REPLAGAL

Israel - English - Ministry of Health

Buy It Now

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.

Similar products

Search alerts related to this product

View documents history

Share this information