ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Fabrazyme 35 mg, powder for concentrate for solution for infusion.
2.
Each vial of Fabrazyme contains a nominal value of 35 mg of agalsidase beta. After reconstitution
with 7.2 ml water for injections, each vial of Fabrazyme contains 5 mg/ml (35 mg/7 ml) of agalsidase
beta. The reconstituted solution must be diluted further (see section 6.6).
Agalsidase beta is a recombinant form of human α-galactosidase A and is produced by recombinant
DNA technology using a mammalian Chinese Hamster Ovary (CHO) cell culture. The amino acid
sequence of the recombinant form, as well as the nucleotide sequence which encoded it, are identical
to the natural form of α-galactosidase.
3.
Powder for concentrate for solution for infusion
White to off-white lyophilized cake or powder
4.
Fabrazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed
diagnosis of Fabry disease (α-galactosidase A deficiency).
Fabrazyme treatment should be supervised by a physician experienced in the management of patients
with Fabry Disease or other inherited metabolic diseases.
The recommended dose of Fabrazyme is 1mg/kg body weight administered once every 2 weeks as an
intravenous infusion. For further instructions see section 6.6.
Alternative dosing regimens have been used in clinical studies. In one of these studies, after an initial
dose of 1.0 mg/kg every 2 weeks for 6 months, 0.3 mg/kg every 2 weeks may maintain clearance of
GL-3 in certain cell types in some patients; however, the long term clinical relevance of these findings
has not been established (see section 5.1).
The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise the potential
occurrence of infusion-associated reactions. After patient tolerance is established, the infusion rate
may be increased gradually with subsequent infusions.
No dose adjustment is necessary for patients with renal insufficiency.
Studies in patients with hepatic insufficiency have not been performed.
The safety and efficacy of Fabrazyme in patients older than 65 years have not been established and no
dosage regimen can presently be recommended in these patients.
2
Paediatric patients
Studies in children 0-7 years have not been performed and no dosage regimen can presently be
recommended in patients in this paediatric age group as safety and efficacy have not yet been
established. No dose adjustment is necessary for children 8-16 years.
Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the
excipients.
Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is
expected in patients with little or no residual enzyme activity. The majority of patients developed IgG
antibodies to r-hαGAL, typically within 3 months of the first infusion with Fabrazyme. Over time, the
majority of seropositive patients in clinical trials demonstrated either a downward trend in titers (based
on a ≥ 4-fold reduction in titer from the peak measurement to the last measurement) (40% of the
patients), tolerised (no detectable antibodies confirmed by 2 consecutive radioimmunoprecipitation
(RIP) assays) (14% of the patients) or demonstrated a plateau (35% of the patients).
Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated
reactions (IARs), which are defined as any related adverse event occurring on the infusion day. These
patients should be treated with caution when re-administering agalsidase beta (See section 4.8).
Antibody status should be regularly monitored.
In clinical trials, sixty seven percent (67 %) of the patients experienced at least one infusion-associated
reaction (See section 4.8). The frequency of IARs decreased over time. Patients experiencing mild or
moderate infusion-associated reactions when treated with agalsidase beta during clinical trials have
continued therapy after a reduction in the infusion rate (~0.15 mg/min; 10 mg/hr) and/or pre-treatment
with antihistamines, paracetamol, ibuprofen and/or corticosteroids.
As with any intravenous protein product, allergic-type hypersensitivity reactions are possible.
A small number of patients have experienced reactions suggestive of immediate (Type I)
hypersensitivity. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of
the administration of Fabrazyme should be considered and appropriate treatment initiated. The current
medical standards for emergency treatment are to be observed. With careful rechallenge Fabrazyme
has been re-administered to all 6 patients who tested positive for IgE antibodies or had a positive skin
test to Fabrazyme in a clinical trial. In this trial, the initial rechallenge administration was at a low
dose and a lower infusion rate (
1
/
2
the therapeutic dose at
1
/
25
the initial standard recommended rate).
Once a patient tolerates the infusion, the dose may be increased to reach the therapeutic dose of 1
mg/kg and the infusion rate may be increased by slowly titrating upwards, as tolerated.
The effect of Fabrazyme treatment on the kidneys may be limited in patients with advanced renal
disease.
Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of
fertility.
No interaction studies and no
in vitro
metabolism studies have been performed. Based on its
metabolism, agalsidase beta is an unlikely candidate for cytochrome P450 mediated drug-drug
interactions.
Fabrazyme should not be administered with chloroquine, amiodarone, benoquin or gentamycin due to
a theoretical risk of inhibition of intra-cellular α-galactosidase activity.
3
There are no adequate data from the use of agalsidase beta in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal
development (See section 5.3).
Fabrazyme should not be used during pregnancy unless clearly necessary.
Agalsidase beta may be excreted in milk. Because there are no data available on effects in neonates
exposed to agalsidase beta via breast milk, it is recommended to stop breast-feeding when Fabrazyme
is used.
No studies on the ability to drive and use machines have been performed with Fabrazyme.
Adverse drug reactions (ADRs) reported from clinical trials to be related to Fabrazyme administered at
a dose of 1mg/kg
in a total of 168 patients (154 males and 14 females) treated with Fabrazyme for a
minimum of one infusion up to a maximum of 5 years are listed by System Organ Class and frequency
(very common ≥ 1/10; common ≥ 1/100 to < 1/10 and uncommon ≥ 1/1000 to < 1/100) in the table
below. The occurrence of an ADR in a single patient is defined as uncommon in light of the relatively
small number of patients treated. ADRs only reported during the Post Marketing period are also
included in the table below at a frequency category of “unknown”. ADRs were mostly mild to
moderate in severity:
Incidence of Related Adverse Events with Fabrazyme Treatment
System Organ
Class
Very common
Common
Uncommon
Frequency
unknown
Infections and
infestations
---
nasopharyngitis
rhinitis
Immune system
disorders
---
---
---
anaphylactoid
reaction
Nervous system
disorders
headache,
paraesthesia
Dizziness,
somnolence,
hypoaesthesia,
burning sensation,
lethargy, syncope
hyperaesthesia,
tremor
---
Eye disorders
---
lacrimation
increased
eye pruritus, ocular
hyperaemia
---
Ear and
labyrinth
disorders
---
tinnitus, vertigo
auricular swelling,
ear pain
---
Cardiac
Disorders
---
tachycardia,
palpitations,
bradycardia
sinus bradycardia
---
4
Incidence of Related Adverse Events with Fabrazyme Treatment (continued)
System Organ
Class
Very common
Common
Uncommon
Frequency
unknown
Vascular
disorders
---
flushing,
hypertension, pallor,
hypotension, hot
flush
peripheral coldness ---
Respiratory,
thoracic and
mediastinal
disorders
---
dyspnoea, nasal
congestion, throat
tightness, wheezing,
cough, dyspnoea
exacerbated
bronchospasm,
pharyngolaryngeal
pain, rhinnorhoea,
tachypnoea, upper
respiratory tract
congestion
hypoxia
Gastrointestinal
Disorders
nausea, vomiting
abdominal pain,
abdominal pain
upper, abdominal
discomfort, stomach
discomfort,
hypoaesthesia oral,
diarrhoea
dyspepsia,
dysphagia
---
Skin and
subcutaneous
tissue disorders
---
pruritus, urticaria,
rash, erythema,
pruritus generalized,
angioneurotic
oedema, swelling
face, rash maculo-
papular
livedo reticularis,
rash erythematous,
rash pruritic, skin
discolouration, skin
discomfort
leukocytoclastic
vasculitis
Musculoskeletal
and connective
tissue disorders
---
pain in extremity,
myalgia, back pain,
muscle spasms,
arthralgia, muscle
tightness,
musculoskeletal
stiffness
musculoskeletal
pain
---
General
disorders and
administration
site conditions
chills, pyrexia,
feeling cold
fatigue, chest
discomfort, feeling
hot, oedema
peripheral, pain,
asthenia, chest pain,
face oedema,
hyperthermia
feeling hot and cold,
influenza-like
illness, infusion site
pain, infusion site
reaction, injection
site thrombosis,
malaise, oedema
---
Investigations
oxygen saturation
decreased
AE terminology is based upon the Medical Dictionary for Regulatory Activities (MedDRA)
Infusion associated reactions consisted most often of fever and chills. Additional symptoms included
mild or moderate dyspnoea, hypoxia (oxygen saturation decreased), throat tightness, chest discomfort,
flushing, pruritus, urticaria, face oedema, angioneurotic oedema, rhinitis, bronchospasm, tachypnoea,
wheezing, hypertension, hypotension, tachycardia, palpitations, abdominal pain, nausea, vomiting,
infusion-related pain including pain at the extremities, myalgia, and headache.
The infusion-associated reactions were managed by a reduction in the infusion rate together with the
administration of non-steroidal anti-inflammatory medicinal products, antihistamines and/or
corticosteroids.
Sixty seven percent (67%) of the patients experienced at least one infusion-associated
5
For the purpose of this table, ≥1% is defined as events occurring in 2 or more patients.
reaction. The frequency of these reactions decreased over time. The majority of these reactions can be
attributed to the formation of IgG antibodies and/or complement activation. In a limited number of
patients IgE antibodies were demonstrated (see Section 4.4).
Paediatric patients
Limited information suggests that the safety profile of Fabrazyme treatment in paediatric patients
(above the age of 7) is not different with that seen in adults.
No case of overdose has been reported. In clinical trials doses up to 3mg/kg body weight were used.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alimentary tract and metabolism products – enzymes.
ATC code: A16AB04 agalsidase beta.
Fabry disease is an inherited heterogeneous and multisystemic progressive disease, that affects both
males and females. It is characterised by the deficiency of α-galactosidase. Reduced or absent α-
galactosidase activity results in the accumulation of GL-3 in the lysosomes of many cell types
including the endothelial and parenchymal cells, ultimately leading to life-threatening clinical
deteriorations as a result of renal, cardiac and cerebrovascular complications. The rationale for enzyme
replacement therapy is to restore a level of enzymatic activity sufficient to clear the accumulating
substrate in the organ tissues; thereby, preventing, stabilizing or reversing the progressive decline in
function of these organs before irreversible damage has occurred.
After intravenous infusion, agalsidase beta is rapidly removed from the circulation and taken up by
vascular endothelial and parenchymal cells into lysosomes, likely through the mannose-6 phosphate,
mannose and asialoglycoprotein receptors.
Efficacy and safety of Fabrazyme was evaluated in one study with children, one dose-finding study,
two double-blind placebo-controlled studies, and one open-label extension study in both male and
female patients.
In the dose finding study, the effects of 0.3, 1.0 and 3.0 mg/kg once every 2 weeks and 1.0 and 3.0
mg/kg once every 2 days were evaluated. A reduction in GL-3 was observed in kidney, heart, skin and
plasma at all doses. Plasma GL-3 was cleared in a dose dependent manner, but was less consistent at
the dose of 0.3 mg/kg. In addition, infusion-associated reactions were dose dependent.
In the first placebo-controlled clinical trial, Fabrazyme was effective in clearing GL-3 from the
vascular endothelium of the kidney after 20 weeks of treatment. This clearance was achieved in 69%
(20/29) of the Fabrazyme treated patients, but in none of the placebo patients (p<0.001). This finding
was further supported by a statistically significant decrease in GL-3 inclusions in kidney, heart and
skin combined and in the individual organs in patients treated with agalsidase beta compared to
placebo patients (p<0.001). Sustained clearance of GL-3 from kidney vascular endothelium upon
agalsidase beta treatment was demonstrated further in the open label extension of this trial. This was
achieved in 47 of the 49 patients (96%) with available information at month 6, and in 8 of the 8
patients (100%) with available information at the end of the study (up to a total of 5 years of
treatment). Clearance of GL-3 was also achieved in several other cell types from the kidney. Plasma
GL-3 levels rapidly normalised with treatment and remained normal through 5 years.
Renal function, as measured by glomerular filtration rate and serum creatinine, as well as proteinuria,
remained stable in the majority of the patients. However, the effect of Fabrazyme treatment on the
kidney function was limited in some patients with advanced renal disease.
6
Although no specific study has been conducted to assess the effect on the neurological signs and
symptoms, the results also indicate that patients may achieve reduced pain and enhanced quality of life
upon enzyme replacement therapy.
Another double-blind, placebo-controlled study of 82 patients was performed to determine whether
Fabrazyme would reduce the rate of occurrence of renal, cardiac, or cerebrovascular disease or death.
The rate of clinical events was substantially lower among Fabrazyme-treated patients compared to
placebo-treated patients (risk reduction = 53% intent-to-treat population (p=0.0577); risk reduction =
61 % per-protocol population (p=0.0341)). This result was consistent across renal, cardiac and
cerebrovascular events.
The results of these studies indicate that Fabrazyme treatment at 1 mg/kg every other week provides
clinical benefit on key clinical outcomes in patients with early and advanced Fabry disease. Because
this condition is slowly progressive, early detection and treatment is critical to achieve the best
outcomes.
In the open-label paediatric study, sixteen patients with Fabry disease (8-16 years old; 14 males, 2
females) had been treated for one year. Clearance of GL-3 in the superficial skin vascular endothelium
was achieved in all patients who had accumulated GL-3 at baseline. The 2 female patients had little or
no GL-3 accumulation in the superficial skin vascular endothelium at baseline, making this conclusion
applicable in male patients only.
In an additional study, 21 male patients were enrolled to follow GL3 clearance in kidney and skin
tissues at an alternative dosing regimen. Following treatment with 1 mg/kg every other week for 24
weeks, a dose regimen of 0.3 mg/kg every 2 weeks for 18 months was able to maintain the clearance
of cellular GL-3 in the capillary endothelium of the kidney, other kidney cell types and skin
(superficial skin capillary endothelium) in the majority of patients. However, at the lower dose, IgG
antibodies may play a role with respect to GL-3 clearance in some patients. Due to the limitations of
the study design (small number of patients), no definitive conclusion regarding the dose maintenance
regimen can be drawn, but these findings suggest that, after an initial debulking dose of 1.0 mg/kg
every 2 weeks, 0.3 mg/kg every 2 weeks may be sufficient in some patients to maintain clearance of
GL-3.
5.2 Pharmacokinetic properties
Following an intravenous administration of agalsidase beta to adults at doses of 0.3 mg, 1 mg and
3 mg/kg body weight, the AUC values increased more than dose proportional, due to a decrease in
clearance, indicating a saturated clearance. The elimination half-life was dose dependent and ranged
from 45 to 100 minutes.
After intravenous administration of agalsidase beta to adults with an infusion time of approximately
300 minutes and at a dose of 1 mg/kg body weight, biweekly, mean C
max
plasma concentrations ranged
from 2000-3500 ng/ml, while the AUC
inf
ranged from 370-780 µg·min/ml. Vss ranged from 8.3-40.8 l,
plasma clearance from 119-345 ml/min and the mean elimination half-life from 80-120 minutes.
Fabrazyme pharmacokinetics was also evaluated in 15 paediatric patients (8.5 to 16 years old
weighing 27.1 to 64.9 kg). Agalsidase clearance was not influenced by weight in this population.
Baseline clearance was 77 ml/min with a volume of distribution at steady-state (Vss) of 2.6 l; half-life
was 55 min. After IgG seroconversion, clearance decreased to 35 ml/min, Vss increased to 5.4 l, and
half-life increased to 240 min. The net effect of these changes after seroconversion was an increase in
exposure of 2- to 3-fold based on AUC and C
max
. No unexpected safety issues were encountered in
patients with an increase in exposure after seroconversion.
Agalsidase beta is a protein and is expected to be metabolically degraded through peptide hydrolysis.
Consequently, impaired liver function is not expected to affect the pharmacokinetics of agalsidase beta
7
in a clinically significant way. Renal elimination of agalsidase beta is considered to be a minor
pathway for clearance.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, single
dose toxicity, repeated dose toxicity and embryonal/foetal toxicity. Studies with regard to other stages
of the development have not been carried out. Genotoxic and carcinogenic potential are not expected.
6.
6.1 List of excipients
Mannitol
Sodium phosphate monobasic, monohydrate
Sodium phosphate dibasic, heptahydrate.
6.2 Incompatibilities
In the absence of compatibility studies, Fabrazyme must not be mixed with other medicinal products
in the same infusion.
6.3 Shelf life
3 years.
Reconstituted and diluted solutions
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage and conditions prior to use are the responsibility of the user. The
reconstituted solution cannot be stored and should be promptly diluted; only the diluted solution can
be held for up to 24 hours at 2 °C-8 °C.
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
6.5 Nature and contents of container
Fabrazyme 35 mg is supplied in clear Type I glass 20 ml vials. The closure consists of a siliconised
butyl stopper and an aluminium seal with a plastic flip-off cap.
Package sizes: 1, 5 and 10 vials per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The powder for concentrate for solution for infusion has to be reconstituted with water for injections,
diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous
infusion.
Use Aseptic Technique
1.
Determine the number of vials to be reconstituted based on the individual patient’s weight and
remove the required vials from the refrigerator in order to allow them to reach room temperature
(in approximately 30 minutes). Each vial of Fabrazyme is intended for single use only.
8
Reconstitution
2.
Reconstitute each vial of Fabrazyme 35 mg with 7.2 ml water for injections. Avoid forceful
impact of the water for injections on the powder and avoid foaming. This is done by slow drop-
wise addition of the water for injection down the inside of the vial and not directly onto the
lyophilized cake. Roll and tilt each vial gently. Do not invert, swirl or shake the vial.
3.
The reconstituted solution contains 5 mg agalsidase beta per ml, and appears as a clear
colourless solution. The pH of the reconstituted solution is approximately 7.0. Before further
dilution, visually inspect the reconstituted solution in each vial for particulate matter and
discoloration. Do not use the solution if foreign particles are observed or if the solution is
discoloured.
4.
After reconstitution it is recommended to promptly dilute the vials, to minimize protein particle
formation over time.
5.
Any unused product or waste material should be disposed of in accordance with local
requirements.
Dilution
6.
Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it is
recommended to remove an equal volume of 0.9% sodium chloride intravenous solution, from
the infusion bag.
7.
Remove the airspace within the infusion bag to minimize the air/liquid interface.
8.
Slowly, withdraw 7.0 ml (equal to 35 mg) of the reconstituted solution from each vial up to the
total volume required for the patient dose. Do not use filter needles and avoid foaming.
9.
Then slowly inject the reconstituted solution directly into the 0.9% sodium chloride intravenous
solution (not in any remaining airspace) to a final concentration between 0.05 mg/ml and
0.7 mg/ml. Determine the total volume of sodium chloride 0.9% solution for infusion (between
50 and 500 ml) based on the individual dose. For doses lower than 35 mg use a minimum of
50 ml, for doses 35 to 70 mg use a minimum of 100 ml, for doses 70 to 100 mg use a minimum
of 250 ml and for doses greater than 100 mg use only 500 ml. Gently invert or lightly massage
the infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion
bag.
Administration
10.
It is recommended to administer the diluted solution through an in-line low protein-binding
0.2 µm filter to remove any protein particles which will not lead to any loss of agalsidase beta
activity. The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise
the potential occurrence of infusion-associated reactions. After patient tolerance is established,
the infusion rate may be increased gradually with subsequent infusions.
7.
Genzyme Europe B.V., Gooimeer 10, NL-1411DD Naarden, The Netherlands
8.
MARKETING AUTHORISATION NUMBERS
EU/1/01/188/001-003
9
9.
Date of first authorisation: 03/08/2001
Date of last renewal: 03/08/2006
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu.
10
1.
Fabrazyme 5 mg, powder for concentrate for solution for infusion.
2.
Each vial of Fabrazyme contains a nominal value of 5 mg of agalsidase beta. After reconstitution with
1.1 ml water for injections, each vial of Fabrazyme contains 5 mg/ml of agalsidase beta. The
reconstituted solution must be diluted further (see section 6.6).
Agalsidase beta is a recombinant form of human α-galactosidase A and is produced by recombinant
DNA technology using a mammalian Chinese Hamster Ovary (CHO) cell culture. The amino acid
sequence of the recombinant form, as well as the nucleotide sequence which encoded it, are identical
to the natural form of α-galactosidase.
3.
Powder for concentrate for solution for infusion
White to off-white lyophilized cake or powder
4.
Fabrazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed
diagnosis of Fabry disease (α-galactosidase A deficiency).
Fabrazyme treatment should be supervised by a physician experienced in the management of patients
with Fabry Disease or other inherited metabolic diseases.
The recommended dose of Fabrazyme is 1mg/kg body weight administered once every 2 weeks as an
intravenous infusion. For further instructions see section 6.6.
Alternative dosing regimens have been used in clinical studies. In one of these studies, after an initial
dose of 1.0 mg/kg every 2 weeks for 6 months, 0.3 mg/kg every 2 weeks may maintain clearance of
GL-3 in certain cell types in some patients; however, the long term clinical relevance of these findings
has not been established (see section 5.1).
The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise the potential
occurrence of infusion-associated reactions. After patient tolerance is established, the infusion rate
may be increased gradually with subsequent infusions.
No dose adjustment is necessary for patients with renal insufficiency.
Studies in patients with hepatic insufficiency have not been performed.
The safety and efficacy of Fabrazyme in patients older than 65 years have not been established and no
dosage regimen can presently be recommended in these patients.
11
Paediatric patients
Studies in children 0-7 years have not been performed and no dosage regimen can presently be
recommended in patients in this paediatric age group as safety and efficacy have not yet been
established. No dose adjustment is necessary for children 8-16 years.
Life threatening hypersensitivity (anaphylactic reaction) to the active substance or any of the
excipients.
Since agalsidase beta (r-hαGAL) is a recombinant protein, the development of IgG antibodies is
expected in patients with little or no residual enzyme activity. The majority of patients developed IgG
antibodies to r-hαGAL, typically within 3 months of the first infusion with Fabrazyme. Over time, the
majority of seropositive patients in clinical trials demonstrated either a downward trend in titers (based
on a ≥ 4-fold reduction in titer from the peak measurement to the last measurement) (40% of the
patients), tolerised (no detectable antibodies confirmed by 2 consecutive radioimmunoprecipitation
(RIP) assays) (14% of the patients) or demonstrated a plateau (35% of the patients).
Patients with antibodies to r-hαGAL have a greater potential to experience infusion-associated
reactions (IARs), which are defined as any related adverse event occurring on the infusion day. These
patients should be treated with caution when re-administering agalsidase beta (See section 4.8).
Antibody status should be regularly monitored.
In clinical trials, sixty seven percent (67 %) of the patients experienced at least one infusion-associated
reaction (See section 4.8). The frequency of IARs decreased over time. Patients experiencing mild or
moderate infusion-associated reactions when treated with agalsidase beta during clinical trials have
continued therapy after a reduction in the infusion rate (~0.15 mg/min; 10 mg/hr) and/or pre-treatment
with antihistamines, paracetamol, ibuprofen and/or corticosteroids.
As with any intravenous protein product, allergic-type hypersensitivity reactions are possible.
A small number of patients have experienced reactions suggestive of immediate (Type I)
hypersensitivity. If severe allergic or anaphylactic-type reactions occur, immediate discontinuation of
the administration of Fabrazyme should be considered and appropriate treatment initiated. The current
medical standards for emergency treatment are to be observed. With careful rechallenge Fabrazyme
has been re-administered to all 6 patients who tested positive for IgE antibodies or had a positive skin
test to Fabrazyme in a clinical trial. In this trial, the initial rechallenge administration was at a low
dose and a lower infusion rate (
1
/
2
the therapeutic dose at
1
/
25
the initial standard recommended rate).
Once a patient tolerates the infusion, the dose may be increased to reach the therapeutic dose of 1
mg/kg and the infusion rate may be increased by slowly titrating upwards, as tolerated.
The effect of Fabrazyme treatment on the kidneys may be limited in patients with advanced renal
disease.
Studies have not been conducted to assess the potential effects of Fabrazyme on impairment of
fertility.
No interaction studies and no
in vitro
metabolism studies have been performed. Based on its
metabolism, agalsidase beta is an unlikely candidate for cytochrome P450 mediated drug-drug
interactions.
Fabrazyme should not be administered with chloroquine, amiodarone, benoquin or gentamycin due to
a theoretical risk of inhibition of intra-cellular α-galactosidase activity.
12
There are no adequate data from the use of agalsidase beta in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to embryonal/foetal
development (See section 5.3).
Fabrazyme should not be used during pregnancy unless clearly necessary.
Agalsidase beta may be excreted in milk. Because there are no data available on effects in neonates
exposed to agalsidase beta via breast milk, it is recommended to stop breast-feeding when Fabrazyme
is used.
No studies on the ability to drive and use machines have been performed with Fabrazyme.
Adverse drug reactions (ADRs) reported from clinical trials to be related to Fabrazyme administered at
a dose of 1mg/kg
in a total of 168 patients (154 males and 14 females) treated with Fabrazyme for a
minimum of one infusion up to a maximum of 5 years are listed by System Organ Class and frequency
(very common ≥ 1/10; common ≥ 1/100 to < 1/10 and uncommon ≥ 1/1000 to < 1/100) in the table
below. The occurrence of an ADR in a single patient is defined as uncommon in light of the relatively
small number of patients treated. ADRs only reported during the Post Marketing period are also
included in the table below at a frequency category of “unknown”. ADRs were mostly mild to
moderate in severity:
Incidence of Related Adverse Events with Fabrazyme Treatment
System Organ
Class
Very common
Common
Uncommon
Frequency
unknown
Infections and
infestations
---
nasopharyngitis
rhinitis
Immune system
disorders
---
---
---
anaphylactoid
reaction
Nervous system
disorders
Headache,
paraesthesia
dizziness,
somnolence,
hypoaesthesia,
burning sensation,
lethargy, syncope
hyperaesthesia,
tremor
---
Eye disorders
---
lacrimation
increased
eye pruritus, ocular
hyperaemia
---
Ear and
labyrinth
disorders
---
tinnitus, vertigo
auricular swelling,
ear pain
---
Cardiac
Disorders
---
tachycardia,
palpitations,
bradycardia
sinus bradycardia
---
13
Incidence of Related Adverse Events with Fabrazyme Treatment (continued)
System Organ
Class
Very common
Common
Uncommon
Frequency
unknown
Vascular
disorders
---
flushing,
hypertension, pallor,
hypotension, hot
flush
peripheral coldness ---
Respiratory,
thoracic and
mediastinal
disorders
---
dyspnoea, nasal
congestion, throat
tightness, wheezing,
cough, dyspnoea
exacerbated
bronchospasm,
pharyngolaryngeal
pain, rhinnorhoea,
tachypnoea, upper
respiratory tract
congestion
hypoxia
Gastrointestinal
Disorders
nausea, vomiting
abdominal pain,
abdominal pain
upper, abdominal
discomfort, stomach
discomfort,
hypoaesthesia oral,
diarrhoea
dyspepsia,
dysphagia
---
Skin and
subcutaneous
tissue disorders
---
pruritus, urticaria,
rash, erythema,
pruritus generalized,
angioneurotic
oedema, swelling
face, rash maculo-
papular
livedo reticularis,
rash erythematous,
rash pruritic, skin
discolouration, skin
discomfort
leukocytoclastic
vasculitis
Musculoskeletal
and connective
tissue disorders
---
pain in extremity,
myalgia, back pain,
muscle spasms,
arthralgia, muscle
tightness,
musculoskeletal
stiffness
musculoskeletal
pain
---
General
disorders and
administration
site conditions
chills, pyrexia,
feeling cold
fatigue, chest
discomfort, feeling
hot, oedema
peripheral, pain,
asthenia, chest pain,
face oedema,
hyperthermia
feeling hot and cold,
influenza-like
illness, infusion site
pain, infusion site
reaction, injection
site thrombosis,
malaise, oedema
---
Investigations
oxygen saturation
decreased
AE terminology is based upon the Medical Dictionary for Regulatory Activities (MedDRA)
Infusion associated reactions consisted most often of fever and chills. Additional symptoms included
mild or moderate dyspnoea, hypoxia (oxygen saturation decreased), throat tightness, chest discomfort,
flushing, pruritus, urticaria, face oedema, angioneurotic oedema, rhinitis, bronchospasm, tachypnea,
wheezing, hypertension, hypotension, tachycardia, palpitations, abdominal pain, nausea, vomiting,
infusion-related pain including pain at the extremities, myalgia, and headache.
The infusion-associated reactions were managed by a reduction in the infusion rate together with the
administration of non-steroidal anti-inflammatory medicinal products, antihistamines and/or
corticosteroids.
Sixty seven percent (67%) of the patients experienced at least one infusion-associated
14
For the purpose of this table, ≥1% is defined as events occurring in 2 or more patients.
reaction. The frequency of these reactions decreased over time. The majority of these reactions can be
attributed to the formation of IgG antibodies and/or complement activation. In a limited number of
patients IgE antibodies were demonstrated (see Section 4.4).
Paediatric patients
Limited information suggests that the safety profile of Fabrazyme treatment in paediatric patients
(above the age of 7) is not different with that seen in adults.
No case of overdose has been reported. In clinical trials doses up to 3mg/kg body weight were used.
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Alimentary tract and metabolism products – enzymes. ATC code:
A16AB04 agalsidase beta.
Fabry disease is an inherited heterogeneous and multisystemic progressive disease, that affects both
males and females. It is characterised by the deficiency of α-galactosidase. Reduced or absent α-
galactosidase activity results in the accumulation of GL-3 in the lysosomes of many cell types
including the endothelial and parenchymal cells, ultimately leading to life-threatening clinical
deteriorations as a result of renal, cardiac and cerebrovascular complications. The rationale for enzyme
replacement therapy is to restore a level of enzymatic activity sufficient to clear the accumulating
substrate in the organ tissues; thereby, preventing, stabilizing or reversing the progressive decline in
function of these organs before irreversible damage has occurred.
After intravenous infusion, agalsidase beta is rapidly removed from the circulation and taken up by
vascular endothelial and parenchymal
cells into lysosomes, likely through the mannose-6 phosphate,
mannose and asialoglycoprotein receptors.
Efficacy and safety of Fabrazyme was evaluated in one study with children, one dose-finding study,
two double-blind placebo-controlled studies, and one open-label extension study in both male and
female patients.
In the dose finding study, the effects of 0.3, 1.0 and 3.0 mg/kg once every 2 weeks and 1.0 and 3.0
mg/kg once every 2 days were evaluated. A reduction in GL-3 was observed in kidney, heart, skin and
plasma at all doses. Plasma GL-3 was cleared in a dose dependent manner, but was less consistent at
the dose of 0.3 mg/kg. In addition, infusion-associated reactions were dose dependent.
In the first placebo-controlled clinical trial, Fabrazyme was effective in clearing GL-3 from the
vascular endothelium of the kidney after 20 weeks of treatment. This clearance was achieved in 69%
(20/29) of the Fabrazyme treated patients, but in none of the placebo patients (p<0.001). This finding
was further supported by a statistically significant decrease in GL-3 inclusions in kidney, heart and
skin combined and in the individual organs in patients treated with agalsidase beta compared to
placebo patients (p<0.001). Sustained clearance of GL-3 from kidney vascular endothelium upon
agalsidase beta treatment was demonstrated further in the open label extension of this trial. This was
achieved in 47 of the 49 patients (96%) with available information at month 6, and in 8 of the 8
patients (100%) with available information at the end of the study (up to a total of 5 years of
treatment). Clearance of GL-3 was also achieved in several other cell types from the kidney. Plasma
GL-3 levels rapidly normalised with treatment and remained normal through 5 years.
Renal function, as measured by glomerular filtration rate and serum creatinine, as well as proteinuria,
remained stable in the majority of the patients. However, the effect of Fabrazyme treatment on the
kidney function was limited in some patients with advanced renal disease.
15
Although no specific study has been conducted to assess the effect on the neurological signs and
symptoms, the results also indicate that patients may achieve reduced pain and enhanced quality of life
upon enzyme replacement therapy.
Another double-blind, placebo-controlled study of 82 patients was performed to determine whether
Fabrazyme would reduce the rate of occurrence of renal, cardiac, or cerebrovascular disease or death.
The rate of clinical events was substantially lower among Fabrazyme-treated patients compared to
placebo-treated patients (risk reduction = 53% intent-to-treat population (p=0.0577); risk reduction =
61 % per-protocol population (p=0.0341)). This result was consistent across renal, cardiac and
cerebrovascular events.
The results of these studies indicate that Fabrazyme treatment at 1 mg/kg every other week provides
clinical benefit on key clinical outcomes in patients with early and advanced Fabry disease. Because
this condition is slowly progressive, early detection and treatment is critical to achieve the best
outcomes.
In the open-label paediatric study, sixteen patients with Fabry disease (8-16 years old; 14 males, 2
females) had been treated for one year. Clearance of GL-3 in the superficial skin vascular endothelium
was achieved in all patients who had accumulated GL-3 at baseline. The 2 female patients had little or
no GL-3 accumulation in the superficial skin vascular endothelium at baseline, making this conclusion
applicable in male patients only.
In an additional study, 21 male patients were enrolled to follow GL3 clearance in kidney and skin
tissues at an alternative dosing regimen. Following treatment with 1 mg/kg every other week for 24
weeks, a dose regimen of 0.3 mg/kg every 2 weeks for 18 months was able to maintain the clearance
of cellular GL-3 in the capillary endothelium of the kidney, other kidney cell types and skin
(superficial skin capillary endothelium) in the majority of patients. However, at the lower dose, IgG
antibodies may play a role with respect to GL-3 clearance in some patients. Due to the limitations of
the study design (small number of patients), no definitive conclusion regarding the dose maintenance
regimen can be drawn, but these findings suggest that, after an initial debulking dose of 1.0 mg/kg
every 2 weeks, 0.3 mg/kg every 2 weeks may be sufficient in some patients to maintain clearance of
GL-3.
5.2 Pharmacokinetic properties
Following an intravenous administration of agalsidase beta to adults at doses of 0.3 mg, 1 mg and
3 mg/kg body weight, the AUC values increased more than dose proportional, due to a decrease in
clearance, indicating a saturated clearance. The elimination half-life was dose dependent and ranged
from 45 to 100 minutes.
After intravenous administration of agalsidase beta to adults with an infusion time of approximately
300 minutes and at a dose of 1 mg/kg body weight, biweekly, mean C
max
plasma concentrations ranged
from 2000 –3500 ng/ml, while the AUC
inf
ranged from 370-780 µg.min/ml. Vss ranged from 8.3-40.8
l, plasma clearance from 119-345 ml/min and the mean elimination half-life from 80-120 minutes.
Fabrazyme pharmacokinetics was also evaluated in 15 paediatric patients (8.5 to 16 years old
weighing 27.1 to 64.9 kg). Agalsidase clearance was not influenced by weight in this population.
Baseline clearance was 77 ml/min with a volume of distribution at steady-state (Vss) of 2.6 l; half-life
was 55 min. After IgG seroconversion, clearance decreased to 35 ml/min, Vss increased to 5.4 l, and
half-life increased to 240 min. The net effect of these changes after seroconversion was an increase in
exposure of 2- to 3-fold based on AUC and C
max
. No unexpected safety issues were encountered in
patients with an increase in exposure after seroconversion.
Agalsidase beta is a protein and is expected to be metabolically degraded through peptide hydrolysis.
Consequently, impaired liver function is not expected to affect the pharmacokinetics of agalsidase beta
16
in a clinically significant way. Renal elimination of agalsidase beta is considered to be a minor
pathway for clearance.
5.3 Preclinical safety data
Non-clinical data reveal no special hazard for humans based on studies of safety pharmacology, single
dose toxicity, repeated dose toxicity and embryonal/foetal toxicity. Studies with regard to other stages
of the development have not been carried out. Genotoxic and carcinogenic potential are not expected.
6.
6.1 List of excipients
Mannitol
Sodium phosphate monobasic, monohydrate
Sodium phosphate dibasic, heptahydrate.
6.2 Incompatibilities
In the absence of compatibility studies, Fabrazyme must not be mixed with other medicinal products
in the same infusion.
6.3 Shelf life
3 years.
Reconstituted and diluted solutions
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage and conditions prior to use are the responsibility of the user. The
reconstituted solution cannot be stored and should be promptly diluted; only the diluted solution can
be held for up to 24 hours at 2 °C-8 °C.
6.4 Special precautions for storage
Store in a refrigerator (2 °C – 8 °C).
6.5 Nature and contents of container
Fabrazyme 5 mg is supplied in clear Type I glass 5 ml vials. The closure consists of a siliconised butyl
stopper and an aluminium seal with a plastic flip-off cap.
Package sizes: 1, 5 and 10 vials per carton.
Not all pack sizes may be marketed.
6.6 Special precautions for disposal
The powder for concentrate for solution for infusion has to be reconstituted with water for injections,
diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous
infusion.
Use Aseptic Technique
1.
Determine the number of vials to be reconstituted based on the individual patient’s weight and
remove the required vials from the refrigerator in order to allow them to reach room temperature
(in approximately 30 minutes). Each vial of Fabrazyme is intended for single use only.
17
Reconstitution
2.
Reconstitute each vial of Fabrazyme 5 mg with 1.1 ml water for injections. Avoid forceful
impact of the water for injections on the powder and avoid foaming. This is done by slow drop-
wise addition of the water for injection down the inside of the vial and not directly onto the
lyophilized cake. Roll and tilt each vial gently. Do not invert, swirl or shake the vial.
3.
The reconstituted solution contains 5 mg agalsidase beta per ml, and appears as a clear
colourless solution. The pH of the reconstituted solution is approximately 7.0. Before further
dilution, visually inspect the reconstituted solution in each vial for particulate matter and
discoloration. Do not use the solution if foreign particles are observed or if the solution is
discoloured.
4.
After reconstitution it is recommended to promptly dilute the vials, to minimize protein particle
formation over time.
5.
Any unused product or waste material should be disposed of in accordance with local
requirements.
Dilution
6.
Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it is
recommended to remove an equal volume of 0.9% sodium chloride intravenous solution, from
the infusion bag.
7.
Remove the airspace within the infusion bag to minimize the air/liquid interface.
8.
Slowly, withdraw 1.0 ml (equal to 5 mg) of the reconstituted solution from each vial up to the
total volume required for the patient dose. Do not use filter needles and avoid foaming.
9.
Then slowly inject the reconstituted solution directly into the 0.9% sodium chloride intravenous
solution (not in any remaining airspace) to a final concentration between 0.05 mg/ml and
0.7 mg/ml. Determine the total volume of sodium chloride 0.9% solution for infusion (between
50 and 500 ml) based on the individual dose. For doses lower than 35 mg use a minimum of
50 ml, for doses 35 to 70 mg use a minimum of 100 ml, for doses 70 to 100 mg use a minimum
of 250 ml and for doses greater than 100 mg use only 500 ml. Gently invert or lightly massage
the infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion
bag.
Administration
10.
It is recommended to administer the diluted solution through an in-line low protein-binding
0.2 µm filter to remove any protein particles which will not lead to any loss of agalsidase beta
activity. The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise
the potential occurrence of infusion-associated reactions. After patient tolerance is established,
the infusion rate may be increased gradually with subsequent infusions.
7.
Genzyme Europe B.V., Gooimeer 10, NL-1411DD Naarden, The Netherlands
8.
MARKETING AUTHORISATION NUMBERS
EU/1/01/188/004-006
18
9.
Date of first authorisation: 03/08/2001
Date of last renewal: 03/08/2006
Detailed information on this product is available on the website of the European Medicines Agency
(EMEA)
http://www.emea.europa.eu.
19
ANNEX II
A. MANUFACTURERS OF THE BIOLOGICAL ACTIVE
SUBSTANCE AND MANUFACTURING AUTHORISATION
HOLDER RESPONSIBLE FOR BATCH RELEASE
B. CONDITIONS OF THE MARKETING AUTHORISATION
20
A. MANUFACTURER(S) OF THE BIOLOGICAL ACTIVE SUBSTANCE(S) AND
MANUFACTURING AUTHORISATION HOLDER(S) RESPONSIBLE FOR BATCH
RELEASE
Name and address of the manufacturers of the biological active substance
Genzyme Corp.
45, 51, 74, 76 and 80 New York Avenue
Framingham
MA 01701-9322
USA
Genzyme Corp.
500 Soldiers Field Road
Allston
MA 02134
USA
Name and address of the manufacturer responsible for batch release
Genzyme Ltd.
37 Hollands Road
Haverhill
Suffolk CB9 8PU
United Kingdom
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
Not applicable.
21
ANNEX III
LABELLING AND PACKAGE LEAFLET
22
A. LABELLING
23
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON, 1 VIAL, 5 VIALS, 10 VIALS
1.
Fabrazyme 35 mg powder for concentrate for solution for infusion
agalsidase beta
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial of powder contains 35 mg of agalsidase beta.
3.
LIST OF EXCIPIENTS
Excipients :
mannitol
sodium phosphate monobasic, monohydrate
sodium phosphate dibasic, heptahydrate.
4.
1 vial of powder for concentrate for solution for infusion.
5 vials of powder for concentrate for solution for infusion.
10 vials of powder for concentrate for solution for infusion.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For 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
For single use only.
8.
EXPIRY DATE
EXP {month/year}
24
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2 °C – 8 °C).
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused solution should be discarded.
Marketing authorisation holder:
Genzyme Europe B.V.
Gooimeer 10
NL-1411DD Naarden
The Netherlands
EU/1/01/188/001
EU/1/01/188/002
EU/1/01/188/003
13. BATCH NUMBER
Batch{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
25
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Fabrazyme 35 mg
powder for concentrate for solution for infusion
agalsidase beta
For intravenous use.
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP : {month/year}
4.
BATCH NUMBER
Batch {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
Genzyme Europe B.V.-NL
Store in a refrigerator (2 °C – 8 °C).
26
PARTICULARS TO APPEAR ON THE OUTER PACKAGING
OUTER CARTON, 1 VIAL, 5 VIALS, 10 VIALS
1.
Fabrazyme 5 mg powder for concentrate for solution for infusion
agalsidase beta
2.
STATEMENT OF ACTIVE SUBSTANCE(S)
One vial of powder contains 5 mg of agalsidase beta.
3.
LIST OF EXCIPIENTS
Excipients :
mannitol
sodium phosphate monobasic, monohydrate
sodium phosphate dibasic, heptahydrate.
4.
1 vial of powder for concentrate for solution for infusion.
5 vials of powder for concentrate for solution for infusion.
10 vials of powder for concentrate for solution for infusion.
5.
METHOD AND ROUTE(S) OF ADMINISTRATION
For 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
For single use only.
8.
EXPIRY DATE
EXP {month/year}
27
9.
SPECIAL STORAGE CONDITIONS
Store in a refrigerator (2 °C – 8 °C).
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF
APPROPRIATE
Any unused solution should be discarded.
Marketing authorisation holder:
Genzyme Europe B.V.
Gooimeer 10
NL-1411DD Naarden
The Netherlands
EU/1/01/188/004
EU/1/01/188/005
EU/1/01/188/006
13. BATCH NUMBER
Batch{number}
14. GENERAL CLASSIFICATION FOR SUPPLY
Medicinal product subject to medical prescription.
15. INSTRUCTIONS ON USE
16. INFORMATION IN BRAILLE
28
MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS
VIAL
1.
Fabrazyme 5 mg
powder for concentrate for solution for infusion
agalsidase beta
For intravenous use.
2.
METHOD OF ADMINISTRATION
3.
EXPIRY DATE
EXP : {month/year}
4.
BATCH NUMBER
Batch {number}
5.
CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT
6.
OTHER
Genzyme Europe B.V.- NL
Store in a refrigerator (2 °C – 8 °C)
29
B. PACKAGE LEAFLET
30
PACKAGE LEAFLET: INFORMATION FOR THE USER
Fabrazyme 35 mg powder for concentrate for solution for infusion
Agalsidase beta
Read all of this leaflet carefully before you start using this medicine.
-
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. 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 Fabrazyme is and what it is used for
2.
Before you use Fabrazyme
3.
How to use Fabrazyme
4.
Possible side effects
5.
How to store Fabrazyme
6.
Further information
1.
WHAT FABRAZYME IS AND WHAT IT IS USED FOR
Fabrazyme is used as enzyme replacement therapy in Fabry disease, where the level of α-
galactosidase enzyme activity is absent or lower than normal. If you suffer from Fabry disease a fat
substance, called globotriaosylceramide (GL-3), is not removed from the cells of your body and starts
to accumulate in the walls of the blood vessels of your organs.
Fabrazyme is indicated for use as long-term enzyme replacement therapy in patients with a confirmed
diagnosis of Fabry disease.
2.
BEFORE YOU USE FABRAZYME
Do not use Fabrazyme
If you have experienced an allergic anaphylactic reaction to agalsidase beta or if you are allergic
(hypersensitive) to any of the other ingredients of Fabrazyme.
Take special care with Fabrazyme
If you are treated with Fabrazyme, you may develop infusion associated reactions. An infusion-
associated reaction is any side effect occurring during the infusion or until the end of the infusion day
(See 4 “Possible Side Effects”). If you experience a reaction like this, you should
tell your doctor
immediately
. You may need to be given additional medicines to prevent such reactions from
occurring.
Different groups of patients using Fabrazyme
The information in this leaflet applies to all patient groups including children, adolescents, adults and
the elderly.
Using other medicines
There are no known interactions with other medicinal products. Fabrazyme should not be administered
with chloroquine, amiodarone, benoquin or gentamicin due to a theoretical risk of decreased
agalsidase beta activity. Please tell your doctor or pharmacist if you are taking or have recently taken
any other medicines, including medicines obtained without a prescription.
31
Using Fabrazyme with food and drink
Interactions with food and drink are unlikely.
Pregnancy and breast-feeding
Use of Fabrazyme during pregnancy is not recommended. There is no experience with the use of
Fabrazyme in pregnant women. Fabrazyme may get into breast milk. Use of Fabrazyme during breast-
feeding is not recommended. Ask your doctor or pharmacist for advice before taking this medicine.
3.
HOW TO USE FABRAZYME
Fabrazyme is given through a drip into a vein (by intravenous infusion). It is supplied as a powder
which will be mixed with sterile water before it is given (see information for Health Care
Professionals)
Fabrazyme is only used under the supervision of a doctor who is knowledgeable in the treatment of
Fabry disease.
The recommended dose of Fabrazyme for adults and children 8 – 16 years is 1 mg/kg body weight,
once every 2 weeks. No changes in dose are necessary for patients with kidney disease.
If you use more Fabrazyme than you should
There are no cases of overdose of Fabrazyme reported. Doses up to 3 mg/kg body weight have shown
to be safe.
If you forget to use Fabrazyme
If you have missed an infusion of Fabrazyme, please contact your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Fabrazyme can cause side effects, although not everybody gets them.
In clinical studies side effects were mainly seen while patients were being given the medicine or
shortly after. If you experience any serious side effect or side effects not listed, please
tell your doctor
immediately.
32
In clinical trials the following side effects were reported:
Very common (occurring in more than 1 in 10 patients):
•
abnormal touch feeling (pins
and needles)
•
feeling cold
•
fever
•
nausea
•
headache
•
vomiting
Common (occurring in 1 in 100 to 1 in 10 patients):
•
sleepiness •
fatigue
•
difficulty in breathing •
increased heart beat •
flushing
•
pallor
•
abdominal pain •
pain
•
itching
•
back pain
•
throat tightness
•
abnormal tear secretion •
rash
•
dizziness
•
feeling weak
•
low heart rate
•
palpitations
•
tinnitus
•
lethargy
•
decreased sensitivity to pain
•
nasal congestion •
syncope
•
burning sensation
•
diarrhoea
•
cough
•
wheezing
•
redness
•
abdominal discomfort •
urticaria
•
muscle pain
•
swelling face
•
pain at the extremities
•
increased blood pressure •
joint pain
•
nasopharyngitis
•
sudden swelling of the face
or throat
•
decreased blood pressure •
hot flush
•
oedema in extremities •
chest discomfort •
feeling hot
•
vertigo
•
face oedema
•
hyperthermia
•
stomach discomfort •
exacerbated difficulty in
breathing
•
decreased mouth sensitivity
•
muscle spasms •
muscle tightness •
musculoskeletal stiffness
Uncommon (occurring in 1 in 1000 to 1 in 100 patients):
•
itching eyes •
low heart rate due to conduction
disturbances
•
red eyes •
ear swelling •
increased sensitivity to pain
•
ear pain •
bronchospasm •
upper respiratory tract congestion
•
throat pain •
runny nose •
red rash
•
fast breathing •
heart burn •
(mottled purplish) skin discoloration
•
itchy rash •
skin discomfort •
coldness of the extremities
•
feeling hot and cold •
musculoskeletal pain •
injection site blood clotting
•
difficulty swallowing •
rhinitis •
skin discoloration
•
infusion site pain •
influenza-like illness •
oedema
•
infusion site reaction •
malaise
Unknown frequency
•
Serious allergic reactions •
serious inflammation of the
vessels
•
lower blood oxygen levels
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.
33
•
chills
•
chest pain
•
tremor
5.
HOW TO STORE FABRAZYME
Keep out of the reach and sight of children.
Unopened vials
Store in a refrigerator (2 °C – 8 °C).
Do not use Fabrazyme after the expiry date which is stated on the labelling after the letters ‘EXP’.
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 Fabrazyme contains
-
The active substance is agalsidase beta, one vial contains 35 mg.
Mannitol
-
Sodium phosphate monobasic, monohydrate
-
Sodium phosphate dibasic, heptahydrate.
What Fabrazyme looks like and contents of the pack
Fabrazyme is supplied as a white to off-white, powder. After reconstitution it is a clear, colourless
liquid, free from foreign matter. The reconstituted solution must be further diluted. Package sizes: 1, 5
and 10 vials per carton. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder
Genzyme Europe B.V., Gooimeer 10, NL-1411DD Naarden, The Netherlands.
Manufacturer
Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom.
34
-
Other ingredients are:
-
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien/
Luxemburg/Luxembourg
Genzyme Belgium N.V.,
Tel/Tél: + 32 2 714 17 11
Italia/Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349811
България
Търговско представителство на Genzyme
CEE GmbH
Тел. +359 2 971 1001
Magyarország
Genzyme Europe B.V. Képviselet
Tel: +36 1 310 7440
Česká Republika/Slovenská Republika/
Slovenija
Genzyme Czech s.r.o.,
Tel: +420 227 133 665
Nederland
Genzyme Europe B.V.,
Tel: +31 35 6991200
Danmark/Norge/Sverige/Suomi/Finland/
Ísland
Genzyme A/S, (Danmark/Tanska/Danmörk),
Tlf/Puh./Sími: + 45 32712600
Österreich
Genzyme Austria GmbH,
Tel: + 43 1 774 65 38
Deutschland
Genzyme GmbH,
Tel: +49 610236740
Polska/Eesti/Latvija/Lietuva
Genzyme Polska Sp. z o. o.
(Poola/Polija/Lenkija),
Tel: + 48 22 24 60 900
Ελλάδα/Κύπρος
Genzyme Hellas Ltd. (Ελλάδα)
Τηλ: +30 210 99 49 270
Portugal
Genzyme Portugal, S.A.,
Tel: +351 21 422 0100
España
Genzyme, S.L..,
Tel: +34 91 6591670
România
Genzyme CEE GmbH- Reprezentanţa pentru
România
Tel: +40 21 243 42 28
France
Genzyme S.A.S,
Tél: + 33 (0) 825 825 863
United Kingdom/Ireland
Genzyme Therapeutics Ltd. (United
Kingdom),
Tel: +44 1865 405200
This leaflet was last approved in
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.
---------------------------------------------------------------------------------------------------------------------------
35
The following information is intended for medical or healthcare professionals only:
Instructions for use – reconstitution, dilution and administration
The powder for concentrate for solution for infusion has to be reconstituted with water for injections,
diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous
infusion.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage and conditions are the responsibility of the user. The reconstituted solution
cannot be stored and should be promptly diluted; only the diluted solution can be held for up to 24
hours at 2ºC -8º C.
Use Aseptic Technique
1.
Determine the number of vials to be reconstituted based on the individual patient's weight and
remove the required vials from the refrigerator in order to allow them to reach room temperature
(in approximately 30 minutes). Each vial of Fabrazyme is intended for single use only.
Reconstitution
. Avoid forceful
impact of the water for injections on the powder and avoid foaming. This is done by slow drop-
wise addition of the water for injection down the inside of the vial and not directly onto the
lyophilized cake. Roll and tilt each vial gently. Do not invert, swirl or shake the vial.
3.
The reconstituted solution contains 5 mg agalsidase beta per ml, and appears as a clear
colourless solution. The pH of the reconstituted solution is approximately 7.0. Before further
dilution, visually inspect the reconstituted solution in each vial for particulate matter and
discoloration. Do
not
use the solution if foreign particles are observed or if the solution is
discoloured.
4.
After reconstitution it is recommended to
promptly dilute
the vials, to minimize protein particle
formation over time.
5.
Any unused product or waste material should be disposed of in accordance with local
requirements.
Dilution
6.
Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it is
recommended to remove an equal volume of 0.9% sodium chloride
intravenous solution
, from
the infusion bag.
7.
Remove the airspace within the infusion bag to minimize the air/liquid interface.
8.
Slowly, withdraw 7.0 ml (equal to 35 mg) of the reconstituted solution from each vial up to the
total volume required for the patient dose. Do not use filter needles and avoid foaming.
(not in any remaining airspace) to a final concentration between 0.05 mg/ml and 0.7
mg/ml. Determine the total volume of sodium chloride 0.9% solution for infusion (between 50
and 500 ml) based on the individual dose. For doses lower than 35 mg use a minimum of 50 ml,
for doses 35 to 70 mg use a minimum of 100 ml, for doses 70 to 100 mg use a minimum of 250
ml and for doses greater than 100 mg use only 500 ml. Gently invert or lightly massage the
infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion bag.
36
2.
Reconstitute each vial of Fabrazyme 35 mg with 7.2 ml
water for injections
9.
Then slowly inject the reconstituted solution directly into the
0.9% sodium chloride intravenous
solution
Administration
10.
It is recommended to administer the diluted solution through an in-line low protein-binding 0.2
µm filter to remove any protein particles which will not lead to any loss of agalsidase beta
activity. The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise
the potential occurrence of infusion-associated reactions. After patient tolerance is established,
the infusion rate may be increased gradually with subsequent infusions.
37
PACKAGE LEAFLET: INFORMATION FOR THE USER
Fabrazyme 5 mg powder for concentrate for solution for infusion
Agalsidase beta
Read all of this leaflet carefully before you start using this medicine.
-
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. 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 Fabrazyme is and what it is used for
2.
Before you use Fabrazyme
3.
How to use Fabrazyme
4.
Possible side effects
5.
How to store Fabrazyme
6.
Further information
1.
WHAT FABRAZYME IS AND WHAT IT IS USED FOR
Fabrazyme is used as enzyme replacement therapy in Fabry disease, where the level of α-
galactosidase enzyme activity is absent or lower than normal. If you suffer from Fabry disease a fat
substance, called globotriaosylceramide (GL-3), is not removed from the cells of your body and starts
to accumulate in the walls of the blood vessels of your organs.
Fabrazyme is indicated for use as long-term enzyme replacement therapy in patients with a confirmed
diagnosis of Fabry disease.
2.
BEFORE YOU USE FABRAZYME
Do not use Fabrazyme
If you have experienced an allergic anaphylactic reaction to agalsidase beta or if you are allergic
(hypersensitive) to any of the other ingredients of Fabrazyme.
Take special care with Fabrazyme
If you are treated with Fabrazyme, you may develop infusion associated reactions. An infusion-
associated reaction is any side effect occurring during the infusion or until the end of the infusion day
(See 4 “Possible Side Effects”). If you experience a reaction like this, you should
tell your doctor
immediately
. You may need to be given additional medicines to prevent such reactions from
occurring.
Different groups of patients using Fabrazyme
The information in this leaflet applies to all patient groups including children, adolescents, adults and
the elderly.
Using other medicines
There are no known interactions with other medicinal products. Fabrazyme should not be administered
with chloroquine, amiodarone, benoquin or gentamicin due to a theoretical risk of decreased
agalsidase beta activity. Please tell your doctor or pharmacist if you are taking or have recently taken
any other medicines, including medicines obtained without a prescription.
38
Using Fabrazyme with food and drink
Interactions with food and drink are unlikely.
Pregnancy and breast-feeding
Use of Fabrazyme during pregnancy is not recommended. There is no experience with the use of
Fabrazyme in pregnant women. Fabrazyme may get into breast milk. Use of Fabrazyme during breast-
feeding is not recommended. Ask your doctor or pharmacist for advice before taking this medicine.
3.
HOW TO USE FABRAZYME
Fabrazyme is given through a drip into a vein (by intravenous infusion). It is supplied as a powder
which will be mixed with sterile water before it is given (see information for Health Care
Professionals)
Fabrazyme is only used under the supervision of a doctor who is knowledgeable in the treatment of
Fabry disease.
The recommended dose of Fabrazyme for adults and children 8 – 16 years is 1 mg/kg body weight,
once every 2 weeks. No changes in dose are necessary for patients with kidney disease.
If you use more Fabrazyme than you should
There are no cases of overdose of Fabrazyme reported. Doses up to 3 mg/kg body weight have shown
to be safe.
If you forget to use Fabrazyme
If you have missed an infusion of Fabrazyme, please contact your doctor.
4.
POSSIBLE SIDE EFFECTS
Like all medicines, Fabrazyme can cause side effects, although not everybody gets them.
In clinical studies side effects were mainly seen while patients were being given the medicine or
shortly after. If you experience any serious side effect or side effects not listed, please
tell your doctor
immediately.
39
In clinical trials the following side effects were reported:
Very common (occurring in more than 1 in 10 patients):
•
abnormal touch feeling (pins
and needles)
•
feeling cold
•
fever
•
nausea
•
headache
•
vomiting
Common (occurring in 1 in 100 to 1 in 10 patients):
•
sleepiness •
fatigue
•
difficulty in breathing •
increased heart beat •
flushing
•
pallor
•
abdominal pain •
pain
•
itching
•
back pain
•
throat tightness
•
abnormal tear secretion •
rash
•
dizziness
•
feeling weak
•
low heart rate
•
palpitations
•
tinnitus
•
lethargy
•
decreased sensitivity to pain
•
nasal congestion •
syncope
•
burning sensation
•
diarrhoea
•
cough
•
wheezing
•
redness
•
abdominal discomfort •
urticaria
•
muscle pain
•
swelling face
•
pain at the extremities
•
increased blood pressure •
joint pain
•
nasopharyngitis
•
sudden swelling of the face
or throat
•
decreased blood pressure •
hot flush
•
oedema in extremities •
chest discomfort •
feeling hot
•
vertigo
•
face oedema
•
hyperthermia
•
stomach discomfort •
exacerbated difficulty in
breathing
•
decreased mouth sensitivity
•
muscle spasms •
muscle tightness •
musculoskeletal stiffness
Uncommon (occurring in 1 in 1000 to 1 in 100 patients):
•
itching eyes •
low heart rate due to conduction
disturbances
•
red eyes •
ear swelling •
increased sensitivity to pain
•
ear pain •
bronchospasm •
upper respiratory tract congestion
•
throat pain •
runny nose •
red rash
•
fast breathing •
heart burn •
(mottled purplish) skin discoloration
•
itchy rash •
skin discomfort •
coldness of the extremities
•
feeling hot and cold •
musculoskeletal pain •
injection site blood clotting
•
difficulty swallowing •
rhinitis •
skin discoloration
•
infusion site pain •
influenza-like illness •
oedema
•
infusion site reaction •
malaise
Unknown frequency
•
Serious allergic reactions •
serious inflammation of the
vessels
•
lower blood oxygen levels
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.
40
•
chills
•
chest pain
•
tremor
5.
HOW TO STORE FABRAZYME
Keep out of the reach and sight of children.
Unopened vials
Store in a refrigerator (2 °C – 8 °C).
Do not use Fabrazyme after the expiry date which is stated on the labelling after the letters ‘EXP’.
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 Fabrazyme contains
-
The active substance is agalsidase beta, one vial contains 5 mg.
Mannitol
-
Sodium phosphate monobasic, monohydrate
-
Sodium phosphate dibasic, heptahydrate.
What Fabrazyme looks like and contents of the pack
Fabrazyme is supplied as a white to off-white powder. After reconstitution it is a clear, colourless
liquid, free from foreign matter. The reconstituted solution must be further diluted. Package sizes: 1, 5
and 10 vials per carton. Not all pack sizes may be marketed.
Marketing Authorisation Holder and Manufacturer
Marketing authorisation holder
Genzyme Europe B.V., Gooimeer 10, NL-1411DD Naarden, The Netherlands.
Manufacturer
Genzyme Ltd., 37 Hollands Road, Haverhill, Suffolk CB9 8PU, United Kingdom.
41
-
Other ingredients are:
-
For any information about this medicinal product, please contact the local representative of the
Marketing Authorisation Holder:
België/Belgique/Belgien/
Luxemburg/Luxembourg
Genzyme Belgium N.V.,
Tel/Tél:: + 32 2 714 17 11
Italia/Malta
Genzyme Srl (Italia/Italja),
Tel: +39 059 349811
България
Търговско представителство на Genzyme
CEE GmbH
Тел. +359 2 971 1001
Magyarország
Genzyme Europe B.V. Képviselet
Tel: +36 1 310 7440
Česká Republika/Slovenská Republika/
Slovenija
Genzyme Czech s.r.o.,
Tel: +420 227 133 665
Nederland
Genzyme Europe B.V.,
Tel: +31 35 6991200
Danmark/Norge/Sverige/Suomi/Finland/
Ísland
Genzyme A/S, (Danmark/Tanska/Danmörk),
Tlf/Puh./Sími: + 45 32712600
Österreich
Genzyme Austria GmbH,
Tel: + 43 1 774 65 38
Deutschland
Genzyme GmbH,
Tel: +49 610236740
Polska/Eesti/Latvija/Lietuva
Genzyme Polska Sp. z o. o.
(Poola/Polija/Lenkija),
Tel: + 48 22 24 60 900
Ελλάδα/Κύπρος
Genzyme Hellas Ltd. (Ελλάδα)
Τηλ: +30 210 99 49 270
Portugal
Genzyme Portugal, S.A.,
Tel: +351 21 422 0100
España
Genzyme, S.L.,
Tel: +34 91 6591670
România
Genzyme CEE GmbH- Reprezentanţa pentru
România
Tel: +40 21 243 42 28
France
Genzyme S.A.S,
Tél: + 33 (0) 825 825 863
United Kingdom/Ireland
Genzyme Therapeutics Ltd. (United
Kingdom),
Tel: +44 1865 405200
This leaflet was last approved in
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.
---------------------------------------------------------------------------------------------------------------------------
42
The following information is intended for medical or healthcare professionals only:
Instructions for use – reconstitution, dilution and administration
The powder for concentrate for solution for infusion has to be reconstituted with water for injections,
diluted with 0.9% sodium chloride intravenous solution and then administered by intravenous
infusion.
From a microbiological point of view, the product should be used immediately. If not used
immediately, in-use storage and conditions are the responsibility of the user. The reconstituted solution
cannot be stored and should be promptly diluted; only the diluted solution can be held for up to 24
hours at 2ºC -8º C.
Use Aseptic Technique
1.
Determine the number of vials to be reconstituted based on the individual patient's weight and
remove the required vials from the refrigerator in order to allow them to reach room temperature
(in approximately 30 minutes). Each vial of Fabrazyme is intended for single use only.
Reconstitution
. Avoid forceful
impact of the water for injections on the powder and avoid foaming. This is done by slow drop-
wise addition of the water for injection down the inside of the vial and not directly onto the
lyophilized cake. Roll and tilt each vial gently. Do not invert, swirl or shake the vial.
3.
The reconstituted solution contains 5 mg agalsidase beta per ml, and appears as a clear
colourless solution. The pH of the reconstituted solution is approximately 7.0. Before further
dilution, visually inspect the reconstituted solution in each vial for particulate matter and
discoloration. Do not use the solution if foreign particles are observed or if the solution is
discoloured.
4.
After reconstitution it is recommended to
promptly dilute
the vials, to minimize protein particle
formation over time.
5.
Any unused product or waste material should be disposed of in accordance with local
requirements.
Dilution
6.
Prior to adding the reconstituted volume of Fabrazyme required for the patient dose, it is
recommended to remove an equal volume of 0.9% sodium chloride
intravenous solution
, from
the infusion bag.
7.
Remove the airspace within the infusion bag to minimize the air/liquid interface.
8.
Slowly, withdraw 1.0 ml (equal to 5 mg) of the reconstituted solution from each vial up to the
total volume required for the patient dose. Do not use filter needles and avoid foaming.
(not in any remaining airspace) to a final concentration between 0.05 mg/ml and 0.7
mg/ml. Determine the total volume of sodium chloride 0.9% solution for infusion (between 50
and 500 ml) based on the individual dose. For doses lower than 35 mg use a minimum of 50 ml,
for doses 35 to 70 mg use a minimum of 100 ml, for doses 70 to 100 mg use a minimum of 250
ml and for doses greater than 100 mg use only 500 ml. Gently invert or lightly massage the
infusion bag to mix the diluted solution. Do not shake or excessively agitate the infusion bag.
43
2.
Reconstitute each vial of Fabrazyme 5 mg with 1.1 ml
water for injections
9.
Then slowly inject the reconstituted solution directly into the
0.9% sodium chloride intravenous
solution
Administration
10.
It is recommended to administer the diluted solution through an in-line low protein-binding 0.2
µm filter to remove any protein particles which will not lead to any loss of agalsidase beta
activity. The initial infusion rate should be no more than 0.25 mg/min (15 mg/hour) to minimise
the potential occurrence of infusion-associated reactions. After patient tolerance is established,
the infusion rate may be increased gradually with subsequent infusions.
44
Source: European Medicines Agency
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