SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT
Replagal
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 concentratecontains 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.
Excipient(s) with known effectThis medicinal product contains 14.2 mg sodium per vial.
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 years have not been performed and no dosage regimen canpresently 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 isrecommended.
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.
In clinical studies of children (7-18 years) who received Replagal 0.2 mg/kg every other week, no unexpected safetyissues 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
Traceability
In order to improve the traceability of biological medicinal products, the name and batch number of the administeredproduct should be clearly recorded.

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%) paediatricpatients <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 ofFabry 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, theadministration 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 todevelop following approximately 3-12 months of treatment. After 12 to 54 months of therapy, 17% of Replagal treatedpatients 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 years of age, 1/16 male patients tested positive for IgG anti- agalsidase alfa antibodies during thestudy. No increase in the incidence of adverse events was detected for this patient. In paediatric patients <7 years ofage, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. 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 tounderlying irreversible pathological changes. In such cases, the loss of renal function remains within the expected rangeof the natural progression of disease.

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

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 thesesubstances 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-druginteractions. In clinical studies, neuropathic pain medicinal products (such as carbamazepine, phenytoin andgabapentin) 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 (seeSection 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 breastfeeding women.
Fertility
No effects on male fertility were seen in reproductive studies in male rats.

4.7

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

4.8

Undesirable effects
Summary of safety profile
The most commonly reported adverse reactions were infusion associated reactions, which occurred in 13.7% of adultpatients 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 344 patients treated with Replagal in clinical trials, including 21 patientswith history of end stage renal disease, 30 paediatric patients (≤18 years of age) and 17 female patients, and frompost-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 “notknown (cannot be estimated from the available data)” are derived from post-marketing spontaneous reports. Withineach frequency grouping, undesirable effects are presented in order of decreasing seriousness. The occurrence of anevent 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:
Table 1
System organ class

Adverse reaction
Very common

CommonMetabolism andnutrition disorders

peripheral oedema

Nervous systemdisordersheadache, dizziness, dysgeusia,
neuropathic pain,
hypersomnia,
tremor, hypoesthesia,
paraesthesia

Uncommonparosmia

Not known

Eye disorders

lacrimation increased

Ear and labyrinth
disorderstinnitus

tinnitus
aggravatedCardiac disorders

palpitations

tachycardia,
atrialfibrillation

Vascular disorders

corneal reflex
decreasedtachyarrhythmia

hypertension,
hypotension, flushing

Respiratory, thoracic andmediastinal disorders

dyspnoea, cough,nasopharyngitis,
pharyngitis,

hoarseness, throat
tightness,rhinorrhoea

Gastrointestinal
disorders

vomiting, nausea,
abdominal

abdominal discomfort

oxygensaturation
decreased, throat
secretion
increased

pain, diarrhoea
Skin and subcutaneous
tissue disorders

rash

urticaria, erythema,pruritus, acne,
hyperhidrosis

angioneurotic
oedema, livedo
reticularis

Musculoskeletal,
connective tissue andbone disorders

arthralgia, pain in
limb, myalgia, backpain

musculoskeletal
discomfort, peripheral
swelling, joint swelling

sensation ofheaviness

hypersensitivity

anaphylactic
reactionchest tightness,fatigue aggravated,feeling hot, feelingcold, influenza likeillness, discomfort,
malaiseinjection site rash

Immune systemdisorders

General disorders andadministration site
conditions

chest pain, rigors,
pyrexia, pain,
asthenia fatigue

myocardial ischaemia,
heart failure,
ventricular
extrasystoles,

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 inpatients with Fabry disease involving the heart structures. The most common infusion related reactions were mild andinclude rigors, pyrexia, flushing, headache, nausea, dyspnoea, tremor and pruritus. Infusion-related symptoms may also
include dizziness, hyperhidrosis, hypotension, cough, vomiting and fatigue. Hypersensitivity, including anaphylaxis, hasbeen reported.
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.
Other special populations
Patients with renal disease
Adverse drug reactions reported in patients with history of end stage renal disease were similar to those reported in thegeneral patient population.
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. Any suspected
adverse events should be reported to the Ministry of Health according to the National Regulation byusing an online form https://sideeffects.health.gov.il

4.9

Overdose
In clinical trials doses up to 0.4 mg/kg weekly were used, and their safety profile was not different from therecommended 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.
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 aterminal 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 cellline to provide for a human glycosylation profile that can influence uptake by mannose-6-phosphate receptors on thesurface of target cells. The selection of 0.2 mg/kg dose (infused over 40 minutes) for the registration clinical studies wasintended to temporarily saturate the ability of the mannose-6-phosphate receptors to internalize the agalsidase alfa in theliver 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 firststudy 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 andnumber of days on pain medication. In subsequent studies, in male paediatric patients above the age of 7, a reduction inpain 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 byvalidated instruments.
After 6 months of therapy Replagal stabilised renal function compared with a decline in placebo treatedpatients. Kidney biopsy specimens revealed a significant increase in the fraction of normal glomeruli and asignificant 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 andprogression 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 andentered 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 inleft 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 ventricularmass 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 ofReplagal 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 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 involvementin 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 monthsof Replagal therapy in 15 boys and the improvement was sustained through 6.5 years of Replagal 0.2 mg/kg therapy inan 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 theleft ventricular hypertrophy (LVH) threshold throughout the 6.5 years of treatment. In a second study, in 14 patients ≥ 7years 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 inother 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 meanchange 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 bytreatment 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.

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 andfemale 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 bodyweight was 2.66 and 2.10 ml/min/kg for males and females, respectively. Based on the similarity ofpharmacokinetic 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 anapparent increase in clearance. These changes were associated with the development of low titre antibodies toagalsidase 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 drugdrug 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 thepharmacokinetics 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 lesscomparable between adolescents and young children (see section 5.1).
5.3 Preclinical safety dataNon-clinical data reveal no special hazard for humans based on studies of repeated dose toxicity. Genotoxic andcarcinogenic potential are not expected. Reproduction toxicity studies in female rats and rabbits have shown no effect onpregnancy 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
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
The expiry date of the product is indicated on the packaging materials.
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 size of 1vial.

6.6

Special precautions for disposal and other handling• 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%) sodium chloride solution forinfusion. 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 (seesection 6.3).
• 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.

Manufacturer
Takeda Pharmaceuticals International AG Ireland Branch
Block 2 Miesian Plaza
50-58 Baggot Street Lower
Dublin 2
D02 HW68
Ireland8.

License Holder
Takeda Israel Ltd.,25 Efal st., 4951125, Petach Tikva

9.

Registration number
124-32-30382
This leaflet was revised in June 2023 according to MOHs guidelines.