FABRAZYME 35 MG

Israel - English - Ministry of Health

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Active ingredient:
AGALSIDASE BETA
Available from:
SANOFI - AVENTIS ISRAEL LTD
ATC code:
A16AB04
Pharmaceutical form:
POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION
Composition:
AGALSIDASE BETA 35 MG/VIAL
Administration route:
I.V
Prescription type:
Required
Manufactured by:
GENZYME EUROPE B.V., THE NETHERLANDS
Therapeutic group:
AGALSIDASE BETA
Therapeutic area:
AGALSIDASE BETA
Therapeutic indications:
Fabrazyme is indicated for use as long-term enzyme replacement therapy in patients with a confirmed diagnosis of Fabry disease. (alfa - galactosidase A deficiency).
Authorization number:
124 94 30313 00
Authorization date:
2017-05-31

לע העדוה לע העדוה לע העדוה ( הרמחה ( הרמחה ( הרמחה

עדימ עדימ עדימ ל ןולעב )תוחיטב ל ןולעב )תוחיטב ל ןולעב )תוחיטב אפור אפור אפור

ןכדועמ( ןכדועמ( ןכדועמ(

05.2013

05.2013

05.2013

________ ךיראת

29/10/17

תילגנאב רישכת םש

Fabrazyme 5mg and Fabrazyme 35mg

םושיר רפסמ

0

0

-

30313

-

94

-

24

1

00

-

31079

-

99

-

131

םושירה לעב םש

__

יפונאס

-

לארשי סיטנווא

__________

________________

ה טורפל דעוימ הז ספוט דבלב תורמחה

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

4.1 Therapeutic

indications

ןמוסמ הרמחה הווהמו ףסוותהש עדימ

ב

בוהצ

,

לש אלמ עדימ :)אלמה ןולעב אוצמל ןתינ הז ףיעס

Fabrazyme is indicated in adults, children

and adolescents aged 8 years and older

4.2

Posology and

method of

administration

ןמוסמ הרמחה הווהמו ףסוותהש עדימ

ב

בוהצ

,

לש אלמ עדימ :)אלמה ןולעב אוצמל ןתינ הז ףיעס

Paediatric population

The safety and efficacy of Fabrazyme in

children aged 0

years have not yet been

established. Currently available data are

described in sections 5.1 and 5.2 but no

recommendation on posology can be made in

children aged 5 to 7 years. No data are

available in children 0 to 4 years

4.8 Undesirable

effects

מ

ןמוסמ הרמחה הווהמו ףסוותהש עדי

ב

בוהצ

,

לש אלמ עדימ :)אלמה ןולעב אוצמל ןתינ הז ףיעס

Limited information from clinical trials

suggests that the safety profile of Fabrazyme

treatment in paediatric patients ages 5-7,

treated with either 0.5 mg/kg every 2 weeks

or 1.0 mg/kg every 4 weeks is similar to that

of patients (above the age of 7) treated at

1.0 mg/kg every 2 weeks.

5.1

Pharmacodynamic

properties

In an additional 5-year open-label paediatric

study, 31 male patients aged 5 to 18 years

were randomized prior to the onset of

clinical symptoms involving major organs

and treated with two lower dose regimens

of agalsidase beta, 0.5 mg/kg every 2 weeks

or 1.0 mg/kg every 4 weeks. Results were

similar between the two treatment groups.

Superficial skin capillary endothelium GL-3

scores were reduced to zero or maintained

at zero at all time points post-baseline upon

treatment in 19/27 patients completing the

study without a dose increase. Both baseline

and 5-year kidney biopsies were obtained in

a subset of 6 patients: in all, kidney capillary

endothelium GL-3 scores were reduced to

zero but highly variable effects were

observed in podocyte GL-3, with a reduction

in 3 patients. Ten (10) patients met per

protocol dose increase criteria, two (2) had a

dose increase to the recommended dose of

1.0 mg/kg every 2 weeks.

5.2 Pharmacokinetic

properties

In another study with 30 paediatric patients

with available pharmacokinetics data, aged 5

to 18 years, treated with two lower dose

regimens of 0.5 mg/kg every 2 weeks and

1.0 mg/kg every 4 weeks, mean CL was 4.6

and 2.3 ml/min/kg, respectively, mean Vss

was 0.27 and 0.22 l/kg, respectively, and

mean elimination half-life was 88 and 107

minutes, respectively. After IgG

seroconversion, there was no apparent

change in CL (+24% and +6%, resp.), while

Vss was 1.8 and 2.2 fold higher, with the net

effect being a small decrease in C

(up to -

34% and -11%, resp.) and no change in AUC

(-19% and -6%, resp

העדוה העדוה

לע לע

הרמחה הרמחה

(

(

עדימ עדימ

)תוחיטב )תוחיטב :ךיראת

4.6.2012

םש

רישכת

:תילגנאב

Fabrazyme 5mg & Fabrazyme 35mg

רפסמ

:םושיר

Fabrazyme 5 : 131-99-31079-00

Fabrazyme 35 : 124-94-30313-00

םש

לעב

:םושירה

Genzyme Israel Ltd

.

םייונישה

ןולעב

םינמוסמ

לע

עקר

בוהצ ןולעב ןולעב

אפור אפור םיטרפ

לע

םי/יונישה

םי/שקובמה קרפ

ןולעב טסקט

יחכונ טסקט

שדח

2

.

QUALITATIVE

AND

QUANTITATIV

E

COMPOSITION

Each vial of Fabrazyme 5 mg 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).

Each vial of Fabrazyme 35

mg

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

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

-galactosidase.

For excipients, see section 6.1.

Each vial of Fabrazyme 5 mg 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).

Each vial of Fabrazyme 35

mg

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

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

-galactosidase.

For the full list of excipients, see section 6.1.

3.

PHARMAC

EUTICAL

FORM

Powder for concentrate for solution for

infusion.

Powder for concentrate for solution for infusion.

White to off-white lyophilised cake or powder.

Green = text moved without

any changes

Blue

new text added

= old text removed

קרפ

ןולעב טסקט

יחכונ טסקט

שדח

4.2

Posology

and

method

of

administr

ation

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.

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.

Fabrazyme treatment should be supervised by a

physician experienced in the management of patients

with Fabry Disease or other inherited metabolic

diseases.

Posology

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.

Infusion of Fabrazyme at home may be considered for

patients who are tolerating their infusions well. The

decision to have a patient move to home infusion

should be made after evaluation and recommendation

by the treating physician. Patients experiencing adverse

events during the home infusion need to immediately

stop the infusion process and seek the attention of a

healthcare professional. Subsequent infusions may

need to occur in a clinical setting. Dose and infusion

rate should remain constant while at home, and not be

changed without supervision of a healthcare

professional.

Special populations

Patients with renal impairment

No dose adjustment is necessary for patients with renal

insufficiency.

Patients with hepatic impairment

Studies in patients with hepatic insufficiency have not

been performed.

Elderly patients

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.

Paediatric population

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

The safety and efficacy of Fabrazyme in

children below the age of 16 years and in

patients older than 65 years have not been

established and no dosage regimen can

presently be recommended in these patients.

efficacy have not yet been established. No dose

adjustment is necessary for children 8-16 years.

The safety and efficacy of Fabrazyme in children

below the age of 16 years and in patients older than 65

years have not been established and no dosage regimen

can presently be recommended in these patients.

Method of administration

For instructions on reconstitution and dilution of the

medicinal product before administration, see

section 6.6.

4.3

Contra

indication

s

Life threatening hypersensitivity

(anaphylactic reaction) to the active

substance or any of the excipients.

Life threatening hypersensitivity (anaphylactic

reaction) to the active substance or any of the

excipients listed in section 6.1.

4.4

Special

warnings

and

special

precaution

s for use

Almost all patients are expected to developed

IgG antibodies to agalsidase beta using the

advised starting dose, mostly within 3

months of initiation of treatment.

After up to 2 years of therapy, 63% of

patients who were antibody positive show a

significant reduction in antibody titer over

time.

The remaining 37% of patients demonstrated

a plateau in their antibody titer.

In a limited number of patients IgE

antibodies were demonstrated. Two of these

patients were subsequently rechallenged

uneventfully with Fabrazyme and continue to

receive treatment.

Patients with antibodies to agalsidase beta

have a higher risk of infusion-associated

reactions defined as any related adverse

event occurring during the infusion or until

the end of the infusion day (See section 4.8).

These patients should be treated with caution

when re-administering agalsidase beta.

Immunogenicity

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 Almost all patients are expected to

developed IgG antibodies to agalsidase beta using the

advised starting dose, mostly within

3 months of

initiation of treatment

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 radioimmuno¬precipitation (RIP)

assays) (14% of the patients) or demonstrated a plateau

(35% of the patients).

After up to 2 years of therapy, 63% of patients who

were antibody positive show a significant reduction in

antibody titer over time.

The remaining 37% of patients demonstrated a plateau

in their antibody titer.

In a limited number of patients IgE antibodies were

demonstrated. Two of these patients were subsequently

rechallenged uneventfully with Fabrazyme and

continue to receive treatment.

Patients with antibodies to agalsidase beta have a

higher risk of infusion-associated reactions defined as

any related adverse event occurring during the infusion

or until the end of the infusion day (See section 4.8).

These patients should be treated with caution when re-

administering agalsidase beta.

Initially, approximately half of the patients experienced

Initially, approximately half of the patients

experienced infusion-associated reactions

(See section 4.8). In the phase 3 clinical

study and its extension, infusion-associated

reactions were managed by slowing the rate

of infusion and by pre-treating the patients

with antihistamines, paracetamol, ibuprofen

and/or corticosteroids.

As with any intravenous protein product,

allergic-type hypersensitivity reactions are

possible.

Patients experiencing mild or moderate

hypersensitivity reactions when treated with

agalsidase beta during clinical trials have

continued therapy after a reduction in the

rate of infusion (~0.15 mg/min; 10 mg/hr)

and pre-treatment with antihistamines,

paracetamol, ibuprofen and/or

corticosteroids.

A small number of patients has 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 an

appropriate treatment has to be initiated. The

current medical standards for emergency

treatment are to be observed.

Studies have not been conducted to assess

the potential effects of Fabrazyme on

impairment of fertility.

infusion-associated reactions (See section 4.8). In the

phase 3 clinical study and its extension, infusion-

associated reactions were managed by slowing the rate

of infusion and by pre-treating the patients with

antihistamines, paracetamol, ibuprofen and/or

corticosteroids.

As with any intravenous protein product, allergic-type

hypersensitivity reactions are possible.

Patients experiencing mild or moderate hypersensitivity

reactions when treated with agalsidase beta during

clinical trials have continued therapy after a reduction

in the rate of infusion (~0.15 mg/min; 10 mg/hr) and

pre-treatment with antihistamines, paracetamol,

ibuprofen and/or corticosteroids.

A small number of patients has 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 an appropriate

treatment has to be initiated. The current medical

standards for emergency treatment are to be observed.

Studies have not been conducted to assess the potential

effects of Fabrazyme on impairment of fertility.

Infusion associated reactions

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.

Hypersensitivity

As with any intravenous protein medicinal product,

allergic-type hypersensitivity reactions are possible.

A small number of patients have experienced reactions

suggestive of immediate (Type I) hypersensitivity. If

The effect of Fabrazyme treatment on the

kidneys may be limited in patients with

advanced renal disease.

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.

Patients with advanced renal disease

The effect of Fabrazyme treatment on the kidneys may

be limited in patients with advanced renal disease.

4.5

Interaction

with other

medicinal

products

and other

forms of

interactio

n

No in vitro metabolism studies have been

carried out . 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

-galactosidase

activity.

No interaction studies and no in vitro metabolism

studies have been carried out 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

galactosidase activity.

4.6 Pregnancy

and

lactation

4.6

Pregnancy and lactation

There are no adequate data from the use of

agalsidase beta in pregnant women.

Animal studies do not indicate direct or

indirect harmful effects on embryonal/foetal

development (See section 5.3).

Fabrazyme should not be used during

pregnancy unless clearly necessary.

Breast-feeding

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

nursing when Fabrazyme is used.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of agalsidase

beta in pregnant women.

Animal studies do not indicate direct or indirect

harmful effects on with respect to embryonal/foetal

development (See section 5.3).

Fabrazyme should not be used during pregnancy unless

clearly necessary.

Breast-feeding

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 nursing when Fabrazyme is used.

Fertility

Studies have not been conducted to assess the potential

effects of Fabrazyme on impairment of fertility.

4.7 Effects on

ability

to drive

and use

machine

s

No studies on the ability to drive and use

machines have been conducted with

Fabrazyme.

No studies on the ability to drive and use machines

have been conducted with Fabrazyme.

Fabrazyme may have a minor influence on the ability

to drive or use machines on the day of Fabrazyme

administration because dizziness, somnolence, vertigo

and syncope may occur (see section 4.8).

4.8

Undesir

able

effects

Adverse drug reactions (ADRs) reported to

be related to Fabrazyme administered at a

dose of 1mg/kg in a total of 58 patients

treated up to 12 months are listed by system

organ class and frequency (very common: >

10%, common: 5-10%) in the table below.

ADRs were mostly mild to moderate in

severity:

Summary of the safety profile

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.

Patients with antibodies to r-hαGAL have a greater

potential to experience infusion-associated reactions

(IARs). Reactions suggestive of immediate (Type I)

hypersensitivity have been reported in a small number

of patients (see section 4.4).

Very common adverse reactions included chills,

pyrexia, feeling cold, nausea, vomiting, headache and

paraesthesia. Sixty seven percent (67%) of the patients

experienced at least one infusion-associated reaction.

Anaphylactoid reactions have been reported in the

postmarketing setting.

Tabulated list of adverse reactions

Adverse reactions reported from clinical trials with a

total of 168 patients (154 males and 14 females) treated

with Fabrazyme administered at a dose of 1 mg/kg

every 2 weeks 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 adverse reaction in a

single patient is defined as uncommon in light of the

relatively small number of patients treated. Adverse

reactions only reported during the Post Marketing

period are also included in the table below at a

frequency category of “not known” (cannot be

estimated from the available data). Adverse reactions

were mostly mild to moderate in severity:

For detailed current table with ADRs per System

Organ Class and Frequency - see Attachment 1

For detailed marked & updated table ADRs per System

Organ Class and Frequency - see Attachment 2

Description of selected adverse reactions

Infusion associated reactions

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

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).

Initially, approximately half of the patients

experienced infusion-associated reactions.

These reactions consisted most often of

fever/chills. Additional symptoms included

mild to moderate dyspnoea, throat tightness,

chest tightness, flushing, pruritus, urticaria,

face oedema, angioneurotic oedema, rhinitis,

bronchial constriction, tachypnea and/or

wheezing, moderate 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 rate of

infusion together with the administration of

non-steroidal anti-inflammatory medicinal

products, antihistamines and/or

corticosteroids. After up to 2 years less than

37% of the patients experienced infusion-

associated reactions. 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. Two of

these patients were subsequently

rechallenged uneventfully with Fabrazyme

and continue to receive treatment.

Initially, approximately half of the patients experienced

infusion-associated reactions. These reactions consisted

most often of fever/chills. Additional symptoms

included mild to moderate dyspnoea, throat tightness,

chest tightness, flushing, pruritus, urticaria, face

oedema, angioneurotic oedema, rhinitis, bronchial

constriction, tachypnea and/or wheezing, moderate

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 rate of infusion together with the

administration of non-steroidal anti-inflammatory

medicinal products, antihistamines and/or

corticosteroids. After up to 2 years less than 37% of the

patients experienced infusion-associated reactions. 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. Two of these patients

were subsequently rechallenged uneventfully with

Fabrazyme and continue to receive treatment.

Paediatric population

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.

4.9

Overdose

No case of overdose has been reported. In

clinical trials doses up to 3mg/kg body

weight were used.

No case of overdose has been reported. In clinical trials

doses up to 3mg/kg body weight were used.

5.1

Pharma

codyna

mic

properti

es

Pharmacotherapeutic group: Alimentary tract

and metabolism products – enzymes.

ATC code: A16AB04 agalsidase beta.

Fabry disease is a heterogeneous and

multisystemic disorder , that affects both

males and females. It is characterised by the

deficiency of

-galactosidase. Reduced or

absent

-galactosidase activity results in the

accumulation of GL-3 in many cell types

Pharmacotherapeutic group: Other alimentary tract and

metabolism products – enzymes.

ATC code: A16AB04 agalsidase beta.

Fabry disease

Fabry disease is an inherited a heterogeneous and

multisystemic disorder progressive disease , that affects

both males and females. It is characterised by the

deficiency of

-galactosidase. Reduced or absent

galactosidase activity results in the accumulation of

GL-3 in the lysosomes of many cell types including

including the endothelial and parenchymal

cells, ultimately leading to life-threatening

clinical deteriorations as a result of renal,

cardiac and cerebrovascular complications.

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……

Mechanism of action

The rationale for enzyme replacement therapy

is…….

Clinical efficacy and safety

Efficacy and safety of Fabrazyme was

evaluated in, one dose-finding study, and two

double-blind placebo-controlled studies, 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).

These results were confirmed by an interim

analysis of an open label extension of the

placebo controlled trial in which patients

from both randomisation groups were

scheduled to receive Fabrazyme for an

additional 18 months. Clearance of GL-3 in

the vascular endothelium of the kidney was

achieved in 98% of the 48 patients for whom

information is available. The average renal

function, as measured by glomerular

filtration rate and serum creatinine, remained

stable during two years of agalsidase beta

treatment.

Clinical efficacy and safety

Efficacy and safety of Fabrazyme was evaluated in one

study with children, one dose-finding study, and two

double-blind placebo-controlled studies, and one open-

label extensive 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.

These results were confirmed by an interim analysis

of an open label extension of the placebo controlled

trial in which patients from both randomisation groups

were scheduled to receive Fabrazyme for an additional

18 months. Clearance of GL-3 in the vascular

endothelium of the kidney was achieved in 98% of the

48 patients for whom information is available. The

average renal function, as measured by glomerular

filtration rate and serum creatinine, remained stable

during two years of agalsidase beta treatment.

Although improvement in the pain score was seen in

the first six months, this was seen both in the placebo

and active treated groups. Quality of life scores

Although improvement in the pain score was

seen in the first six months, this was seen

both in the placebo and active treated groups.

Quality of life scores improved numerically

but not statistically during treatment over a

period for up to two years. Therefore, no

conclusions on the effect of enzyme

replacement therapy on pain and quality of

life can be drawn at this time. No systematic

studies have been conducted to assess the

effect of replacement therapy on the

neurological signs and symptoms of the

disease.

Plasma GL-3 levels rapidly normalised with

treatment.

Another double-blind, placebo-controlled

study of 82 patients was conducted 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 may be critical to achieve the best

outcomes.

improved numerically but not statistically during

treatment over a period for up to two years. Therefore,

no conclusions on the effect of enzyme replacement

therapy on pain and quality of life can be drawn at this

time. No systematic studies have been conducted to

assess the effect of replacement therapy on the

neurological signs and symptoms of the disease.

Plasma GL-3 levels rapidly normalised with treatment.

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.

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 conducted 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 may

be critical to achieve the best outcomes.

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.

In the postmarketing setting, experience was gained in

patients who initiated treatment at a dose of 1 mg/kg

every 2 weeks and subsequently received a reduced

dose for an extended period. In some of these patients,

an increase of some of the following symptoms was

spontaneously reported: pain, paraesthesia and

diarrhoea, as well as cardiac, central nervous system

and renal manifestations. These reported symptoms

resemble the natural course of Fabry disease.

Paediatric population

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.

5.2

Pharma

cokineti

c

properti

es

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 with an infusion time of ca.

300 minutes and at a dose of 1 mg/kg body

weight, biweekly, mean C

plasma

concentrations ranged from 2000 –3500 ng/

ml, while the AUC

ranged from 370-

g.min/ml. Vss ranged from 0.12-0.57 l/

kg , plasma clearance from 1.7-

4.9 ml/min/kg and the mean elimination half-

life from 80-120 minutes.

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 in a

clinically significant way. Renal elimination

of agalsidase beta is considered to be a minor

pathway for clearance.

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

with an infusion time of ca. approximately 300 minutes

and at a dose of 1 mg/kg body weight, biweekly, mean

plasma concentrations ranged from 2000 –

3500 ng/ml, while the AUC

ranged from 370-

g.min/ml. Vss ranged from 0.12-0.57 l/kg 8.3-

40.8 l , plasma clearance from 1.7-4.9 119-345ml/min/

kg and the mean elimination half-life from 80-120

minutes.

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 in a

clinically significant way. Renal elimination of

agalsidase beta is considered to be a minor pathway for

clearance.

Paediatric population

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

. No unexpected safety issues were

encountered in patients with an increase in exposure

after seroconversion.

5.3

Preclinic

al safety

data

Preclinical 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.

Preclinical 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.

6.3

Shelf life

2 years.

2 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

6.4

Special

precauti

ons for

storage

Store at 2

C – 8

C (in a refrigerator).

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 and would not be longer than 24

hours at 2

Store at 2

C – 8

C (in a refrigerator).

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 and would not be longer than

24 hours at 2

For storage conditions after reconstitution and dilution

of the medicinal product, see section 6.3.

6.6

Instructions

for use and

handling, and

disposal

6.6

Special precautions for disposal and other

handling

Instructions for use and handling, and

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.

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.

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

Each vial of Fabrazyme is intended for single

use only.

Use Aseptic Technique

Reconstitution

only.

Use Aseptic Technique

Reconstitution

Fabrazyme 5 mg

Reconstitute each vial of Fabrazyme 5

mg with 1.1

ml water for injections

; avoid

forceful impact

of water for injections on the powder

and avoid foaming of the solution by mixing

gently.

The reconstituted volume contains 5 mg

enzyme /ml, and appears as a

clear colourless solution. The pH of the

reconstituted solution is approximately 7.0.

Fabrazyme 35 mg

Reconstitute each vial of Fabrazyme 35

mg with 7.2

ml water for injections

; avoid

forceful

impact of water for injections on the

powder and avoid foaming of the solution by

mixing gently.

The reconstituted volume is 7.4 ml

containing 5 mg enzyme/ ml, and appears as

a clear colourless solution. The pH of the

reconstituted solution is approximately 7.0.

2. Fabrazyme 5 mg

Reconstitute each vial of Fabrazyme 5 mg with

ml water for injections

; avoid forceful impact

of water for injections on the powder and avoid

foaming of the solution by mixing gently.

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.

The reconstituted volume solution contains 5 mg

enzyme agalsidase beta per ml, and appears as a clear

colourless solution. The pH of the reconstituted

solution is approximately 7.0.

Fabrazyme 35 mg

Reconstitute each vial of Fabrazyme 35 mg with

ml water for injections

; avoid forceful

impact of water for injections on the powder and

avoid foaming of the solution by mixing gently.

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.

The reconstituted volume is 7.4 ml containing solution

contains 5 mg enzyme 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 vials exhibiting particulates or

discoloration.

3. Before further dilution, visually inspect the

reconstituted solution in each vial for particulate

matter and discoloration. Do not use vials exhibiting

particulates or discoloration.the solution if foreign

particles are observed or if the solution is discoloured.

After reconstitution it is recommended to

promptly dilute the vials.

4. After reconstitution it is recommended to promptly

dilute the vials, to minimise protein particle

formation over time.

Any unused product or waste material should

be disposed of in accordance with local

requirements.

5. Any unused product or waste material should be

disposed of in accordance with local requirements.

Dilution

Dilution

The reconstituted solution contains 5 mg

agalsidase beta per ml.

Withdraw 1.0 ml (equal to 5 mg) from the

Fabrazyme 5 mg vial, or 7.0 ml (equal to

35 mg) from the Fabrazyme 35 mg vial of

the reconstituted solution from each vial and

combine the withdrawn volumes. Then dilute

the combined volumes with 0.9% sodium

chloride intravenous solution to a

recommended final volume of 500 ml. Mix

the infusion solution gently.

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. The reconstituted solution contains 5 mg agalsidase

beta per ml.

Fabrazyme 5 mg

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.

Fabrazyme 35 mg

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.

The reconstituted solution contains 5 mg agalsidase

beta per ml.

Withdraw 1.0

(equal to 5 mg) from the Fabrazyme

5 mg vial, or 7.0

(equal to 35 mg) from the

Fabrazyme 35 mg vial of the reconstituted solution

from each vial and combine the withdrawn volumes.

Then dilute the combined volumes with 0.9% sodium

chloride intravenous solution to a recommended final

volume of 500 ml. Mix the infusion solution gently.

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

Administration

The initial infusion rate should be no more

than 0.25 mg/min (15 mg/hour) to minimise

the potential occurrence of infusion-

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

associated reactions. After patient tolerance

is established, the infusion rate may be

increased gradually with subsequent

infusions.

occurrence of infusion-associated reactions. After

patient tolerance is established, the infusion rate may

be increased gradually with subsequent infusions.

Attachment 1

Current table with Adverse Drug Reactions (ADRs) listed by System organ class and frequency

Adverse drug reactions (ADRs) reported to be related to Fabrazyme administered at a dose of 1mg/kg in a total

of 58 patients treated up to 12 months are listed by system organ class and frequency (very common: > 10%,

common: 5-10%) in the table below. ADRs were mostly mild to moderate in severity:

Nervous system disorders

Very common:

Headache, tremor

Common:

Paraesthesia, dizziness, somnolence

Eye disorders

Common:

Vision abnormal, lacrimation abnormal

Cardiac disorders

Common:

Tachycardia, bradycardia

Vascular disorders

Very common:

Hypertension

Common:

Flushing, pallor

Respiratory, thoracic and mediastinal disorders

Very common

Rhinitis, dyspnoea

Common

Bronchospasm, throat tightness

Gastrointestinal disorders

Very common:

Nausea, vomiting

Common:

Abdominal pain

Skin and subcutaneous tissue disorders

Common:

Pruritus

Musculoskeletal and connective tissue disorders

Very common:

Myalgia, pain at the extremities

Common:

Back pain, leg pain

Renal and urinary disorders

Common:

Albuminuria

General disorders and administration site conditions

Very common:

Rigors, temperature changed sensation, fever, oedema of

the extremities

Common:

Chest pain, fatigue, pain, asthenia, malaise

Adverse drug reactions (ADRs) reported to be related to Fabrazyme administered at a dose of 1mg/kg in a total

of 58 patients treated up to 12 months are listed by system organ class and frequency (very common: > 10%,

common: 5-10%) in the table below. ADRs were mostly mild to moderate in severity:

Nervous system disorders

Very common:

Headache, tremor

Common:

Paraesthesia, dizziness, somnolence

Eye disorders

Common:

Vision abnormal, lacrimation abnormal

Cardiac disorders

Common:

Tachycardia, bradycardia

Vascular disorders

Very common:

Hypertension

Common:

Flushing, pallor

Respiratory, thoracic and mediastinal disorders

Very common

Rhinitis, dyspnoea

Common

Bronchospasm, throat tightness

Gastrointestinal disorders

Very common:

Nausea, vomiting

Common:

Abdominal pain

Skin and subcutaneous tissue disorders

Common:

Pruritus

Musculoskeletal and connective tissue disorders

Very common:

Myalgia, pain at the extremities

Common:

Back pain, leg pain

Renal and urinary disorders

Common:

Albuminuria

General disorders and administration site conditions

Very common:

Rigors, temperature changed sensation, fever, oedema of

the extremities

Common:

Chest pain, fatigue, pain, asthenia, malaise

Attachment 2

Proposed Table with Adverse Drug Reactions (ADRs) listed by System

organ class and frequency

System organ

class

Very common

Common

Uncommon

Not known

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

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

For the purpose of this table, ≥1% is defined as reactions occurring in 2 or more patients.

Adverse reaction terminology is based upon the Medical Dictionary for Regulatory Activities (MedDRA)

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