NAGLAZYME

Israel - English - Ministry of Health

Buy It Now

Active ingredient:
GALSULFASE
Available from:
MEDISON PHARMA LTD
ATC code:
A16AB08
Pharmaceutical form:
CONCENTRATE FOR SOLUTION FOR INFUSION
Composition:
GALSULFASE 1 MG/ML
Administration route:
I.V
Prescription type:
Required
Manufactured by:
BIOMARIN PHARMACEUTICAL INC, USA
Therapeutic group:
GALSULFASE
Therapeutic area:
GALSULFASE
Therapeutic indications:
Naglazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed diagnosis of MPSVI (N-acetylglactosamine 4 sulfatase deficiency Maroteaux-Lamy syndrome).
Authorization number:
143 48 31767 00
Authorization date:
2015-04-30

אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה אפורל ןולעב )תוחיטב עדימ ( הרמחה לע העדוה ןכדועמ( ןכדועמ(

05.2013

05.2013

)

)

________ ךיראת

_

04.2015

_____

____________

םושירה רפסמו תילגנאב רישכת םש

143-48-3176-700

_

Reg .No:

__

NAGLAZYME

____

_______________ םושירה לעב םש

Medison Pharma Ltd

_____________________

! דבלב תורמחהה טורפל דעוימ הז ספוט תושקובמה תורמחהה ןולעב קרפ יחכונ טסקט שדח טסקט

Excipients

Each 5 ml vial contains 0.8 mmol (18.4 mg) of sodium

Therapeutic

indications

Naglazyme is indicated for long-term enzyme

replacement therapy in patients with a confirmed

diagnosis of Mucopolysaccharidosis VI (MPS VI; N-

acetylgalactosamine 4-sulfatase deficiency;

Maroteaux-Lamy syndrome) (see section 5.1).

Naglazyme is indicated for long-term enzyme replacement

therapy in patients with a confirmed diagnosis of

Mucopolysaccharidosis VI (MPS VI; N-acetylgalactosamine 4-

sulfatase deficiency; Maroteaux-Lamy syndrome) (see

section 5.1).

A key issue is to treat children aged <5 years suffering from a severe form

of the disease, even though children <5 years were not included in the

pivotal phase 3 study. Limited data are available in patients < 1 year of age

(see section 5.1).

Posology and

method of

administration

Naglazyme treatment should be supervised by a

physician experienced in the management of

patients with MPS VI or other inherited metabolic

diseases. Administration of Naglazyme should be

carried out in an appropriate clinical setting

where resuscitation equipment to manage

medical emergencies would be readily available.

The recommended dosage regimen for galsulfase

is 1 mg/kg body weight administered once every

week as an intravenous infusion over 4 hours.

The initial infusion rate is adjusted so that

approximately 2.5% of the total solution is

infused during the first hour, with infusion of the

remaining volume (approximately 97.5%) over

the next 3 hours. For information on pre-

treatment see section 4.4 and for further

As for all lysosomal genetic disorders, it is of primary importance,

especially in severe forms, to initiate treatment as early as possible, before

appearance of non-reversible clinical manifestations of the disease.

Naglazyme treatment should be supervised by a physician experienced in

the management of patients with MPS VI or other inherited metabolic

diseases. Administration of Naglazyme should be carried out in an

appropriate clinical setting where resuscitation equipment to manage

medical emergencies would be readily available.

Posology

The recommended dose regimen for galsulfase is 1 mg/kg body weight

administered once every week as an intravenous infusion over 4 hours.

Special populations

Elderly

The safety and efficacy of Naglazyme in patients older than 65 years has

not been established, and no alternative dose regimen can be recommended

in these patients.

Renal and hepatic impairment

The safety and efficacy of Naglazyme in patients with renal or hepatic

instructions see section 6.6.

insufficiency have not been evaluated (see section 5.2) and no alternative

dose regimen can be recommended in these patients.

Paediatric population

There is no evidence for special considerations when Naglazyme is

administered to the paediatric population. Currently available data are

described in section 5.1.

Method of administration

The initial infusion rate is adjusted so that approximately 2.5% of the total

solution is infused during the first hour, with infusion of the remaining

volume (approximately 97.5%) over the next 3 hours.

100 ml infusion bags should be considered for patients who are susceptible

to fluid volume overload and weigh less than 20 kg; in this case the infusion

rate (ml/min) should be decreased so that the total duration remains no less

than 4 hours.

Contraindications

Hypersensitivity to the active substance or to any

of the excipients.

Severe or life-threatening hypersensitivity to the active substance or to any

of the excipients, if hypersensitivity is not controllable.

Special warnings

and precautions for

use

Caution must be exercised in the management

and treatment of patients with compromised

airways by limitation or careful monitoring of

antihistamine and other sedative medication use.

Institution of positive–airway pressure during

sleep as well as potential tracheostomy in

clinically appropriate situations should also be

considered.

Consider delaying Naglazyme infusions in

patients who present with an acute febrile or

respiratory illness.

The safety and efficacy of Naglazyme in children

below the age of 5 years and in patients older

than 65 years have not been established.

The safety and efficacy of Naglazyme in patients

with renal or hepatic insufficiency have not been

evaluated (see section 5.2).

Patients treated with Naglazyme have developed

infusion-associated reactions (IARs), defined as

any drug-related adverse event occurring during

the infusion or until the end of the infusion day

(see section 4.8).

Based on data obtained during Naglazyme clinical

trials, the majority of patients are expected to

develop IgG antibodies to galsulfase within 4-8

weeks of treatment initiation. In the Naglazyme

clinical trials, IARs were usually manageable by

interrupting or slowing the rate of infusion and by

(pre-) treating the patient with antihistamines

and/or antipyretics (paracetamol), thus enabling

the patient to continue treatment.

As there is little experience on resumption of

treatment following prolonged interruption,

caution is to be used due to the theoretical

increased risk of hypersensitivity reaction.

With administration of Naglazyme it is

recommended that patients be administered pre-

treatment medications (antihistamines with or

Management of compromised airways

Caution must be exercised in the management and treatment of patients

with compromised airways by limitation or careful monitoring of

antihistamine and other sedative medicinal product use. Institution of

positive–airway pressure during sleep as well as potential tracheostomy in

clinically appropriate situations should also be considered.

Patients who present with an acute febrile or respiratory illness may need to

have their Naglazyme infusions delayed.

The safety and efficacy of Naglazyme in children below the

age of 5 years and in patients older than 65 years have not

been established.

The safety and efficacy of Naglazyme in patients with renal

or hepatic insufficiency have not been evaluated (see

section 5.2).

Management of infusion-associated reactions

Patients treated with Naglazyme have developed infusion-associated

reactions (IARs), defined as any adverse reactions occurring during the

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

Based on data obtained during Naglazyme clinical trials, the majority of

patients are expected to develop IgG antibodies to galsulfase within

4-8 weeks of treatment initiation.

In the Naglazyme clinical trials, IARs were usually manageable by

interrupting or slowing the rate of infusion and by (pre-) treating the patient

with antihistamines and/or antipyretics (paracetamol), thus enabling the

patient to continue treatment.

As there is little experience on resumption of treatment following prolonged

interruption, caution is to be used due to the theoretical increased risk of

hypersensitivity reaction.

With administration of Naglazyme it is recommended that patients be

administered pre-treatment medicinal products (antihistamines with or

without antipyretics) approximately 30-60 minutes prior to the start of the

infusion, to minimise the potential occurrence of IARs.

In case of a mild or moderate IAR, treatment with antihistamines and

paracetamol should be considered and/or a reduction in the infusion rate to

half the rate at which the reaction occurred.

In case of a single severe IAR, the infusion should be stopped until the

symptoms are resolved and treatment with antihistamines and paracetamol

should be considered. The infusion can be restarted with a reduction of the

infusion rate to 50% – 25% of the rate at which the reaction occurred.

In case of a recurrent moderate IAR or re-challenge after a single severe

IAR, pre-treatment should be considered (antihistamines and paracetamol

without antipyretics) approximately 30-60

minutes prior to the start of the infusion, to

minimize the potential occurrence of IARs.

In case of a mild or moderate IAR, treatment with

antihistamines and paracetamol should be

considered and/or a reduction in the infusion rate

to half the rate at which the reaction occurred.

In case of a single severe IAR, the infusion should

be stopped until the symptoms are resolved and

treatment with antihistamines and paracetamol

should be considered. The infusion can be

restarted with a reduction of the infusion rate to

50% – 25% of the rate at which the reaction

occurred.

In case of a recurrent moderate IAR or re-

challenge after a single severe IAR, pre-treatment

should be considered (antihistamines and

paracetamol and/or corticosteroids) and a

reduction of the infusion rate to 50% – 25% of the

rate at which the previous reaction occurred.

As with any intravenous protein product, severe

allergic-type hypersensitivity reactions are

possible.

If these reactions occur, immediate

discontinuation of Naglazyme is recommended

and appropriate medical treatment should be

initiated. The current medical standards for

emergency treatment are to be observed.

and/or corticosteroids) and a reduction of the infusion rate to 50% – 25% of

the rate at which the previous reaction occurred.

As with any intravenous protein medicinal product, severe allergic-type

hypersensitivity reactions are possible. If these reactions occur, immediate

discontinuation of Naglazyme is recommended and appropriate medical

treatment should be initiated. The current medical standards for emergency

treatment are to be observed. In patients who have experienced allergic

reactions during infusion with Naglazyme, caution should be exercised

upon rechallenge; appropriately trained personnel and equipment for

emergency resuscitation (including epinephrine) should be available during

infusions. Severe, or potentially life-threatening hypersensitivity is a

contraindication to rechallenge, if hypersensitivity is not controllable. See

also section 4.3.

This medicinal product contains 0.8 mmol (18.4 mg) sodium per vial and is

administered in sodium chloride 9 mg/ml solution for injection (see section

6.6). To be taken into consideration by patients on a controlled sodium diet.

Spinal or cervical cord compression

Spinal/cervical cord compression (SCC) with resultant myelopathy is a

known and serious complication that can be due to MPS VI. There have

been post-marketing reports of patients treated with Naglazyme who

experienced the onset or worsening of SCC requiring decompression

surgery. Patients should be monitored for signs and symptoms of

spinal/cervical cord compression (including back pain, paralysis of limbs

below the level of compression, urinary and faecal incontinence) and given

appropriate clinical care.

Fertility, pregnancy

and lactation

For Naglazyme, no clinical data on exposed

pregnancies are available. Animal studies do not

indicate direct or indirect harmful effects with

respect to pregnancy or embryo-foetal

development (see section 5.3). Naglazyme should

not be used during pregnancy unless clearly

necessary.

It is not known whether galsulfase is excreted in

milk, therefore breast-feeding should be stopped

during Naglazyme treatment.

Pregnancy

For Naglazyme, no clinical data on exposed pregnancies are available.

Animal studies do not indicate direct or indirect harmful effects with

respect to pregnancy or embryo-foetal development (see section 5.3).

Naglazyme should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is not known whether galsulfase is excreted in milk, therefore breast-

feeding should be stopped during Naglazyme treatment.

Fertility

Reproduction studies have been performed in rats and rabbits at doses up to

3 mg/kg/day and have revealed no evidence of impaired fertility or harm to

the embryo or foetus due to Naglazyme.

Undesirable effects

All patients in the Phase 3 clinical study

experienced Adverse Drug Reactions (ADRs),

regardless of whether they were receiving

Naglazyme or placebo.

ADRs reported during the Phase 3 study, in 39

patients treated up to 6 months, are listed in the

table below by Body System. The ADRs are listed

following the recommended frequency

convention.

Very common adverse events are those with a

frequency of more than 1 in 10. Common events

have a frequency of more than 1 in 100. One

case of sleep apnoea was experienced during this

study.

Within each frequency grouping, undesirable

effects are presented in order of decreasing

seriousness.

Table 1: Number and percentage of patients

with selected adverse events in the placebo

controlled study

MedDRA System

Organ Class

MedDRA

Preferred Term

Frequency

Infections &

Infestations

Pharyngitis

Common

Gastroenteritis

Common

Nervous system

disorders

Areflexia

Common

Eye Disorders

Conjunctivitis

Common

Corneal opacity

Common

Ear & Labyrinth

Disorders

Ear pain

Very common

Vascular Disorders

Hypertension

Common

Respiratory,

Thoracic, &

Mediastinal

Disorders

Dyspnoea

Very common

Apnoea

Common

Nasal congestion

Common)

Gastrointestinal

Disorders

Abdominal pain

Very common

Umbilical hernia

Common

Skin &

Subcutaneous

Tissue Disorders

Face oedema

Common

General Disorders

& Administration

Site Conditions

Pain

Very common

Chest pain

Common

Rigors

Common

Malaise

Common

Infusion reactions, characterized by a recurring

pattern of symptoms occurring during

Naglazymen infusion, were observed in 30 (56%)

of the 54 patients treated with Naglazyme across

all clinical studies. Reactions began as early as

Week 6 and as late as Week 55 of study drug

treatment, and occurred during multiple infusions

though not always in consecutive weeks. The

most common symptoms of these infusion

reactions included fever, chills/rigors, rash, and

urticaria, although

Due to the low number of patients in clinical trials, adverse event (AE) data

from all Naglazyme studies have been pooled and reviewed in a single,

clinical trial safety analysis.

All patients treated with NAGLAZYME (59/59) reported at least one AE.

The majority (42/59; 71%) of patients experienced at least one Adverse

Drug Reaction. The most common adverse reactions were pyrexia, rash,

pruritus, urticaria, chills/rigors, nausea, headache, abdominal pain, vomiting

and dypsnoea. Serious adverse reactions included laryngeal edema, apnoea,

pyrexia, urticaria, respiratory distress, angioedema, asthma and

anaphylactoid reaction.

Infusion reactions, defined as adverse reactions occurring during

Naglazyme infusions or until the end of the infusion day, were observed in

33 (56%) of the 59 patients treated with Naglazyme across five clinical

studies. Infusion reactions began as early as Week 1 and as late as Week

146 of Naglazyme treatment, and occurred during multiple infusions though

not always in consecutive weeks. Very common symptoms of these

infusion reactions were pyrexia, chills/rigors, rash, urticaria and dyspnoea.

Common symptoms of infusion reactions were pruritus, vomiting,

abdominal pain, nausea, hypertension, headache, chest pain, erythema,

cough, hypotension, angioedema, respiratory distress, tremor,

conjunctivitis, malaise, bronchospasm and arthralgia.

Adverse reactions are listed in Table 1 by System Organ Class.

The reactions are listed following the MedDRA frequency convention. Very

common adverse reactions are those with a frequency of

1/10. Common

reactions have a frequency of

1/100 to <1/10. Due to the small patient

population, an adverse reaction in a single patient is classified as common.

Within each frequency grouping, adverse reactions are presented in order of

decreasing seriousness.

Adverse reactions reported during the Post Marketing period are included at

a frequency category of “unknown”.

Overall, one case of sleep apnoea was experienced from all clinical studies.

hypotension, nausea, vomiting, dyspnoea,

bronchospasm, retrosternal pain, abdominal pain,

headache, malaise, respiratory stress,

angioneurotic oedema and joint pain were also

reported.

52/54 patients (96%) treated with Naglazyme

across studies were positive for antibodies to

galsulfase.

The clinical significance of antibodies to

galsulfase is not known.

Table 1: Frequency of adverse drug reactions with Naglazyme

MedDRA

System Organ Class

MedDRA

Preferred Term

Frequency

Immune system disorders

Anaphylaxis, shock

Unknown

Infections and infestations

Pharyngitis

, gastroenteritis

Very common

Nervous system disorders

Areflexia

, headache

Very common

Tremor

Common

Paresthesia

Unknown

Eye disorders

Conjunctivitis

, corneal opacity

Very common

Cardiac disorders

Bradycardia, tachycardia, cyanosis

Unknown

Ear and labyrinth disorders

Ear pain

, hearing impaired

Very common

Vascular disorders

Hypertension

Very common

Hypotension

Common

Pallor

Unknown

Respiratory, thoracic, and

mediastinal disorders

Dyspnoea

, nasal congestion

Very common

Apnoea

, cough, respiratory distress,

asthma, bronchospasm

Common

Laryngeal oedema, hypoxia, tachypnoeaUnknown

Gastrointestinal disorders

Abdominal pain

, umbilical hernia

vomiting, nausea

Very common

Skin and subcutaneous tissue

disorders

Angioeodema

, rash

, urticaria, pruritus

Very Common

Erythema

Common

General disorders and administration

site conditions

Pain

, chest pain

, rigors

, malaise

pyrexia

Very Common

Musculoskeletal and Connective

Tissue Disorders

Arthralgia

Very common

Reactions reported more frequently in the active arm of the placebo-

controlled study than the placebo arm; frequency determined from 39

patients of the blinded Phase 3 study.

Other reactions with known frequency were reported from 59 patients

treated with Naglazyme from all five clinical trials.

Reactions of unknown frequency were reported post-marketing.

In four patients <1 year of age, the overall safety profile of a higher dose (2

mg/kg/week) did not differ in a clinically meaningful manner from that of

the recommended 1 mg/kg/week dose, and was consistent with the safety

profile of Naglazyme in older children.

Immunogenicity

Out of the 59 patients treated with Naglazyme in the clinical studies, 54

were tested for IgG antibodies. 53/54 patients (98%) were positive for IgG

antibodies to galsulfase.

A comprehensive antibody analysis based on data from three clinical

studies has been carried out in 48 patients.

Although a larger proportion of subjects with high total antibody titres

experienced recurrent infusion reactions, neither frequency nor severity

could be predicted based on the anti-galsulfase antibody titre. Likewise,

antibody development is not predictive of decreased efficacy although

subjects with limited response in endurance parameters or urinary

glycosaminoglycans (GAGs) tended to have higher peak anti-galsulfase

titres than those with good response.

Reporting of suspected adverse reactions

Any suspected adverse events should be reported to the

Ministry of Health according to the National Regulation by

using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.as

px?formType=AdversEffectMedic@moh.health.gov.il ) or by

email (adr@MOH.HEALTH.GOV.IL ).

Pharmacodynamic

properties

Pharmacotherapeutic group: Alimentary tract and

metabolism products - enzymes,

ATC code: A16AB

Following 24 weeks of therapy, Naglazyme-

treated patients experienced a 92 ± 40 m

improvement in the distance walked in 12

minutes relative to placebo-treated patients (p =

0.025). Treated patients experienced a 5.7 stair

per minute improvement in the 3 Minute Stair

Climb relative to placebo-treated patients.

Treated patients also experienced a mean

decrease in urinary glycosaminoglycan excretion

of 238 ± 17.8 μg/mg creatinine ± SE following 24

weeks of treatment relative to placebo-treated

patients. GAG results approached the normal

range for age in the Naglazyme treatment group.

Pharmacotherapeutic group: Other alimentary tract and metabolism

products, enzymes, ATC code: A16AB08

Following 24 weeks of therapy, Naglazyme-treated patients experienced a

92 ± 40 m improvement in the distance walked in 12 minutes relative to

placebo-treated patients (p = 0.025). Treated patients experienced a 5.7 stair

per minute improvement in the 3 Minute Stair Climb relative to placebo-

treated patients. Treated patients also experienced a mean decrease in

urinary glycosaminoglycan excretion of 238 ± 17.8 μg/mg creatinine (

Standard Error [SE]) following 24 weeks of treatment relative to placebo-

treated patients. GAG results approached the normal range for age in the

Naglazyme treatment group.

In an additional Phase 4, randomised, two-dose level study, four MPS VI

patients <1 year of age were treated at 1 or 2 mg/kg/week for 53 to 153

weeks.

Although limited by the very small number of patients that were enrolled, the

conclusions that can be drawn from this study are the following:

Treatment with Naglazyme showed improvement, or lack of worsening, of

facial dysmorphism. It did not prevent the progression of skeletal dysplasia

and development of hernias and did not prevent the progression of corneal

clouding. Growth rate remained normal over this limited follow-up period.

Improved hearing was noted in at least one ear for all four subjects. Urinary

GAG levels decreased by more than 70%, consistent with results in older

patients.

Shelf life

Unopened vials: 24 months.

Unopened vials: 3 years.

1.

NAME OF THE MEDICINAL PRODUCT

Naglazyme 1 mg/ml concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml of solution contains 1 mg galsulfase. One vial of 5 ml contains 5 mg galsulfase.

Galsulfase is a recombinant form of human N-acetylgalactosamine 4-sulfatase and is produced by

recombinant DNA technology using mammalian Chinese Hamster Ovary (CHO) cell culture.

Excipients

Each 5 ml vial contains 0.8 mmol (18.4 mg) of sodium.

For a full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion.

A clear to slightly opalescent, and colourless to pale yellow solution.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Naglazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed

diagnosis of Mucopolysaccharidosis VI (MPS VI; N-acetylgalactosamine 4-sulfatase deficiency;

Maroteaux-Lamy syndrome) (see section 5.1).

4.2

Posology and method of administration

A key issue is to treat children aged <5 years suffering from a severe form of the disease, even though

children <5 years were not included in the pivotal phase 3 study. Limited data are available in patients

< 1 year of age (see section 5.1).

As for all lysosomal genetic disorders, it is of primary importance, especially in severe forms, to

initiate treatment as early as possible, before appearance of non-reversible clinical manifestations of

the disease.

Naglazyme treatment should be supervised by a physician experienced in the management of patients

with MPS VI or other inherited metabolic diseases. Administration of Naglazyme should be carried

out in an appropriate clinical setting where resuscitation equipment to manage medical emergencies

would be readily available

.

Posology

The recommended dose regimen for galsulfase is 1 mg/kg body weight administered once every week

as an intravenous infusion over 4 hours.

Special populations

Elderly

The safety and efficacy of Naglazyme in patients older than 65 years has not been established, and no

alternative dose regimen can be recommended in these patients.

Renal and hepatic impairment

The safety and efficacy of Naglazyme in patients with renal or hepatic insufficiency have not been

evaluated (see section 5.2) and no alternative dose regimen can be recommended in these patients.

Paediatric population

There is no evidence for special considerations when Naglazyme is administered to the paediatric

population. Currently available data are described in section 5.1.

Method of administration

The initial infusion rate is adjusted so that approximately 2.5% of the total solution is infused during

the first hour, with infusion of the remaining volume (approximately 97.5%) over the next 3 hours.

100 ml infusion bags should be considered for patients who are susceptible to fluid volume overload

and weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the total

duration remains no less than 4 hours.

For information on pre-treatment see section 4.4 and for further instructions see section 6.6.

4.3

Contraindications

Severe or life-threatening hypersensitivity to the active substance or to any of the excipients, if

hypersensitivity is not controllable.

4.4

Special warnings and precautions for use

Management of compromised airways

Caution must be exercised in the management and treatment of patients with compromised airways by

limitation or careful monitoring of antihistamine and other sedative medicinal product use. Institution

of positive–airway pressure during sleep as well as potential tracheostomy in clinically appropriate

situations should also be considered.

Patients who present with an acute febrile or respiratory illness may need to have their Naglazyme

infusions delayed.

Management of infusion-associated reactions

Patients treated with Naglazyme have developed infusion-associated reactions (IARs), defined as any

adverse reactions occurring during the infusion or until the end of the infusion day (see section 4.8).

Based on data obtained during Naglazyme clinical trials, the majority of patients are expected to

develop IgG antibodies to galsulfase within 4-8 weeks of treatment initiation.

In the Naglazyme clinical trials, IARs were usually manageable by interrupting or slowing the rate of

infusion and by (pre-) treating the patient with antihistamines and/or antipyretics (paracetamol), thus

enabling the patient to continue treatment.

As there is little experience on resumption of treatment following prolonged interruption, caution is to

be used due to the theoretical increased risk of hypersensitivity reaction.

With administration of Naglazyme it is recommended that patients be administered pre-treatment

medicinal products (antihistamines with or without antipyretics) approximately 30-60 minutes prior to

the start of the infusion, to minimise the potential occurrence of IARs.

In case of a mild or moderate IAR, treatment with antihistamines and paracetamol should be

considered and/or a reduction in the infusion rate to half the rate at which the reaction occurred.

In case of a single severe IAR, the infusion should be stopped until the symptoms are resolved and

treatment with antihistamines and paracetamol should be considered. The infusion can be restarted

with a reduction of the infusion rate to 50% – 25% of the rate at which the reaction occurred.

In case of a recurrent moderate IAR or re-challenge after a single severe IAR, pre-treatment should be

considered (antihistamines and paracetamol and/or corticosteroids) and a reduction of the infusion rate

to 50% – 25% of the rate at which the previous reaction occurred.

As with any intravenous protein medicinal product, severe allergic-type hypersensitivity reactions are

possible. If these reactions occur, immediate discontinuation of Naglazyme is recommended and

appropriate medical treatment should be initiated. The current medical standards for emergency

treatment are to be observed. In patients who have experienced allergic reactions during infusion with

Naglazyme, caution should be exercised upon rechallenge; appropriately trained personnel and

equipment for emergency resuscitation (including epinephrine) should be available during infusions.

Severe, or potentially life-threatening hypersensitivity is a contraindication to rechallenge, if

hypersensitivity is not controllable. See also section 4.3.

Spinal or cervical cord compression

Spinal/cervical cord compression (SCC) with resultant myelopathy is a known and serious

complication that can be due to MPS VI. There have been post-marketing reports of patients treated

with Naglazyme who experienced the onset or worsening of SCC requiring decompression surgery.

Patients should be monitored for signs and symptoms of spinal/cervical cord compression (including

back pain, paralysis of limbs below the level of compression, urinary and faecal incontinence) and

given appropriate clinical care.

Risk of Acute Cardio-respiratory Failure

Caution should be exercised when administering Naglazyme to patients susceptible to fluid volume

overload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness,

or patients with compromised cardiac and/or respiratory function, because congestive heart failure

may occur. Appropriate medical support and monitoring measures should be readily available during

Naglazyme infusion, and some patients may require prolonged observation times that should be based

on the individual needs of the patient (see section 4.2).

Immune-mediated Reactions

Type III immune complex-mediated reactions including membranous glomerulonephritis have been

observed with Naglazyme. If immune-mediated reactions occur, discontinuation of the administration

of Naglazyme should be considered, and appropriate medical treatment initiated. The risks and

benefits of re-administering Naglazyme following an immune-mediated reaction should be considered

(see section 4.2).

Sodium restricted diet

This medicinal product contains 0.8 mmol (18.4 mg) sodium per vial and is administered in sodium

chloride 9 mg/ml solution for injection (see section 6.6). To be taken into consideration by patients on

a controlled sodium diet.

4.5

Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

4.6

Fertility, pregnancy and lactation

Pregnancy

For Naglazyme, no clinical data on exposed pregnancies are available. Animal studies do not indicate

direct or indirect harmful effects with respect to pregnancy or embryo-foetal development (see

section 5.3). Naglazyme should not be used during pregnancy unless clearly necessary.

Breast-feeding

It is not known whether galsulfase is excreted in milk, therefore breast-feeding should be stopped

during Naglazyme treatment

.

Fertility

Reproduction studies have been performed in rats and rabbits at doses up to 3 mg/kg/day and have

revealed no evidence of impaired fertility or harm to the embryo or foetus due to Naglazyme.

4.7

Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8

Undesirable effects

Due to the low number of patients in clinical trials, adverse event (AE) data from all Naglazyme

studies have been pooled and reviewed in a single, clinical trial safety analysis.

All patients treated with NAGLAZYME (59/59) reported at least one AE. The majority (42/59; 71%)

of patients experienced at least one Adverse Drug Reaction. The most common adverse reactions were

pyrexia, rash, pruritus, urticaria, chills/rigors, nausea, headache, abdominal pain, vomiting and

dypsnoea. Serious adverse reactions included laryngeal edema, apnoea, pyrexia, urticaria, respiratory

distress, angioedema, asthma and anaphylactoid reaction.

Infusion reactions, defined as adverse reactions occurring during Naglazyme infusions or until the end

of the infusion day, were observed in 33 (56%) of the 59 patients treated with Naglazyme across five

clinical studies. Infusion reactions began as early as Week 1 and as late as Week 146 of Naglazyme

treatment, and occurred during multiple infusions though not always in consecutive weeks. Very

common symptoms of these infusion reactions were pyrexia, chills/rigors, rash, urticaria and

dyspnoea. Common symptoms of infusion reactions were pruritus, vomiting, abdominal pain, nausea,

hypertension, headache, chest pain, erythema, cough, hypotension, angioedema, respiratory distress,

tremor, conjunctivitis, malaise, bronchospasm and arthralgia.

Adverse reactions are listed in Table 1 by System Organ Class.

The reactions are listed following the MedDRA frequency convention. Very common adverse

reactions are those with a frequency of

1/10. Common reactions have a frequency of

1/100 to

<1/10. Due to the small patient population, an adverse reaction in a single patient is classified as

common.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions reported during the Post Marketing period are included at a frequency category of

“unknown”.

Overall, one case of sleep apnoea was experienced from all clinical studies.

Table 1: Frequency of adverse drug reactions with Naglazyme

MedDRA

System Organ Class

MedDRA

Preferred Term

Frequency

Immune system disorders

Anaphylaxis, shock

Unknown

Infections and infestations

Pharyngitis

, gastroenteritis

Very common

Nervous system disorders

Areflexia

, headache

Very common

Tremor

Common

Paresthesia

Unknown

Eye disorders

Conjunctivitis

, corneal opacity

Very common

Cardiac disorders

Bradycardia, tachycardia, cyanosis

Unknown

Ear and labyrinth disorders

Ear pain

, hearing impaired

Very common

Vascular disorders

Hypertension

Very common

Hypotension

Common

Pallor

Unknown

Respiratory, thoracic, and mediastinal

disorders

Dyspnoea

, nasal congestion

Very common

Apnoea

, cough, respiratory distress,

asthma, bronchospasm

Common

Laryngeal oedema, hypoxia,

tachypnoea

Unknown

Gastrointestinal disorders

Abdominal pain

, umbilical hernia

vomiting, nausea

Very common

Skin and subcutaneous tissue

disorders

Angioeodema

, rash

, urticaria, pruritus

Very Common

Erythema

Common

General disorders and administration

site conditions

Pain

, chest pain

, rigors

, malaise

pyrexia

Very Common

Musculoskeletal and Connective

Tissue Disorders

Arthralgia

Very common

Reactions reported more frequently in the active arm of the placebo-controlled study than the placebo arm; frequency

determined from 39 patients of the blinded Phase 3 study.

Other reactions with known frequency were reported from 59 patients treated with Naglazyme from all five clinical trials.

Reactions of unknown frequency were reported post-marketing.

In four patients <1 year of age, the overall safety profile of a higher dose (2 mg/kg/week) did not differ

in a clinically meaningful manner from that of the recommended 1 mg/kg/week dose, and was

consistent with the safety profile of Naglazyme in older children.

Immunogenicity

Out of the 59 patients treated with Naglazyme in the clinical studies, 54 were tested for IgG

antibodies. 53/54 patients (98%) were positive for IgG antibodies to galsulfase.

A comprehensive antibody analysis based on data from three clinical studies has been carried out in

48 patients.

Although a larger proportion of subjects with high total antibody titres experienced recurrent infusion

reactions, neither frequency nor severity could be predicted based on the anti-galsulfase antibody titre.

Likewise, antibody development is not predictive of decreased efficacy although subjects with limited

response in endurance parameters or urinary glycosaminoglycans (GAGs) tended to have higher peak

anti-galsulfase titres than those with good response.

Reporting of suspected adverse reactions

Any suspected adverse events should be reported to the Ministry of Health according to

the National Regulation by using an online form

https://sideeffects.health.gov.il/.

Overdose

Several patients have received their total dose of Naglazyme at approximately twice the recommended

infusion rate without apparent adverse events.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products, enzymes, ATC code:

A16AB08

Mucopolysaccharide storage disorders are caused by the deficiency of specific lysosomal enzymes

required for the catabolism of glycosaminoglycans (GAGs). MPS VI is a heterogeneous and

multisystemic disorder characterized by the deficiency of N-acetylgalactoasamine 4-sulfatase, a

lysosomal hydrolase which catalyses the hydrolysis of sulfate moiety of the glycosaminoglycan,

dermatan sulfate. Reduced or absent N-acetylgalactosamine 4-sulfatase activity results in the

accumulation of dermatan sulfate in many cell types and tissues.

The rationale for enzyme replacement therapy is to restore a level of enzymatic activity sufficient to

hydrolyze the accumulated substrate and to prevent further accumulation.

Purified galsulfase, a recombinant form of human N-acetylgalactosamine 4-sulfatase, is a glycoprotein

with a molecular weight of approximately 56 kD. Galsulfase is comprised of 495 amino acids after

cleavage of the N-terminus. The molecule contains 6 N-linked oligosaccharide modification sites.

After intravenous infusion, galsulfase is rapidly removed from the circulation and taken up by cells

into lysosomes, most likely via mannose-6 phosphate receptors.

The three clinical studies performed with Naglazyme focused on assessing the systemic manifestations

of MPS VI such as endurance, joint mobility, joint pain and stiffness, upper airway obstruction,

manual dexterity and visual acuity.

The safety and efficacy of Naglazyme was assessed in a randomised, double blind, placebo controlled,

Phase 3 study of 39 MPS VI patients, ranging in age from 5 to 29 years. The majority of the patients

presented with short stature, impaired endurance, and musculoskeletal symptoms. Patients who could

walk more than 5 meters (m) but less than 250 m in 6 minutes of a 12 Minute Walk test or less than

400 m at the 12 minute time point at baseline were enrolled in the study.

Patients received either 1 mg/kg of galsulfase or placebo every week for a total of 24 weeks. The

primary efficacy endpoint was the numbers of meters walked in 12 minutes at Week 24 compared to

the number of meters walked at baseline. The secondary efficacy endpoints were the rate of stairs

climbed in three minutes and the urinary glycosaminoglycan excretion of treated patients compared to

placebo at Week 24. Thirty-eight patients subsequently enrolled in an Open Label extension study

where they received 1 mg/kg of galsulfase every week.

Following 24 weeks of therapy, Naglazyme-treated patients experienced a 92 ± 40 m improvement in

the distance walked in 12 minutes relative to placebo-treated patients (p = 0.025). Treated patients

experienced a 5.7 stair per minute improvement in the 3 Minute Stair Climb relative to placebo-treated

patients. Treated patients also experienced a mean decrease in urinary glycosaminoglycan excretion of

238 ± 17.8 μg/mg creatinine (

Standard Error [SE]) following 24 weeks of treatment relative to

placebo-treated patients. GAG results approached the normal range for age in the Naglazyme

treatment group.

In an additional Phase 4, randomised, two-dose level study, four MPS VI patients <1 year of age were

treated at 1 or 2 mg/kg/week for 53 to 153 weeks.

Although limited by the very small number of patients that were enrolled, the conclusions that can be

drawn from this study are the following:

Treatment with Naglazyme showed improvement, or lack of worsening, of facial dysmorphism. It did

not prevent the progression of skeletal dysplasia and development of hernias and did not prevent the

progression of corneal clouding. Growth rate remained normal over this limited follow-up period.

Improved hearing was noted in at least one ear for all four subjects. Urinary GAG levels decreased by

more than 70%, consistent with results in older patients.

This medicinal product has been authorised under "Exceptional Circumstances".

This means that due to the rarity of the disease it has not been possible to obtain complete information

on this medicinal product.

The European Medicines Agency will review any new information which may become available every

year and this SmPC will be updated as necessary.

5.2

Pharmacokinetic properties

The pharmacokinetics of galsulfase were evaluated in 13 patients with MPS VI who received 1 mg/kg

of galsulfase as a 4 hour infusion. After 24 weeks of treatment the mean (

Standard Deviation [SD])

maximum plasma concentration (C

) was 2,357 (± 1,560) ng/ml and the mean (

SD) area under the

plasma concentration-time curve (AUC

) was 5,860 (

4,184) h

ng/ml. The mean (

SD) volume of

distribution (Vz) was 316 (

752) ml/kg and the mean (

SD) plasma clearance (CL) was

7.9 (

14.7) ml/min/kg. The mean (

SD) elimination half-life (t

) was 22.8 (

10.7) minutes at

Week 24.

Pharmacokinetic parameters in Phase 1 patients have remained stable over the long term (through at

least 194 weeks).

Galsulfase 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 galsulfase in a

clinically significant way. Renal elimination of galsulfase is considered a minor pathway for clearance

(see section 4.2).

5.3

Preclinical safety data

Non-clinical data revealed no special hazard for humans based on conventional studies of safety

pharmacology, single-dose toxicity, repeated-dose toxicity or on general reproductive performance or

embryo-foetal development in rats or rabbits. Peri- and post-natal toxicity has not been investigated.

Genotoxic and carcinogenic potential are not expected.

The cause of clinical relevance of the hepatic toxicity (bile duct hyperplasia / periportal inflammation)

seen at clinically relevant doses in the repeated dose monkey toxicity study is not known.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium chloride

Sodium phosphate monobasic, monohydrate

Sodium phosphate dibasic, heptahydrate

Polysorbate 80

Water for injections

6.2

Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in

section 6.6.

6.3

Shelf life

Unopened vials: 3 years.

The expiry date of the product is indicated on the packaging materials

From a microbiological safety point of view, Naglazyme should be used immediately. If not used

immediately, in-use storage times and conditions are the responsibility of the user and should normally

not be longer than 24 hours at 2

C - 8

C followed by up to 24 hours at room temperature (23

C) during administration.

6.4

Special precautions for storage

Store in a refrigerator (2°C - 8°C).

Do not freeze.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5

Nature and contents of container

Vial (type I glass) with a stopper (siliconized chlorobutyl rubber) and a seal (aluminium) with a flip-

off cap (polypropylene).

Pack sizes: 1 vials.

6.6

Special precautions for disposal and other handling

Each vial of Naglazyme is intended for single use only. The concentrate for solution for infusion has

to be diluted with sodium chloride 9 mg/ml (0.9%) solution for infusion using aseptic technique. It is

recommended that the diluted Naglazyme solution be administered to patients using an infusion set

equipped with a 0.2 µm in-line filter.

Any unused product or waste material is to be disposed of in accordance with local requirements.

Preparation of the Naglazyme infusion (aseptic technique is to be used)

The number of vials to be diluted based on the individual patient's weight must be determined and

removed from the refrigerator approximately 20 minutes in advance in order to allow them to reach

room temperature.

Before dilution, each vial is to be inspected for particulate matter and discolouration. The clear to

slightly opalescent and colourless to pale yellow solution must be free of visible particles.

A volume of the sodium chloride 9 mg/ml (0.9%) solution for infusion is to be withdrawn and

discarded from a 250 ml infusion bag equal to the total volume of Naglazyme to be added. 100 ml

infusion bags should be considered for patients who are susceptible to fluid volume overload and

weigh less than 20 kg; in this case the infusion rate (ml/min) should be decreased so that the total

duration remains no less than 4 hours. When using 100 ml bags, the volume of Naglazyme may be

added directly to the infusion bag.

The volume of Naglazyme is to be slowly added to the sodium chloride 9 mg/ml (0.9%) solution for

infusion.

The solution is to be mixed gently before infusion.

The solution is to be visually inspected for particulate matter prior to use. Only clear and colourless

solutions without visible particles should be used.

7. MANUFACTURER

BioMarin Pharmaceutical Inc., Novato, CA, USA

8.

License Holder:

Medison Pharma Ltd. POB 7090 Petach Tikva

9. Registration Number

143-48-31767

Revised on May 2020

Naglazyme -SPC -05/20

05/2020

,םידבכ ה/חקור ,ה/אפור

:ןכדוע רישכתה לש אפורל ןולעה יכ םכעידוהל יירה

NAGLAZYME

-

םייזלגנ

CONCENTRATE FOR SOLUTION FOR INFUSION

:בכרה

Each ml of solution contains 1 mg galsulfase. One vial of 5 ml contains 5 mg galsulfase.

:תרשואמ היוותה

Naglazyme is indicated for long-term enzyme replacement therapy in patients with a confirmed

diagnosis of MPSVI (N-acetylglactosamine 4 sulfatase deficiency Maroteaux-Lamy syndrome).

:אפורל ןולעב םיוכדעה ןלהל

4.4

Special warnings and precautions for use

[......]

This medicinal product contains 0.8 mmol (18.4 mg) sodium per vial and is administered in sodium

chloride 9 mg/ml solution for injection (see section 6.6). To be taken into consideration by patients on a

controlled sodium diet.

Spinal or cervical cord compression

Spinal/cervical cord compression (SCC) with resultant myelopathy is a known and serious complication

that can be due to MPS VI. There have been post-marketing reports of patients treated with Naglazyme

who experienced the onset or worsening of SCC requiring decompression surgery. Patients should be

monitored for signs and symptoms of spinal/cervical cord compression (including back pain, paralysis of

limbs below the level of compression, urinary and faecal incontinence) and given appropriate clinical

care.

Risk of Acute Cardio-respiratory Failure

Caution should be exercised when administering Naglazyme to patients susceptible to fluid volume

overload; such as in patients weighing 20 kg or less, patients with acute underlying respiratory illness, or

patients with compromised cardiac and/or respiratory function, because congestive heart failure may

occur. Appropriate medical support and monitoring measures should be readily available during

Naglazyme infusion, and some patients may require prolonged observation times that should be based on

the individual needs of the patient (see section 4.2).

Immune-mediated Reactions

Type III immune complex-mediated reactions including membranous glomerulonephritis have been

observed with Naglazyme. If immune-mediated reactions occur, discontinuation of the administration of

Naglazyme should be considered, and appropriate medical treatment initiated. The risks and benefits of

re-administering Naglazyme following an immune-mediated reaction should be considered (see section

4.2).

Sodium restricted diet

This medicinal product contains 0.8 mmol (18.4 mg) sodium per vial and is administered in sodium

chloride 9 mg/ml solution for injection (see section 6.6). To be taken into consideration by patients on a

controlled sodium diet.

ןתיו תואירבה דרשמ רתאב תופורתה רגאמב םסרופמ ןכו רושיקב אצמ אפורל ןולעה לעבל היפ ידי לע ספדומ ולבקל .םושירה

,הכרבב

רימע ןורש

הוממ תחקור

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