ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Replagal 1 mg/ml concentrate for solution for infusion.
2.
1 ml of concentrate for solution for infusion contains 1 mg of agalsidase alfa.
Each vial of 1 ml of concentrate 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 a full list of excipients, see section 6.1.
Concentrate for solution for infusion.
A clear and colourless solution.
4.
Replagal is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis
of Fabry Disease (α-galactosidase A deficiency).
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. For preparation and administration instructions, see section 6.6.
Patients aged over 65 years
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 Patients
The experience in children is limited. No dosage regimen in children (0-6 years) can presently be
recommended as safety and efficacy have not yet been sufficiently established. Limited clinical data
in children (7-18 years) do not permit to recommend an optimal dosage regimen presently (see
sections 5.1 and 5.2). Because no unexpected safety issues were encountered in the 6 month study
2
with Replagal administered at 0.2 mg/kg in this population, this dose regimen is suggested for children
between 7– 18 years of age.
Hypersensitivity to the active substance or any of the excipients.
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.
Allergic-type hypersensitivity reactions
As with any intravenous protein product, allergic-type hypersensitivity reactions are possible. If severe
allergic or anaphylactic-type 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.
IgG antibodies to the protein
As with all protein pharmaceutical products, patients may develop IgG 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% remained antibody negative
throughout. The remaining 76% remained 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 apparent for this patient. In paediatric patients <7 yrs
of age, 0/7 male patients tested positive for IgG anti-agalsidase alfa antibodies. No IgE antibodies
have been detected in any patient receiving Replagal.
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.
3
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.
Very limited clinical data on pregnancies exposed to Replagal (n=4) have shown no adverse effects on
the mother and newborn child. Animal studies do not indicate direct or indirect harmful effects with
respect to pregnancy or embryonal/foetal development when exposed during organogenesis (see
Section 5.3).
It is not known whether Replagal is excreted in human milk. Caution should be exercised when
prescribing to pregnant or breast-feeding women.
Replagal has no or negligible influence on the ability to drive and use machines.
The most commonly reported undesirable effects 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. Table 1 lists adverse drug reactions (ADRs) reported for the 177 patients
treated with Replagal in clinical trials, including 21 patients with history of endstage renal disease, 24
paediatric patients (7 to 17 years of age) and 17 female patients. Information is presented by system
organ class and frequency (very common >1/10; common >1/100, <1/10; uncommon >1/1000,
<1/100). 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 ADRs.
Table 1
Metabolism and nutrition
disorders
Common:
peripheral oedema
Nervous system disorders
Very common:
headache
Common:
dizziness, dysgeusia, neuropathic pain, tremor, hypersomnia,
hypoesthesia, paraesthesia
Uncommon:
parosmia
Eye disorders
Common:
lacrimation increased
Ear and labyrinth disorders
Common:
tinnitus, tinnitus aggravated
Cardiac disorders
tachycardia, palpitations
Vascular disorders
flushing
hypertension
Common:
4
Common:
Very Common:
Respiratory, thoracic and
mediastinal disorders
Common:
cough, hoarseness, throat tightness, dyspnoea, nasopharyngitis,
pharyngitis, throat secretion increased, rhinorrhoea
Gastrointestinal disorders
Very common:
diarrhoea , vomiting, abdominal pain/discomfort
Skin and subcutaneous
tissue disorders
Common:
acne, erythema, pruritus, rash, livedo reticularis
Uncommon:
angioneurotic oedema, urticaria
Musculoskeletal,
connective tissue and bone
disorders
Common:
musculoskeletal discomfort, myalgia, back pain, limb pain, peripheral
swelling, arthralgia, joint swelling
Uncommon:
sensation of heaviness
General disorders and
administration site
conditions
Very common:
rigors pyrexia, pain and discomfort, fatigue
Common:
fatigue aggravated, feeling hot, feeling cold, asthenia, chest pain, chest
tightness, influenza like illness, injection site rash, malaise
Investigations
Common:
corneal reflex decreased
Uncommon:
oxygen saturation decreased
See also section 4.4.
Adverse drug reactions reported in patients with history of end stage renal disease were similar to
those reported in the general patient population.
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. Infusion-related symptoms may include dizziness and hyperhidrosis. The most
frequent were mild infusion-related reactions that mainly included rigors, pyrexia, flushing, headache,
nausea, and dyspnoea.
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.
No case of overdose has been reported.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Other alimentary tract and metabolism products - Enzymes.
ATC code: A16AB03 agalsidase alfa.
5
Common:
nausea
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 (also
referred to as Gb3 or 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 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. For patients between 0 and 7 years of age, limited data indicate no
specific safety issues.
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
reated 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 m
2
) and with mild
to moderate renal dysfunction (GFR 60 to < 90 mL/min/1.73 m
2
), 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 m
2
).
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 0.2mg/kg every
other week, the abnormally high eGFR decreased from 143.4 ± 6.8 to 121.3 ± 5.6 mL/min/1.73 m
2
in
this subgroup and these eGFRs stabilized in the normal range during 4 years of Replagal 0.2mg/kg
therapy, as did the eGFRs of the non-hyperfiltrators.
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.
6
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
4.0 years of Replagal 0.2mg/kg therapy in an open-label long-term extension study in 9 boys.
Individual left ventricular mass indexed to height
2.7
was within normal range for children (<39 g/m
2.7
in boys) at baseline. A relative reduction in mean LVM of 11% was observed during the 4.5 years of
treatment. In 5/6 children < 7 years old, individual left ventricular mass indexed to height
2.7
was
borderline elevated or elevated (>95%) for (<39 g/m
2.7
in boys) at baseline. LVMI values for all 5
children fell within normal range after starting therapy.
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 and 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 Gb
3
decreased 40-50% after 6 months of Replagal therapy
0.2mg/kg
and this
reduction persisted after a total
4 years of treatment in 11 patients
..
Antibodies to agalsidase alfa have not been shown to be associated with any clinically significant
effects on safety (e.g. infusion reactions) or efficacy.
Infusion of Replagal at home may be considered for patients who are tolerating their infusions well.
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 (EMEA) will review any new information which may become
available every year and this SPC 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.
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 Gb
3
are
more or less comparable between adolescents and young children (see section 5.1).
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.
7
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 and is therefore: 1) not expected to bind to proteins, 2) expected that
metabolic degradation will follow the pathways of other proteins, i.e. peptide hydrolysis, 3) unlikely to
be a candidate for drug-drug interactions.
Renal elimination of agalsidase alfa is considered to be a minor clearance pathway since
pharmacokinetic parameters are not altered by impaired renal function. 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.
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.
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
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
1 ml of concentrate for solution for infusion in a 3 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.
8
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.
•
The solution should be inspected visually for particulate matter and discolouration prior to
administration.
•
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 and within 3 hours of dilution.
•
Do not infuse Replagal concomitantly in the same intravenous line with other agents.
•
For single use only. Any unused product or waste material should be disposed of in accordance
with local requirements.
7.
Shire Human Genetic Therapies AB, Svärdvägen 11 D, 182 33 Danderyd, Sweden
Tel: +46 8 5449 6400
Fax: +46 8 5449 6429
8.
EU/1/01/189/001-006
9.
Date of first authorisation: 03/08/2001
Date of last renewal: 03/08/2006
Detailed information on this medicinal product is available on the website of the European Medicines
Agency (EMEA) http://www.emea.europa.eu/.
9
ANNEX II
A.
MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE
SUBSTANCE(S) AND MANUFACTURING
AUTHORISATION HOLDER(S) RESPONSIBLE FOR
BATCH RELEASE
B.
CONDITIONS OF THE MARKETING AUTHORISATION
10
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturer of the biological active substance
TK3
205 Alewife Brook Parkway
Cambridge, MA 02138
USA
Name and address of the manufacturer responsible for batch release
Shire Human Genetic Therapies AB
Åldermansgatan 13, 227 64 Lund
Sweden
B. CONDITIONS OF THE MARKETING AUTHORISATION
•
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product
Characteristics, 4.2)
•
CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND
EFFECTIVE USE OF THE MEDICINAL PRODUCT
Not applicable.
•
OTHER CONDITIONS
PSURs should be submitted yearly at the time of the annual reassessment.
C. SPECIFIC OBLIGATIONS TO BE FULFILLED BY THE MARKETING
AUTHORISATION HOLDER
The Marketing Authorisation Holder shall complete the following programme of studies within the
specified time frame, the results of which shall form the basis of the annual reassessment of the
benefit/risk profile.
1a. Five Year Clinical Outcome Study
A study in an adequate number of male and female patients to evaluate the effects of long term
agalsidase alfa therapy on the frequency of clinical events, such as those that arise as a result of
cerebrovascular and cardiovascular pathology, or renal impairment to be undertaken. Within this
population special emphasis will be put on assessment of progression, including reversibility, of organ
dysfunction. Data from historical controls will be collected for comparison.
1b. Alternative Dosing Study
Evaluation of alternative initial dosing schedules to be undertaken. The final report will be submitted
upon completion.
11
1c. Maintenance Dosing Study
Evaluation of maintenance dosing schedules and monitoring methods to be undertaken following
completion of 5 year outcome evaluation. The final report will be submitted upon completion.
2a. Study in Children:
Additional pharmacokinetic analyses from a paediatric maintenance study (TKT029) will be submitted
upon completion.
2b
.
Adverse events
Adverse events from study TKT023 and any other available data for paediatric patients will be
analysed by age and submitted in the next Annual Re-Assessment. The company will elucidate if the
reported adverse events pain exacerbation, reactions to infusions, nasopharyngitis, and cough occur
relatively more frequently in the younger children (versus the older children) and/or if this
phenomenon is due to relative overdosing.
12
ANNEX III
LABELLING AND PACKAGE LEAFLET
13
A. LABELLING
14
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON / 3.5 ML VIAL
1.
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.
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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP: {mon/year}
Use within 3 hours after dilution
15
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Human Genetic Therapies AB, Svärdvägen 11 D, 182 33 Danderyd, Sweden
Tel: +46 8 5449 6400
Fax: +46 8 5449 6429
EU/1/01/189/001
EU/1/01/189/002
EU/1/01/189/003
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15.
INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
16
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL 3.5 ML PRESENTATION
1.
Replagal 1 mg/ml sterile concentrate
Agalsidase alfa
Intravenous use
2.
METHOD
OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP: {mon/year}
4.
BATCH NUMBER
Lot {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
3.5 ml
6.
OTHER
Store in a refrigerator
17
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON / 1 ML VIAL
1.
Replagal 1 mg/ml concentrate for solution for infusion
Agalsidase alfa
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial contains 1 mg of agalsidase alfa
3.
LIST OF EXCIPIENTS
Sodium phosphate monobasic, monohydrate
polysorbate 20
sodium chloride
sodium hydroxide
water for injections
4.
1 x 1 ml concentrate for solution for infusion
4 x 1 ml concentrate for solution for infusion
10 x 1 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 REACH AND SIGHT OF CHILDREN
Keep out of the reach and sight of children
7.
OTHER SPECIAL WARNING(S), IF NECESSARY
8.
EXPIRY DATE
EXP: {mon/year}
Use within 3 hours after dilution
9.
SPECIAL STORAGE CONDITIONS
18
Store in a refrigerator
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Shire Human Genetic Therapies AB, Svärdvägen 11 D, 182 33 Danderyd, Sweden
Tel: +46 8 5449 6400
Fax: +46 8 5449 6429
EU/1/01/189/004
EU/1/01/189/005
EU/1/01/189/006
13. BATCH NUMBER
Lot {number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
19
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL 1 ML PRESENTATION
1.
Replagal 1 mg/ml sterile concentrate
Agalsidase alfa
Intravenous use
2.
METHOD
OF ADMINISTRATION
Read the package leaflet before use
3.
EXPIRY DATE
EXP: {mon/year}
4.
BATCH NUMBER
Lot {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
1 ml
6.
OTHER
Store in a refrigerator
20
B. PACKAGE LEAFLET
21
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.
-
Keep this leaflet. You may need to read it again.
-
This medicine has been prescribed for you. Do not pass it on to others. It may harm them, even
if their symptoms are the same as yours.
-
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,
please tell your doctor or pharmacist.
In this leaflet
:
1.
What Replagal is and what it is used for
2.
Before you take Replagal
4.
Possible side effects
5.
How to store Replagal
6.
Further 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 Fabry Disease. It is used as enzyme replacement therapy when the level of
enzyme in the body is lower than normal as in Fabry Disease.
2.
BEFORE YOU TAKE REPLAGAL
Do not take Replagal
If you are allergic (hypersensitive) to agalsidase alfa or any of the other ingredients of Replagal.
Take special care with Replagal
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;
-
light-headedness;
-
hives, itching or rash;
-
swelling in your hands, feet, ankles, face, lips, mouth or throat which may cause difficulty in
swallowing or breathing;
-
pain or tenderness in chest, muscles or joints.
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.
22
-
If you have any further questions, ask your doctor or pharmacist.
3.
How to take Replagal
-
vomiting;
If treatment with Replagal makes your body produce antibodies this will not stop Replagal working
and the antibodies may disappear with time.
Use in Children
There is limited clinical data in children 7-18 years old. No unexpected safety issues were
encountered in the studies with Replagal in children 7-18 years of age. Following treatment with
Replagal 0.2mg/kg every other week, changes in the clinical parameters of Fabry disease in children
were similar to those seen in earlier adult Fabry patient studies.
Using other medicines
There is no known interaction of Replagal with other medicines.
Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines,
including medicines obtained without a prescription.
Taking Replagal with food and drink
Interactions with food or drink are unlikely.
Pregnancy and breast feeding
Very limited clinical data on pregnancies exposed to Replagal (n=4) have shown no adverse effects on
the mother and newborn child. Ask your doctor or pharmacist for advice before taking any medicine.
Driving and using machines
You may drive and operate machinery whilst on Replagal.
3.
HOW TO TAKE REPLAGAL
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 usual 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. 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 forget to have Replagal
If you have missed a Replagal infusion, please contact your doctor.
If you have any further questions on the use of this product, ask your doctor or pharmacist.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Replagal can cause side effects, although not everybody gets them. Most side
effects are mild to moderate. About 1 out of 7 patients may have a reaction during or following an
infusion of Replagal. These effects include chills, headache, nausea, fever, facial flushing (redness)
and tiredness. However some effects may be serious and may need treatment.
23
Very common side effects (occurring in more than 1 in 10 treated patients) include the following:
-
flushing (redness)
-
nausea
-
chills, fever
-
general pain or discomfort, tiredness.
Common side effects (occurring in less than 1 in 10 treated patients) include the following:
-
tingling or numbness or pain in fingers or toes, change in the taste of food, eyes tearing, ears
ringing, shakes, unsteadiness, prolonged sleep
-
palpitations, increased heart rate, increased blood pressure
-
cough, chest pain or tightness, hoarseness, sore or tight throat, sticky throat secretions, runny
nose
-
vomiting, abdominal pain or discomfort, diarrhoea
-
acne, red or itchy or mottled skin, rash at the infusion site
-
back or limb pain, swelling of the extremities or joints
-
feeling cold or hot, flu-like symptoms, malaise
If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet, please
tell your doctor or pharmacist.
5.
HOW TO STORE REPLAGAL
Keep out of the reach and sight of children.
Do not use Replagal after the expiry date which is stated on the label after the letters 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.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to
dispose of medicines no longer required. These measures will help to protect the environment.
6.
FURTHER INFORMATION
What Replagal contains
-
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
either 1 mg/1 ml or 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, Svärdvägen 11 D, 182 33 Danderyd, Sweden
24
-
headache
-
The active substance is agalsidase alfa
Tel: +46 8 5449 6400
Fax: +46 8 5449 6429
Manufacturer
Shire Human Genetic Therapies AB, Åldermansgatan 13, 227 64 Lund, Sweden
This leaflet was last approved in:
This medicine has been authorised under “exceptional circumstances”.
This means that because of the rarity of this disease it has been impossible to get complete information
on this medicine.
The European Medicines Agency (EMEA) will review any new information on the medicine every
year and this leaflet will be updated as necessary.
Detailed information on this medicine is available on the European Medicines Agency (EMEA) web
site: http://www.emea.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
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 and within 3 hours of dilution. 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.
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Source: European Medicines Agency
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