 enzyme 
replacement therapy. Limited data are available in patients on dialysis or post-kidney transplantation, 
no dose adjustment is recommended. 
 
Paediatric Population 
The safety and efficacy of Replagal in children aged 0-6 years has not yet been established. Currently 
available data are described in section 5.1 but no recommendation on posology can be made. 
 

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In clinical studies of children (7-18 years) who received Replagal 0.2 mg/kg every other week, no 
unexpected safety issues were encountered (see section 5.1). 
 
Method of administration 
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 integral 
filter.  
 
Do not infuse Replagal concomitantly in the same intravenous line with other agents. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 
4.4 Special warnings and precautions for use 
 
Idiosyncratic infusion related reactions 
13.7% of adult patients treated with Replagal in clinical trials have experienced idiosyncratic infusion 
related reactions. Four of 17 (23.5%) paediatric patients ≥7 years of age enrolled in clinical trials 
experienced at least one infusion reaction over a period of 4.5 years of treatment (mean duration of 
approx. 4 years). Three of 8 (37.5%) paediatric patients <7 years of age experienced at least one 
infusion related reaction over a mean observation time of 4.2 years. The most common symptoms 
have been rigors, headache, nausea, pyrexia, flushing and fatigue. Serious infusion reactions have been 
reported uncommonly; symptoms reported include pyrexia, rigors, tachycardia, urticaria, 
nausea/vomiting, angioneurotic oedema with throat tightness, stridor and swollen tongue. Other 
infusion-related symptoms may include dizziness and hyperhidrosis. A review of cardiac events 
showed that infusion reactions may be associated with hemodynamic stress triggering cardiac events 
in patients with pre-existing cardiac manifestations of Fabry disease.  
 
The onset of infusion related reactions has generally occurred within the first 2-4 months after 
initiation 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, medical 
attention must be sought immediately and appropriate actions instituted. The infusion can be 
temporarily interrupted (5 to 10 minutes) until symptoms subside and the infusion may then be 
restarted. Mild and transient effects may not require medical treatment or discontinuation of the 
infusion. 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 where 
symptomatic treatment was required. 
 
Hypersensitivity reactions 
Hypersensitivity reactions have been reported. If severe hypersensitivity or anaphylactic reactions 
occur, the administration of Replagal should be discontinued immediately and appropriate treatment 
initiated. 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 low 
titre 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 paediatric 
population. These IgG antibodies appeared to develop following approximately 3-12 months of 
treatment. After 12 to 54 months of therapy, 17% of Replagal treated patients were still antibody 
positive whereas 7% showed evidence for the development of immunologic tolerance, based on the 
disappearance of IgG antibodies over time. The remaining 76% were antibody negative throughout. In 
paediatric patients >7 yrs of age, 1/16 male patients tested positive for IgG anti-agalsidase alfa 
antibodies during the study. No increase in the incidence of adverse events was detected for this 
patient. In paediatric patients <7 yrs of age, 0/7 male patients tested positive for IgG anti-agalsidase 

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alfa antibodies. Borderline IgE antibody positivity not associated with anaphylaxis has been reported 
in clinical trials in a very limited number of patients. 
 
Patients with renal impairment 
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 function 
remains within the expected range of the natural progression of disease. 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
Replagal should not be co-administered with chloroquine, amiodarone, benoquin or gentamicin since 
these 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 P450 
mediated drug-drug interactions. In clinical studies, neuropathic pain medicinal products (such as 
carbamazepine, phenytoin and gabapentin) were administered concurrently to most patients without 
any evidence of interaction. 
 
4.6 Fertility, pregnancy and lactation 
 
Pregnancy 
There is very limited data on pregnancies exposed to Replagal. Animal studies do not indicate direct 
or indirect harmful effects with respect to pregnancy or embryonic/fetal development when exposed 
during organogenesis (see Section 5.3). Caution should be exercised when prescribing to pregnant 
women. 
 
Breast-feeding 
It is not known whether Replagal is excreted in human milk. Caution should be exercised when 
prescribing to breast-feeding women. 
 
Fertility 
No effects on male fertility were seen in reproductive studies in male rats. 
 
4.6 Effects on ability to drive and use machines 
 
Replagal has no or negligible influence on the ability to drive and use machines. 
 
4.7 Undesirable effects 
 
Summary of safety profile 
The most commonly reported adverse reactions were infusion associated reactions, which occurred in 
13.7% of adult patients treated with Replagal in clinical trials. Most undesirable effects were mild to 
moderate in severity. 
 
Tabulated list of adverse reactions 
Table 1 lists adverse reactions reported for the 177 patients treated with Replagal in clinical trials, 
including 21 patients with history of end stage renal disease, 24 paediatric patients (7 to 17 years of 
age) and 17 female patients, and from post-marketing spontaneous reports. Information is presented by 
system 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 be estimated 
from the available data)” are derived from post-marketing spontaneous reports. Within each frequency 
grouping, undesirable effects are presented in order of decreasing seriousness. The occurrence of an 
event in a single patient is defined as uncommon in view of the number of patients treated. A single 
patient could be affected by several adverse reactions.  
 
The following adverse reactions have been identified for agalsidase alfa: 
 

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Table 1 
System organ class Adverse reaction 
 Very 

common 
Common Uncommon Not known 

Metabolism and 
nutrition disorders 

 peripheral 
oedema 

  

Nervous system 
disorders  

headache dizziness, 
dysgeusia, 
neuropathic 
pain, tremor, 
hypersomnia, 
hypoesthesia, 
paraesthesia 

parosmia  

Eye disorders   corneal reflex 
decreased, 
lacrimation 
increased 

  

Ear and labyrinth 
disorders 
  

 tinnitus, tinnitus 
aggravated 

  
 

Cardiac disorders  
 

 tachycardia, 
palpitations 

 cardiac arrhythmias 
(atrial fibrillation, 
ventricular 
extrasystoles, 
tachyarrhythmia), 
myocardial 
ischaemia, heart 
failure 

Vascular disorders  flushing hypertension  hypotension 
Respiratory, thoracic 
and mediastinal 
disorders  

 

 cough, 
hoarseness, 
throat tightness, 
dyspnoea, 
nasopharyngitis, 
pharyngitis, 
throat secretion 
increased, 
rhinorrhoea 

oxygen 
saturation 
decreased 

 
 

Gastrointestinal 
disorders  

nausea diarrhoea , 
vomiting, 
abdominal 
pain/discomfort 

  
 

Skin and subcutaneous 
tissue disorders  

 acne, erythema, 
pruritus, rash, 
livedo reticularis 

angioneurotic 
oedema, 
urticaria 

hyperhidrosis 
 

Musculoskeletal, 
connective tissue and 
bone disorders 

 musculoskeletal 
discomfort, 
myalgia, back 
pain, limb pain, 
peripheral 
swelling, 
arthralgia, joint 
swelling 

sensation of 
heaviness 

 
 

Immune system 
disorders 

  Anaphylactic 
reaction, 
hypersensitivity 

 

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Table 1 
System organ class Adverse reaction 
 Very 

common 
Common Uncommon Not known 

General disorders and 
administration site 
conditions 

rigors, 
pyrexia, 
pain and 
discomfort,  
fatigue 

fatigue 
aggravated, 
feeling hot, 
feeling cold, 
asthenia, chest 
pain, chest 
tightness, 
influenza like 
illness, injection 
site rash, 
malaise 

  
 

 
See also section 4.4. 
 
Description of selected adverse reactions 
Infusion related reactions reported in the postmarketing setting (also see section 4.4) may include 
cardiac events such as cardiac arrhythmias (atrial fibrillation, ventricular extrasystoles, 
tachyarrhythmia), myocardial ischemia, and heart failure in patients with Fabry disease involving the 
heart structures. The most common infusion related reactions were mild and include rigors, pyrexia, 
flushing, headache, nausea, dyspnea, tremor and pruritus. Infusion-related symptoms may also include 
dizziness, hyperhidrosis, hypotension, cough, vomiting and fatigue. Hypersensitivity, including 
anaphylaxis, has been reported. 
 
Patients with renal disease 
Adverse drug reactions reported in patients with history of end stage renal disease were similar to 
those reported in the general patient population. 
 
Paediatric population 
Adverse drug reactions reported in the paediatric population (children and adolescents) were, in 
general, similar to those reported in adults. However, infusion related reactions (pyrexia, dyspnoea, 
chest pain) and pain exacerbation occurred more frequently.   
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
In clinical trials doses up to 0.4 mg/kg weekly were used, and their safety profile was not different 
from the recommended dose of 0.2 mg/kg biweekly. 
 
 
5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Other alimentary tract and metabolism products - Enzymes.ATC code: 
A16AB03. 
 

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Mechanism of action 
Fabry Disease is a glycosphingolipid storage disorder that is caused by deficient activity of the 
lysosomal 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 the 
molecule. Treatment with the enzyme has been shown to reduce accumulation of Gb3 in many cell 
types including endothelial and parenchymal cells. Agalsidase alfa has been produced in a human cell 
line to provide for a human glycosylation profile that can influence uptake by mannose-6-phosphate 
receptors on the surface of target cells. The selection of 0.2 mg/kg dose (infused over 40 minutes) for 
the registration clinical studies was intended to temporarily saturate the ability of the mannose-6-
phosphate receptors to internalize the agalsidase alfa in the liver and allow distribution of enzyme to 
other relevant organ tissues. Data with patients indicates that at least 0.1mg/kg is required to achieve a 
pharmacodynamics response. 
 
Clinical efficacy and safety 
The safety and efficacy of Replagal was assessed in two randomised, double blind, placebo controlled 
studies and open label extension studies, in a total of forty patients with a diagnosis of Fabry Disease 
based on clinical and biochemical evidence. Patients received the recommended dosage of 0.2 mg/kg 
of Replagal. Twenty-five patients completed the first study and entered an extension study. After 6 
months of therapy there was a significant reduction in pain in the Replagal treated patients compared 
with placebo (p=0.021), as measured by the Brief Pain Inventory (a validated pain measurement 
scale). This was associated with a significant reduction in chronic neuropathic pain medication use and 
number of days on pain medication. In subsequent studies, in male paediatric patients above the age of 
7, a reduction in pain was observed after 9 and 12 months of Replagal therapy compared to pre-
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), as 
measured by validated instruments.  
 
After 6 months of therapy Replagal stabilised renal function compared with a decline in placebo 
treated patients. Kidney biopsy specimens revealed a significant increase in the fraction of normal 
glomeruli and a significant decrease in the fraction of glomeruli with mesangial widening in patients 
treated with Replagal in contrast to the patients treated with placebo. After 12 to 18 months of 
maintenance therapy, Replagal improved renal function as measured by inulin based glomerular 
filtration rate by 8.7 ± 3.7 ml/min. (p=0.030). Longer term therapy (48-54 months) resulted in 
stabilisation of GFR in male patients with normal baseline GFR (≥ 90 mL/min/1.73 m2) and with mild 
to moderate renal dysfunction (GFR 60 to < 90 mL/min/1.73 m2), and in slowing of the rate of decline 
in renal function and progression to end-stage renal disease in male Fabry patients with more severe 
renal dysfunction (GFR 30 to < 60 mL/min/1.73 m2). 
 
In a second study, fifteen patients with left ventricular hypertrophy completed a 6 month placebo-
controlled study and entered an extension study. Treatment with Replagal resulted in an 11.5 g 
decrease in left ventricular mass as measured by magnetic resonance imaging (MRI) in the controlled 
study, while patients receiving placebo exhibited an increase in left ventricular mass of 21.8 g. In 
addition, in the first study involving 25 patients, Replagal effected a significant reduction in cardiac 
mass after 12 to 18 months of maintenance therapy (p<0.001). Replagal was also associated with 
improved myocardial contractility, a decrease in mean QRS duration and a concomitant decrease in 
septal thickness on echocardiography. Two patients with right bundle branch block in the studies 
conducted reverted to normal following therapy with Replagal. Subsequent open label studies 
demonstrated significant reduction from baseline in left ventricular mass by echocardiography in both 
male and female Fabry patients over 24 to 36 months of Replagal treatment. The reductions in LV 
mass 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. 
 

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Compared with placebo, treatment with Replagal also reduced accumulation of Gb3. After the first 6 
months of therapy mean decreases of approximately 20 - 50 % were observed in plasma, urine 
sediment, liver, kidney, and heart biopsy samples. After 12 to 18 months treatment a reduction of 50 – 
80% was observed in plasma and urine sediment. The metabolic effects were also associated with 
clinically significant weight gain, increased sweating and increased energy. Consistent with the 
clinical effects of Replagal, treatment with the enzyme reduced accumulation of Gb3 in many cell 
types, including renal glomerular and tubular epithelial cells, renal capillary endothelial cells (cardiac 
and 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 this 
reduction 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. 
 
Paediatric population 
In male paediatric Fabry patients ≥ 7 years of age, hyperfiltration can be the earliest manifestation of 
renal involvement in the disease. Reduction in their hypernormal eGFRs was observed within 
6 months of initiating Replagal therapy. After one year of treatment with agalsidase alfa 0.2 mg/kg 
every other week, the abnormally high eGFR decreased from 143.4 ± 6.8 to 121.3 ± 
5.6 mL/min/1.73 m2 in this subgroup and these eGFRs stabilized in the normal range during 4 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 and 
improved after 6 months of Replagal therapy in 15 boys and the improvement was sustained through 
6.5 years of Replagal 0.2 mg/kg therapy in an open-label long-term extension study in 9 boys. Among 
9 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 ventricular hypertrophy 
(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. In this 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 that 
serious adverse events were reported in 39.4% of those patients who switched from agalsidase beta 
compared to 31.0% in those who were naïve to therapy prior to study entry. Patients switched from 
agalsidase beta to Replagal had a safety profile consistent with that observed in other clinical 
experience. 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 adult 
patients treated for 52 weeks with 0.2 mg/kg intravenously every other week (n=20) and those treated 
with 0.2 mg/kg weekly (n=19) in mean change from baseline LVMI or other endpoints (cardiac 
functional status, renal function, and pharmacodynamic activity). In each treatment group, LVMI 
remained stable over the treatment period of the study. The overall incidence of SAEs by treatment 
group did not show any obvious effect of treatment regimen on the SAE profile of the different 
treatment groups. 
 
Immunogenicity 
Antibodies to agalsidase alfa have not been shown to be associated with any clinically significant 
effects on safety (e.g. infusion reactions) or efficacy. 
 

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5.2 Pharmacokinetic properties 
 
Single doses ranging from 0.007 - 0.2 mg enzyme per kg body weight were administered to adult male 
patients as 20 - 40 minute intravenous infusions while female patients received 0.2 mg enzyme per kg 
body weight as 40 minute infusions. The pharmacokinetic properties were essentially unaffected by 
the dose of the enzyme. Following a single intravenous dose of 0.2 mg/kg, agalsidase alfa had a 
biphasic distribution and elimination profile from the circulation. Pharmacokinetic parameters were 
not significantly different between male and female patients. Elimination half-lives were 108 ± 17 
minutes in males compared to 89 ± 28 minutes in females and volume of distribution was 
approximately 17% body weight in both sexes. Clearance normalised for body weight was 2.66 and 
2.10 ml/min/kg for males and females, respectively. Based on the similarity of pharmacokinetic 
properties of agalsidase alfa in both males and females, tissue distribution in major tissues and organs 
is also expected to be comparable in male and female patients. 
 
Following six months of Replagal treatment 12 of 28 male patients showed altered pharmacokinetics 
including an apparent increase in clearance. These changes were associated with the development of 
low titre antibodies to agalsidase alfa but no clinically significant effects on safety or efficacy were 
observed in the patients studied. 
 
Based on the analysis of pre- and post-dose liver biopsies in males with Fabry Disease, the tissue half-
life has been estimated to be in excess of 24 hours and hepatic uptake of the enzyme estimated to be 
10% of administered dose. 
 
Agalsidase alfa is a protein. It is not expected to bind to proteins. It is expected that its metabolic 
degradation will follow the pathways of other proteins, i.e. peptide hydrolysis. Agalsidase alfa is 
unlikely to be a candidate for drug-drug interactions. 
 
Renal impairment 
Renal elimination of agalsidase alfa is considered to be a minor clearance pathway since 
pharmacokinetic parameters are not altered by impaired renal function.   
 
Hepatic impairment 
As metabolism is expected to occur by peptide hydrolysis, impaired liver function is not expected to 
affect the pharmacokinetics of agalsidase alfa in a clinically significant manner. 
 
Paediatric population 
In children (aged 7-18 years), Replagal administered at 0.2 mg/kg was cleared faster from the 
circulation 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 are 
more or less comparable between adolescents and young children (see section 5.1). 
 
5.3 Preclinical safety data 
 
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 rats 
and rabbits have shown no effect on pregnancy or the developing foetus. No studies have been 
conducted with respect to parturition or peri/post-natal development. It is not known whether Replagal 
crosses the placenta. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium phosphate monobasic, monohydrate 
Polysorbate 20 

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Sodium chloride 
Sodium hydroxide 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies this medicinal product must not be mixed with other medicinal 
products. 
 
6.3 Shelf life 
 
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 used 
immediately, in-use storage times and conditions prior to use are the responsibility of the user and 
would normally not be longer than 24 hours at 2 to 8°C, unless dilution has taken place in controlled 
and validated aseptic conditions.  
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2°C – 8°C).  
 
6.5 Nature and contents of container 
 
3.5 ml of concentrate for solution for infusion in a 5 ml vial (Type I glass) with a stopper (fluoro-resin 
coated 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. 
 
6.6 Special precautions for disposal and other handling 
 
• Calculate the dose and number of Replagal vials needed. 
 
• Dilute the total volume of Replagal concentrate required in 100 ml of 9 mg/ml (0.9%) sodium 

chloride solution for infusion. Care must be taken to ensure the sterility of the prepared 
solutions since Replagal does not contain any preservative or bacteriostatic agent; aseptic 
technique 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 as 

possible after dilution. 
 
• The solution should be inspected visually for particulate matter and discolouration prior to 

administration. 
 
• For single use only. Any unused product or waste material should be disposed of in accordance 

with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Shire Human Genetic Therapies AB,  
Vasagatan 7   
111 20 Stockholm   
Sweden 
 

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8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/189/001-003 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 03/08/2001 
Date of last renewal: 03/08/2006 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu/. 

11 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE 
SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE 
FOR BATCH RELEASE 

 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT  

 
E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE MARKETING 
AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 

 

12 



A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND 
MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 

 
Name and address of the manufacturer of the biological active substance 
 
Shire Human Genetic Therapies Inc., 
205 Alewife Brook Parkway 
Cambridge, MA 02138 
USA 
 
Shire Human Genetic Therapies Inc., 
400 Shire Way  
Lexington, MA 02421 
USA 
 
Name and address of the manufacturer responsible for batch release 
 
Shire Pharmaceuticals Ireland Limited 
Block 2 & 3 Miesian Plaza 
50 – 58 Baggot Street Lower 
Dublin 2 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, Section 4.2) 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The marketing authorisation holder shall submit periodic safety update reports for this product in 
accordance with the requirements set out in the list of Union reference dates (EURD list) provided for 
under Article 107c(7) of Directive 2001/83/EC and published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT   
 
Not applicable. 
 
 
E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL 
CIRCUMSTANCES 

 
Not applicable 
 

13 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 
 

14 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 
 

15 



PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON / 3.5 ML VIAL 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Replagal 1 mg/ml concentrate for solution for infusion 
agalsidase alfa 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
One vial contains 3.5 mg of agalsidase alfa 
 
 
3. LIST OF EXCIPIENTS 
 
Sodium phosphate monobasic, monohydrate  
polysorbate 20 
sodium chloride 
sodium hydroxide 
water for injections 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
1 x 3.5 ml concentrate for solution for infusion 
4 x 3.5 ml concentrate for solution for infusion 
10 x 3.5 ml concentrate for solution for infusion 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Intravenous use  
Read the package leaflet before use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator 

16 



 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Shire Human Genetic Therapies AB,  
Vasagatan 7 
111 20 Stockholm   
Sweden 
 
 
12. MARKETING AUTHORISATION NUMBER(S)    
 
EU/1/01/189/001 
EU/1/01/189/002 
EU/1/01/189/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
Medicinal product subject to medical prescription 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Justification for not including Braille accepted 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN:  
NN:  

17 



MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
VIAL 3.5 ML PRESENTATION 
 
 
1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 
 
Replagal 1 mg/ml sterile concentrate 
agalsidase alfa 
Intravenous use 
 
 
2. METHOD OF ADMINISTRATION 
 
Read the package leaflet before use 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot  
 
 
5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 
 
3.5 ml 
 
 
6. OTHER 
 
Store in a refrigerator  
 
 

18 



 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 
 

19 



Package leaflet: Information for the user 
 

Replagal 1 mg/ml concentrate for solution for infusion 
Agalsidase alfa 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet: 
 
1. What Replagal is and what it is used for 
2. What you need to know before you are given Replagal 
3. How Replagal is given 
4. Possible side effects 
5. How to store Replagal 
6. Contents of the pack and other information 
 
 
1. What Replagal is and what it is used for 
 
The active substance in Replagal is agalsidase alfa (1mg/ml). Agalsidase alfa is a form of the human 
enzyme α-galactosidase. It is produced by switching on the gene for α-galactosidase A in cells. The 
enzyme is then removed from the cells and made into a sterile concentrate for solution for infusion. 
 
Replagal is used to treat adult patients, as well as adolescents and children from the age of 7, with 
confirmed diagnosis of Fabry Disease. It is used as long-term enzyme replacement therapy when the 
level of enzyme in the body is absent or lower than normal as in Fabry Disease. 
 
After 6 months of therapy Replagal significantly reduced pain in patients when compared to placebo 
(dummy) treated patients. Replagal reduced left ventricle mass in treated patients compared to placebo 
treated patients. These results suggest the symptoms of the disease are improving or the disease is 
becoming stable. 
 
 
2. What you need to know before Replagal is given 
 
You must not be given Replagal 
 
- if you are allergic to agalsidase alfa or any of the other ingredients of this medicine (listed in 

section 6). 
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before Replagal is used. 
 
If you notice any of these effects during or after an infusion you should tell your doctor immediately: 
- high fever, chills, sweating, fast heart rate; 
- vomiting; 
- light-headedness; 
- hives; 

20 



- swelling in your hands, feet, ankles, face, lips, mouth or throat which may cause difficulty in 
swallowing or breathing. 

 
Your doctor may stop the infusion temporarily (5 –10 min) until the symptoms go away and then 
begin the infusion again. 
 
Your doctor may also treat the symptoms with other medicines (antihistamines or corticosteroids). 
Most of the time you can still be given Replagal even if these symptoms occur. 
 
If you experience a severe allergic (anaphylactic-type) reaction, the administration of Replagal will be 
immediately discontinued and an appropriate treatment will have to be initiated by your doctor. 
 
If treatment with Replagal makes your body produce antibodies this will not stop Replagal from 
working and the antibodies may disappear with time. 
 
If you have advanced renal disease, you may find that your Replagal treatment has a limited effect on 
your kidneys. Talk to your doctor or pharmacist before using Replagal. 
 
Children 
 
The experience in children 0-6 years old is limited and therefore no dose can be recommended for this 
age group. 
 
Other medicines and Replagal 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Tell your doctor if you use any medicines containing chloroquine, amiodarone, benoquin or 
gentamicin. There is a theoretical risk of decreased agalsidase alfa activity. 
 
Pregnancy and breast feeding 
 
Very limited clinical data on pregnancies exposed to Replagal have shown no adverse effects on the 
mother and newborn child.  
 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 
your doctor or pharmacist for advice before taking this medicine. 
 
Driving and using machines 
 
You may drive and use machines whilst on Replagal. 
 
 
3. How Replagal is given 
 
This medicine should be applied and supervised by appropriately trained personnel, who will also 
calculate the dose that you will be given. 
 
The recommended dose is an infusion of 0.2 mg for every kg you weigh. This would be about 14 mg 
or 4 vials (glass bottles) of Replagal for an average size (70 kg) individual. 
 
Use in children and adolescents 
 
For children and adolescents 7-18 years old a dose of 0.2 mg/kg every other week may be used. 
 

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Children and adolescents may be more likely than adults to experience an infusion related reaction. 
Tell your doctor if you experience any side effects whilst having the infusion. 
 
Method of administration 
 
Replagal has to be diluted in 9 mg/ml (0.9%) sodium chloride solution before use. After dilution 
Replagal is given in a vein. This will usually be in your arm. 
 
The infusion will be given every two weeks. 
 
Each time you are treated it will take 40 minutes for Replagal to be given to you in a vein. Your 
treatment will be supervised by a doctor who specialises in the treatment of Fabry Disease. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
If you experience a severe allergic (anaphylactic-type) reaction, the administration of Replagal will be 
immediately discontinued and an appropriate treatment will have to be initiated by your doctor. 
 
Most side effects are mild to moderate. About 1 out of 7 patients (frequency “very common”) may 
have a reaction during or following an infusion of Replagal (infusion related reaction). These effects 
include chills, headache, nausea, fever, facial flushing (redness), tiredness, low blood pressure, 
unsteadiness, sweating, difficulty breathing, itching, shaking, cough and vomiting. However some 
effects may be serious and may need treatment. Infusion related reactions involving the heart 
including heart rhythm problems, heart muscle ischemia and heart failure, may occur in patients with 
Fabry disease involving the heart structures (frequency “not known” (cannot be estimated from the 
available data)). Your doctor may stop the infusion temporarily (5 - 10 min) until the symptoms go 
away and then begin the infusion again. Your doctor may also treat the symptoms with other 
medicines (antihistamines or corticosteroids). Most of the time you can still be given Replagal even if 
these symptoms occur. 
 
List of other side effects: 
 
Very common:  may affect more than 1 in 10 people 
- general pain or discomfort. 
 
Common:  may affect up to 1 in 10 people: 
- tingling or numbness or pain in fingers or toes, change in the taste of food, eyes tearing, blink 

reflex abnormal, ears ringing, shakes, prolonged sleep 
- palpitations, increased heart rate, increased blood pressure 
- cough, chest pain or tightness, hoarseness, sore or tight throat, sticky throat secretions, runny 

nose, cold symptoms 
- vomiting, abdominal pain or discomfort, diarrhoea 
- acne, red or itchy or mottled skin, rash at the infusion site 
- back or limb pain, muscle pain, joint pain, muscle and bone discomfort, swelling of the 

extremities or joints 
- feeling cold or hot, flu-like symptoms, feeling sick, feeling lack of energy 
 
Uncommon:  may affect up to 1 in 100 people: 
- severe allergic (anaphylactic-type) reaction  
 

22 



Children and adolescents 
 
Side effects reported in children were, in general, similar to those reported in adults. However, 
infusion related reactions (fever, difficulty breathing, chest pain) and pain aggravated occurred more 
frequently. 
 
Reporting of side effects 
 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store Replagal 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The 
expiry date refers to the last day of that month. 
 
Store in a refrigerator (2°C – 8°C).  
 
Do not use Replagal if you notice that there is discolouration or other foreign particles present. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help to protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Replagal contains 
 
- The active substance is agalsidase alfa. Each ml of Replagal contains 1 mg of agalsidase alfa. 
- The other ingredients are: Sodium phosphate monobasic, monohydrate 

Polysorbate 20 
Sodium chloride 
Sodium hydroxide 
Water for injections 

 
What Replagal looks like and contents of the pack 
 
Replagal is a concentrate for solution for infusion. Your medicine is available in vials containing 
3.5 mg/ 3.5 ml of agalsidase alfa. Pack sizes of 1, 4 or 10 vials are available. Not all pack sizes may be 
marketed. 
 
Marketing Authorisation Holder  
 
Shire Human Genetic Therapies AB,  
Vasagatan 7 
111 20 Stockholm 
Sweden 
Tel: +44(0)1256 894 959 
E-mail: medinfoEMEA@shire.com 
 

23 



Manufacturer 
 
Shire Pharmaceuticals Ireland Limited 
Block 2 & 3 Miesian Plaza 
50 – 58 Baggot Street Lower 
Dublin 2 
Ireland 
 
This leaflet was last revised in  
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 
 
------------------------------------------------------------------------------------------------------------------------- 
The following information is intended for medical or healthcare professionals only: 
 
Instructions for use, handling and disposal 
 
Replagal treatment should be supervised by a physician experienced in the management of patients 
with 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 infusion 
over 40 minutes. 
 
1. Calculate the dose and number of Replagal vials needed. 
 
2. Dilute the total volume of Replagal concentrate required in 100 ml 9 mg/ml sodium chloride 

solution for infusion (0.9%w/v). Care must be taken to ensure the sterility of the prepared 
solutions since Replagal does not contain any preservative or bacteriostatic agent; aseptic 
technique must be observed. Once diluted, the solution should be mixed gently but not shaken. 

 
3. The solution should be inspected visually for particulate matter and discolouration prior to 

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

integral filter. Since no preservative is present, it is recommended that administration is started 
as soon as possible. However, the chemical and physical stability of the diluted solution has 
been demonstrated for 24 hours at 25°C. 

 
5. Do not infuse Replagal concomitantly in the same intravenous line with other agents. 
 
6. For single use only. Any unused product or waste material should be disposed of in accordance 

with local requirements. 
 

24 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET