Replagal PPI 09/2014

9/14 ‫פורמט עלון זה נקבע ע"י משרד הבריאות ותוכנו נבדק ואושר‬

SUMMARY OF PRODUCT CHARACTERISTICS

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.

1
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 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

2
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 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.

4.7 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 adult patients treated with Replagal in clinical trials. Most undesirable
effects were mild to moderate in severity.

3
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:

Table 1
System organ class Adverse reaction
Very Common Uncommon Not known
common
Metabolism and peripheral oedema
nutrition disorders
Nervous system headache dizziness, parosmia
disorders dysgeusia,
neuropathic pain,
tremor,
hypersomnia,
hypoesthesia,
paraesthesia
Eye disorders corneal reflex
decreased,
lacrimation
increased
Ear and labyrinth tinnitus, tinnitus
disorders aggravated

Cardiac disorders tachycardia, cardiac

palpitations arrhythmias
(atrial fibrillation,
ventricular
extrasystoles,
tachyarrhythmia),
myocardial
ischaemia, heart
failure
Vascular disorders flushing hypertension hypotension
Respiratory, thoracic cough, hoarseness, oxygen
and mediastinal throat tightness, saturation
disorders dyspnoea, decreased
nasopharyngitis,
pharincreased,
rhinorrhoea
Gastrointestinal nausea diarrhoea ,
disorders vomiting,
abdominal
pain/discomfort

4
Table 1
System organ class Adverse reaction
Very Common Uncommon Not known
common
Skin and subcutaneous acne, erythema, angioneurotic hyperhidrosis
tissue disorders pruritus, rash, oedema,
livedo reticularis urticaria
Musculoskeletal, musculoskeletal sensation of
connective tissue and discomfort, heaviness
bone disorders myalgia, back pain,
limb pain,
peripheral swelling,
arthralgia, joint
swelling
Immune system Anaphylactic
disorders reaction,
hypersensitivity
General disorders and rigors, fatigue aggravated,
administration site pyrexia, feeling hot, feeling
conditions pain and cold, asthenia,
discomfort, chest pain, chest
fatigue 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. Any suspected adverse events should be reported to the
Ministry of Health according to the National Regulation by using an online form
https://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=
[email protected]

4.9 Overdose

5
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.

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.

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

6
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.

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

7
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.

This medicinal product has been authorised under “Exceptional Circumstances”. This means
that due to the rarity of the disease it has not been possible to obtain complete information on
this medicinal product.

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

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.

8
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
Sodium chloride
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.

6.6 Special precautions for disposal and other handling

 Calculate the dose and number of Replagal vials needed.

9
 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 INC., USA

8. LICENSE HOLDER

Shire Pharmaceuticals Israel Ltd.,

Electra Tower, Yigal Alon 98, Tel Aviv

10