Patient Information leaflet
(PIL) 17-08-2016
Summary of Product characteristics
(SPC) 12-05-2020
Public Assessment Report
(PAR) 18-08-2016
- Active ingredient:
- AGALSIDASE ALFA
- Available from:
- TAKEDA ISRAEL LTD
- ATC code:
- A16AB03
- Pharmaceutical form:
- CONCENTRATE FOR SOLUTION FOR INFUSION
- Composition:
- AGALSIDASE ALFA 1 MG/ML
- Administration route:
- I.V
- Prescription type:
- Required
- Manufactured by:
- SHIRE HUMAN GENETIC THERAPIES INC., USA
- Therapeutic group:
- AGALSIDASE ALFA
- Therapeutic area:
- AGALSIDASE ALFA
- Therapeutic indications:
- Replagal is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of fabry disease (alfa-galactosidase A deficiency).
- Authorization number:
- 124 32 30382 00
- Authorization date:
- 2011-11-30
העדוה העדוה
לע לע
הרמחה הרמחה
(
(
עדימ עדימ
ןולעב )תוחיטב ןולעב )תוחיטב
ל
ל
אפור אפור
ןכדועמ( ןכדועמ(
05.2013
05.2013
ךיראת
__
11/09/2014
_____
םש
רישכת
תילגנאב
רפסמו
םושירה
_
124-32-30382-00
Replagal
__
םש
לעב
םושירה
___
ןוסידמ
המראפ
מ"עב
____
ספוט
הז
דעוימ
טורפל
תורמחהה
דבלב
תורמחהה
תושקובמה קרפ
ןולעב טסקט
יחכונ טסקט
שדח
4.2
Posology and
method of
administration
Paediatric Population
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 with
Replagal administered at 0.2 mg/kg in
this population, this dose regimen is
suggested for children between 7- 18
years of age.
Paediatric Population
The experience in children is limited. No
dosage regimen in children (0-6 years) can
presently be recommended as safety and
efficacy haveof Replagal in children aged 0-
6 years has not yet been sufficiently
established. Currently available data are
described in section 5.1 but no
recommendation on posology can be made.
LimitedIn clinical data instudies of children
(7-18 years) do not permit to recommend an
optimal dosage regimen presently (see
sections 5.1 and 5.2). Becausewho received
Replagal 0.2 mg/kg every other week, no
unexpected safety issues were encountered in
the 6 month study with Replagal
administered at 0.2 mg/kg in this population,
this dose regimen is suggested for children
between 7- 18 years of age.(see section 5.1).
4.4
Special warnings
and precautions
for use
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.
Allergic-type hypersensitivity
Hypersensitivity reactions
As with any intravenous protein product,
allergic-type hypersensitivityHypersensitivity
reactions are possible.have been reported. If
severe allergic hypersensitivity 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
…
No IgE antibodies have been detected
in any patient receiving Replagal.
IgG antibodiesAntibodies to the protein
As with all protein pharmaceutical products,
patients may develop IgG antibodies to the
protein …
No IgE antibodies have been detected in any
patient receiving Replagal. In clinical trials
one case of transient IgE antibody positivity
not associated with anaphylaxis was reported.
4.6
Pregnancy
Pregnancy
Fertility,
pregnancy and
lactation
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).
Breastfeeding
It is not known whether Replagal is
excreted in human milk. Caution
should be exercised when prescribing
to pregnant or breast-feeding women.
VeryThere is 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/foetalembryonic/fetal
development when exposed during
organogenesis (see Section 5.3). Caution
should be exercised when prescribing to
pregnant women.
Breast-feeding
It is not known whether Replagal is excreted
in human milk. Caution should be exercised
when prescribing to pregnant or breast-
feeding women.
Fertility
No effects on male fertility were seen in
reproductive studies in male rats.
4.8
Undesirable
effects
Infusion related reactions reported in
the postmarketing setting (also see
section 4.4 Special warnings and
precautions for use) may also 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, hyperhidrosis,
and hypotension. The most frequent
were mild infusion-related reactions
that mainly included rigors, pyrexia,
flushing, headache, nausea, and
dyspnoea.
Description of selected adverse reactions
Infusion related reactions reported in the
postmarketing setting (also see section 4.4
Special warnings and precautions for use)
may also 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, hyperhidrosis, and
hypotension. The most frequent were mild
common infusion- related reactions that
mainly included were mild and include
rigors, pyrexia, flushing, headache, nausea,
dyspnea, tremor and dyspnoeapruritus.
Infusion-related symptoms may also include
dizziness, hyperhidrosis, hypotension, cough,
vomiting and fatigue. Hypersensitivity,
including anaphylaxis, has been reported.
4.9 Overdose
No case of overdose has been reported.
No case of overdose has been reported.
In clinical trials doses up to 0.4 mg/kg
weekly were used, and their safety profile
was not different from the recommended
dose of 0.2 mg/kg biweekly.
5.1
Pharmacodynamic
properties
Paediatric population
....
In male paediatric patients > 7 years of
age, heart rate variability was
Paediatric population
In male paediatric patients >≥ 7 years of age,
heart rate variability was abnormal at
Table 1
System
organ
class
Adverse reaction
Very
common
Uncommo
known
Immune
system
disorders
rigors
pyrexia,
pain and
discomfort,
fatigue
Anaphyla
ctic
reaction,
hypersensi
tivity
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 0.2 mg/kg therapy in an
open-label long-term extension study
in 9 boys. Individual left ventricular
mass indexed to height
was within
normal range for children (<39 g/m
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
was borderline
elevated or elevated (>95%) for (<39
in boys) at baseline. LVMI
values for all 5 children fell within
normal range after starting therapy.
For patients between 0 and 7 years of
age, limited data indicate no specific
safety issues.
baseline and improved after 6 months of
Replagal therapy in 15 boys and the
improvement was sustained through 4.06.5
years of Replagal 0.2 mg/kg therapy in an
open-label long-term extension study in 9
boys. IndividualAmong 9 boys with left
ventricular mass (LVMI) indexed to height
was within the normal range for children
(<39 g/m
in boys) at baseline. A relative
reduction in mean LVM of 11% was
observed during the 4, LVMI remained stable
at levels below the left ventricular
hypertrophy (LVH) threshold throughout the
6.5 years of treatment. In 5/6 children <a
second study, in 14 patients ≥ 7 years old,
individual left ventricular mass indexed to
height
was borderline elevated or elevated
(>95%) for (<39 g/m
in boys)of age, the
results regarding heart rate variability were
consistent with previous findings. In this
study, only one patient had LVH at baseline.
LVMI values for all 5 children fell within
normal range after starting therapy and
remained stable over time.
For patients between 0 and 7 years of age,
limited data indicate no specific safety issues.
Study in patients switching from agalsidase
beta to Replagal (agalsidase alfa)
100 patients (naïve (n=29); or previously
treated with agalsidase beta who switched to
Replagal (n=71)) were treated for up to
30 months in an open label, uncontrolled
study. An analysis showed that serious
adverse events were reported in 39.4% of
those patients who switched from agalsidase
beta compared to 31.0% in those who were
naïve to therapy prior to study entry. Patients
switched from agalsidase beta to Replagal
had a safety profile consistent with that
observed in other clinical experience.
Infusion related reactions have been
experienced by 9 patients of the naïve
population (31.0%) compared to 27 patients
of the switched population (38.0%).
Study with various dosing regimen
In an open-label randomised study, there
were no statistically significant differences
between adult patients treated for 52 weeks
with 0.2 mg/kg intravenously every other
week (n=20) and those treated with
0.2 mg/kg weekly (n=19) in mean change
from baseline LVMI or other endpoints
(cardiac functional status, renal function, and
pharmacodynamic activity). In each
treatment group, LVMI remained stable over
the treatment period of the study. The overall
incidence of SAEs by treatment group did not
show any obvious effect of treatment regimen
on the SAE profile of the different treatment
groups.
העדוה
לע
הרמחה
(
עדימ
)תוחיטב :ךיראת
30.04.12
םש
רישכת
:תילגנאב
Replagal
רפסמ
:םושיר
124
32
30382
00
םש
לעב
ןוסידמ :םושירה
המראפ
מ"עב םייונישה
ןולעב
םינמוסמ
לע
עקר
בוהצ ןולעב
אפור קרפ
ןולעב טסקט
יחכונ טסקט
שדח
4.2
Posology and
method of
administratio
n
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.
Replagal treatment should be supervised
by a physician experienced in the
management of patients with Fabry
Disease or other inherited metabolic
diseases
Posology
Replagal is administered at a dose of
0.2 mg/kg body weight every other week
by intravenous infusion over 40 minutes.
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.
:ךשמה
4.2
Posology and
method of
administratio
n
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
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.
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 with Replagal
administered at 0.2 mg/kg in this
population, this dose regimen is
suggested for children between 7– 18
years of age.
Limited data are available in patients on
dialysis or post-kidney transplantation, no
dose adjustment is recommended.
Paediatric patients Population
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 with
Replagal administered at 0.2 mg/kg in this
population, this dose regimen is suggested
for children between 7- 18 years of age.
Method of administration
For instructions on reconstitution of the
medicinal product before administration,
see section 6.6.
Administer the infusion solution over a
period of 40 minutes using an intravenous
line with an integral filter.
Do not infuse Replagal concomitantly in
the same intravenous line with other
agents.
4.8
Unde
sirable
effects
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
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
female patients, and from post-marketing
spontaneous reports. Information is
presented by system organ class and
frequency (very common >1/10; common
>1/100, <1/10; uncommon >1/1000,
<1/100). The ADRs categorized as
incidence “not known” are derived from
post-marketing spontaneous reports and
are shown in italics. 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.
The following ADRs have been identified
for agalsidase alfa
ךשמה
4.8
Unde
sirable
Effects
Table 1
Table 1
ךשמה
4.8
Unde
sirable
Effects
ךשמה
4.8
Unde
sirable
Effects
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.
Infusion related reactions (also see
section 4.4 Special warnings and
precautions for use) may also 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.
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.
Infusion related reactions reported in the
postmarketing setting (also see section 4.4
Special warnings and precautions for use)
may also 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, hyperhidrosis, and hypotension.
The most frequent were mild infusion-
related reactions that mainly included
rigors, pyrexia, flushing, headache,
nausea, and dyspnoea.
Patients with renal disease
Adverse drug reactions reported in
patients with history of end stage renal
disease were similar to those reported in
the general patient population.
Paediatric population
Adverse drug reactions reported in the
paediatric population (children and
adolescents) were, in general, similar to
those reported in adults. However,
infusion related reactions (pyrexia,
dyspnoea, chest pain) and pain
exacerbation occurred more frequently.
6.6
Special
precaution
s 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
Calculate the dose and number of
Replagal vials needed.
Dilute the total volume of Replagal
concentrate required in 100 ml of 9
mg/ml (0.9%) sodium chloride
solution for infusion. Care must be
taken to ensure the sterility of the
prepared solutions since Replagal
does not contain any preservative or
bacteriostatic agent; aseptic
technique must be observed. Once
diluted, the solution should be mixed
gently but not shaken.
Since no preservative is present, it
is recommended that administration
is started as soon as possible after
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.
dilution.
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.
