ELAPRASE

רשוא

–

61

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2

ךיראת

:

61

02.

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תילגנאב רישכת םש

םושירה רפסמו

ELAPRASE

138 94 31772 00

םושירה לעב םש

מ"עב המראפ ןוסידמ

ה טורפל דעוימ הז ספוט דבלב תורמחה

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

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

תושקובמה תורמחהה

ןולעב קרפ

יחכונ טסקט

שדח טסקט

5.PHARMACO

LOGICAL

PROPERTIES

5.1

Pharmacodynam

ic properties

5.1 Pharmacodynamic properties

Among all patients, statistically

significant mean increases from

treatment baseline (TKT024 baseline for

TKT024 idursulfase patients and Week

53 baseline for TKT024 placebo patients)

were seen in the distance walked 6MWT

at the majority of time points tested, with

significant mean and percent increases

ranging from 13.7m to 41.5m and from

6.4% to 11.7% (maximum at Month 20).

At most time points tested, patients who

were from the original TKT024 weekly

treatment group improved their walking

distance to a greater extent that patients

in the other 2 treatment groups.

Among all patients, mean % predicted

FVC was significantly increased at Month

16, although by Month 36, it was similar

to the baseline. Patients with the most

severe pulmonary impairment at baseline

(as measured by % predicted FVC)

tended to show the least improvement.

Statistically significant increases from

treatment baseline in absolute FVC

volume were seen at most visits for each

of the prior TKT024 treatment groups.

Mean changes from 0.07 l to 0.31 l and

percent ranged from 6.3% to 25.1%

(maximum at Month 30). The mean and

percent changes from treatment baseline

were greatest in the group of patients

from the TKT024 study who had received

the weekly dosing, across all time points.

5.1 Pharmacodynamic properties

Among all patients, statistically

significant mean increases from

treatment baseline (TKT024 baseline for

TKT024 idursulfase patients and Week

53 baseline for TKT024 placebo patients)

were seen in the distance walked 6MWT

at the majority of time points tested, with

significant mean and percent increases

ranging from 13.7m to 41.5m and from

6.4% to 11.7% (maximum at Month 20)

and from 6.4% to 13.3% (maximum at

Month 24) respectively. At most time

points tested, patients who were from the

original TKT024 weekly treatment group

improved their walking distance to a

greater extent that patients in the other 2

treatment groups.

Statistically significant increases from

treatment baseline in absolute FVC volume

were seen at most visits for all treatment

groups combined and for each of the prior

TKT024 treatment groups. Mean changes

from 0.07 l to 0.31 l and percent ranged

from 6.3% to 25.51% (maximum at Month

30). The mean and percent changes from

treatment baseline were greatest in the

group of patients from the TKT024 study

who had received the weekly dosing,

across all time points.

6.6

Special

precautions for

disposal and

6.6

Special precautions for disposal

and other handling

6.6

Special precautions for disposal

and other handling

Each vial of Elaprase is intended for

other handling

Each vial of Elaprase is intended for

single use only and contains 6 mg of

idursulfase in 3 ml of solution. Elaprase is

for intravenous infusion and must be

diluted in sodium chloride 9 mg/ml (0.9%)

solution for infusion prior to use.

Determine the number of vials to be

diluted based on the individual

patient’s weight and the

recommended dose of 0.5 mg/kg.

Do not use if the solution in the vials is

discoloured or if particulate matter is

present. Do not shake.

Withdraw the calculated volume of

Elaprase from the appropriate number of

vials.

Dilute the total volume required of

Elaprase in 100 ml of 9 mg/ml (0.9%)

sodium chloride solution for infusion.

Care must be taken to ensure the

sterility of the prepared solutions

since Elaprase does not contain any

preservative or bacteriostatic agent;

aseptic technique must be observed.

Once diluted, the solution should be

mixed gently, but not shaken.

Any unused medicinal product or waste

material should be disposed of in

accordance with local requirements.

single use only and contains 6 mg of

idursulfase in 3 ml of solution. Elaprase

is for intravenous infusion and must be

diluted in sodium chloride 9 mg/ml (0.9%)

solution for infusion prior to use. It is

recommended to deliver the total volume

of infusion using a 0.2 µm in line filter.

Elaprase should not be infused with other

products in the infusion tubing.

Determine the number of vials to be

diluted based on the individual

patient’s weight and the

recommended dose of 0.5 mg/kg.

Do not use if the solution in the vials is

discoloured or if particulate matter is

present. Do not shake.

Withdraw the calculated volume of

Elaprase from the appropriate number of

vials.

Dilute the total volume required of

Elaprase in 100 ml of 9 mg/ml (0.9%)

sodium chloride solution for infusion.

Care must be taken to ensure the

sterility of the prepared solutions

since Elaprase does not contain any

preservative or bacteriostatic agent;

aseptic technique must be observed.

Once diluted, the solution should be

mixed gently, but not shaken.

Any unused medicinal product or waste

material should be disposed of in

accordance with local requirements.

ב"צמ נמוסמ ובש ,ןולעה תו

תורמחהה שקובמה תו בוהצ עקר לע

.

ונמוס תורמחה רדגב םניאש םייוניש )ןולעב(

עבצב קורי

םוקימב םייוניש אלו יתוהמ ןכות קר ןמסל שי .טסקטה

SUMMARY OF PRODUCT CHARACTERISTICS

1.

NAME OF THE MEDICINAL PRODUCT

Elaprase 2 mg/ml concentrate for solution for infusion

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each vial contains 6 mg of idursulfase. Each ml contains 2 mg of idursulfase*.

Excipient with known effect

Each vial contains 0.482 mmol of sodium.

For the full list of excipients, see section 6.1.

* idursulfase is produced by recombinant DNA technology in a continuous human cell line.

3.

PHARMACEUTICAL FORM

Concentrate for solution for infusion (sterile concentrate).

A clear to slightly opalescent, colourless solution.

4.

CLINICAL

PARTICULARS

4.1

Therapeutic indications

Elaprase is indicated for the long-term treatment of patients with Hunter syndrome

(Mucopolysaccharidosis II, MPS II).

Heterozygous females were not studied in the clinical trials.

4.2

Posology and method of administration

This treatment should be supervised by a physician or other healthcare professional experienced

in the management of patients with MPS II disease or other inherited metabolic disorders.

Posology

Elaprase is administered at a dose of 0.5 mg/kg body weight every week by intravenous infusion

over a 3 hour period, which may be gradually reduced to 1 hour if no infusion-associated

reactions are observed (see section 4.4).

For instructions for use see section

6.6.

Infusion

at home may be considered for patients who have received several months of treatment

in the clinic and who are tolerating their infusions well. Home infusions should be performed

under the surveillance of a physician or other healthcare professional.

Special populations

Elderly patients

There is no clinical experience in patients over 65 years of age.

Patients with renal or hepatic impairment

There is no clinical experience in patients with renal or hepatic insufficiency (

ee section 5.2).

Paediatric population

The dose for children and adolescents is the same as for adults, 0.5 mg/kg body weight weekly.

Method of administration

For instructions on dilution of the medicinal product before administration see section 6.6

4.3

Contraindications

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

listed in section 6.1 if hypersensitivity is not controllable.

4.4

Special warnings and precautions for use

Infusion-related reactions

Patients treated with idursulfase may develop infusion-related reactions (see section 4.8). During

clinical trials, the most common infusion-related reactions included cutaneous reactions (rash,

pruritus, urticaria), pyrexia, headache, hypertension, and flushing. Infusion-related reactions

were treated or ameliorated by slowing the infusion rate, interrupting the infusion, or by

administration of medicinal products, such as antihistamines, antipyretics, low-dose

corticosteroids (prednisone and methylprednisolone), or beta-agonist nebulisation. No patient

discontinued treatment due to an infusion reaction during clinical studies.

Special care should be taken when administering an infusion in patients with severe underlying

airway disease. These patients should be closely monitored and infused in an appropriate clinical

setting. Caution must be exercised in the management and treatment of such patients by

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

Institution of positive-airway pressure may be necessary in some cases.

Delaying the infusion in patients who present with an acute febrile respiratory illness should be

considered. Patients using supplemental oxygen should have this treatment readily available

during infusion in the event of an infusion-related reaction.

Anaphylactoid/anaphylactic reactions

Anaphylactoid/anaphylactic reactions, which have the potential to be life threatening, have been

observed in some patients treated with idursulfase up to several years after initiating treatment.

Late emergent symptoms and signs of anaphylactoid/anaphylactic reactions have been observed

as long as 24 hours after an initial reaction. If an anaphylactoid/anaphylactic reaction occurs the

infusion should be immediately suspended and appropriate treatment and observation initiated.

The current medical standards for emergency treatment are to be observed. Patients experiencing

severe or refractory anaphylactoid/anaphylactic reactions may require prolonged clinical

monitoring. Patients who have experienced anaphylactoid/anaphylactic reactions should be

treated with caution when re-administering idursulfase, 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 section 4.3).

Patients with the complete deletion/large rearrangement genotype

Paediatric patients with the complete deletion/large rearrangement genotype have a high

probability of developing antibodies, including neutralizing antibodies, in response to exposure

to idursulfase. Patients with this genotype have a higher probability of developing infusion-

related adverse events and tend to show a muted response as assessed by decrease in urinary

output of glycosaminoglycans, liver size and spleen volume compared to patients with the

missense genotype. Management of patients must be decided on an individual basis (see section

4.8).

Sodium

This medicinal product contains 0.482 mmol sodium (or 11.1 mg) per vial. This is equivalent to

0.6% of the WHO recommended maximum daily intake of 2 g sodium for an adult.

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number

of the administered product should be clearly recorded.

4.5

Interaction with other medicinal products and other forms of interaction

No formal medicinal product interaction studies have been conducted with idursulfase.

Based on its metabolism in cellular lysosomes, idursulfase would not be a candidate for

cytochrome P450 mediated interactions.

4.6

Fertility, pregnancy and lactation

Pregnancy

There are no data or limited amount of data from the use of idursulfase in pregnant women.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive

toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of

idursulfase during pregnancy.

Breast-feeding

It is not known whether idursulfase is excreted in human breast milk. Available data in animals

have shown excretion of idursulfase in milk (see section 5.3). A risk to the newborns/infants

cannot be excluded. A decision must be made whether to discontinue breast-feeding or to

discontinue/abstain from idursulfase therapy taking into account the benefit of breast feeding for

the child and the benefit of therapy for the woman.

Fertility

No effects on male fertility were seen in reproductive studies in male rats.

4.7

Effects on ability to drive and use machines

Idursulfase has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Summary of the safety profile

Adverse reactions that were reported for the 32 patients treated with 0.5 mg/kg idursulfase

weekly in the TKT024 phase II/III 52-week placebo-controlled study were almost all mild to

moderate in severity. The most common were infusion-related reactions, 202 of which were

reported in 22 out of 32 patients following administration of a total of 1580 infusions. In the

placebo treatment group 128 infusion-related reactions were reported in 21 out of 32 patients

following administration of a total of 1612 infusions. Since more than one infusion-related

reaction may have occurred during any single infusion, the above numbers are likely to

overestimate the true incidence of infusion reactions. Related reactions in the placebo group

were similar in nature and severity to those in the treated group. The most common of these

infusion-related reactions included cutaneous reactions (rash, pruritus, urticaria, and erythema),

pyrexia, flushing, wheezing, dyspnoea, headache, vomiting, abdominal pain, nausea, and chest

pain. The frequency of infusion-related reactions decreased over time with continued treatment.

Tabulated list of adverse reactions

Adverse reactions are listed in table 1 with information presented by system organ class and

frequency. Frequency is given as very common (≥1/10), common (≥1/100 to <1/10) or

uncommon (≥1/1,000 to <1/100). The occurrence of an adverse reaction in a single patient is

defined as common in view of the number of patients treated. Within each frequency grouping,

adverse reactions are presented in order of decreasing seriousness. Adverse reactions only

reported during the post marketing period are also included in the table with a frequency “not

known” (cannot be estimated from the available data).

Table 1: Adverse reactions from clinical trials and post-marketing experience in patients

treated with Elaprase.

System organ class

Adverse reaction (preferred term)

Very common

Common

Uncommon

Not known

Immune system disorders

Anaphylactoid/

anaphylactic

reaction

Nervous system disorders

Headache

Dizziness, tremor

Cardiac disorders

Cyanosis,

arrhythmia,

tachycardia

Vascular disorders

Flushing

Hypertension,

Hypotension

Respiratory, thoracic and mediastinal disorders

Wheezing,

dyspnoea

Hypoxia,

bronchospasm,

cough

Tachypnoea

Gastrointestinal disorders

Abdominal pain,

nausea, diarrhoea,

vomiting

Swollen tongue,

dyspepsia

Skin and subcutaneous tissue disorders

Urticaria, rash,

pruritus, erythema

Musculoskeletal and connective disorders

Arthralgia

General disorders and administration site conditions

Pyrexia, chest pain

Infusion-site

swelling, face

oedema, oedema

peripheral

Injury, poisoning and procedural complications

Infusion-related

reaction

Description of selected adverse reactions

Across clinical studies, serious adverse reactions were reported in a total of 5 patients who

received 0.5 mg/kg weekly or every other week. Four patients experienced a hypoxic episode

during one or several infusions, which necessitated oxygen therapy in 3 patients with severe

underlying obstructive airway disease (2 with a pre-existing tracheostomy). The most severe

episode occurred in a patient with a febrile respiratory illness and was associated with hypoxia

during the infusion, resulting in a short seizure. In the fourth patient, who had less severe

underlying disease, spontaneous resolution occurred shortly after the infusion was interrupted.

These events did not recur with subsequent infusions using a slower infusion rate and

administration of pre-infusion medicinal products, usually low-dose steroids, antihistamine, and

beta-agonist nebulisation. The fifth patient, who had pre-existing cardiopathy, was diagnosed

with ventricular premature complexes and pulmonary embolism during the study.

There have been post-marketing reports of anaphylactoid/anaphylactic reactions (see

section 4.4).

Patients with complete deletion/large rearrangement genotype have a higher probability of

developing infusion related adverse events (see section 4.4).

Immunogenicity

Across 4 clinical studies (TKT008, TKT018, TKT024 and TKT024EXT), 53/107 patients (50%)

developed anti-idursulfase IgG antibodies at some point. The overall neutralizing antibody rate

was 26/107 patients (24%).

In the post-hoc immunogenicity analysis of data from TKT024/024EXT studies, 51% (32/63)

patients treated with 0.5mg/kg weekly idursulfase had at least 1 blood sample that tested positive

for anti-idursulfase antibodies, and 37 % (23/63) tested positive for antibodies on at least 3

consecutive study visits. Twenty-one percent (13/63) tested positive for neutralizing antibodies

at least once and 13 % (8/63) tested positive for neutralizing antibodies on at least 3 consecutive

study visits.

Clinical study HGT-ELA-038 evaluated immunogenicity in children 16 months to 7.5 years of

age. During the 53-week study, 67.9% (19 of 28) of patients had at least one blood sample that

tested positive for anti-idursulfase antibodies, and 57.1% (16 of 28) tested positive for antibodies

on at least three consecutive study visits. Fifty-four percent of patients tested positive for

neutralizing antibodies at least once and half of the patients tested positive for neutralizing

antibodies on at least three consecutive study visits.

All patients with the complete deletion/large rearrangement genotype developed antibodies, and

the majority of them (7/8) also tested positive for neutralizing antibodies on at least 3

consecutive occasions. All patients with the frameshift/splice site mutation genotype developed

antibodies and 4/6 also tested positive for neutralizing antibodies on at least 3 consecutive study

visits. Antibody-negative patients were found exclusively in the missense mutation genotype

group (see sections 4.4 and 5.1).

Paediatric population

Adverse reactions reported in the paediatric population were, in general, similar to those

reported in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It

allows continued monitoring of the benefit/risk balance of the medicinal product

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

4.9

Overdose

There is limited information regarding overdose with Elaprase. Evidence suggests that some

patients may experience an anaphylactoid reaction due to overdose (see sections 4.3 and 4.4).

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

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

code: A16AB09

.

Mechanism of action

Hunter syndrome is an X-linked disease caused by insufficient levels of the lysosomal enzyme

iduronate-2-sulfatase. Iduronate-2-sulfatase functions to catabolize the glycosaminoglycans

(GAG) dermatan sulfate and heparan sulfate by cleavage of oligosaccharide-linked sulfate

moieties. Due to the missing or defective iduronate-2-sulfatase enzyme in patients with Hunter

syndrome, glycosaminoglycans progressively accumulate in the cells, leading to cellular

engorgement, organomegaly, tissue destruction, and organ system dysfunction.

Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase, produced in a

human cell line providing a human glycosylation profile, which is analogous to the naturally

occurring enzyme. Idursulfase is secreted as a 525 amino acid glycoprotein and contains 8 N-

linked glycosylation sites that are occupied by complex, hybrid, and high-mannose type

oligosaccharide chains. Idursulfase has a molecular weight of approximately 76 kD.

Treatment of Hunter syndrome patients with intravenous idursulfase provides exogenous

enzyme for uptake into cellular lysosomes. Mannose-6-phosphate (M6P) residues on the

oligosaccharide chains allow specific binding of the enzyme to the M6P receptors on the cell

surface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes and

subsequent catabolism of accumulated GAG.

Clinical efficacy and safety

The safety and efficacy of Elaprase has been shown in three clinical studies: two randomised,

placebo-controlled clinical studies (TKT008 and TKT024) in adults and children above the age

of 5 years and one open-label, safety study (HGT-ELA-038) in children between the age of 16

months and 7.5 years.

A total of 108 male Hunter syndrome patients with a broad spectrum of symptoms were enrolled

in the two randomized, placebo-controlled clinical studies, 106 continued treatment in two open-

label, extension studies.

Study TKT024

In a 52-week, randomized, double-blind, placebo-controlled clinical study, 96 patients between

the ages of 5 and 31 years received Elaprase 0.5 mg/kg every week (n=32) or 0.5 mg/kg every

other week (n=32), or placebo (n=32). The study included patients with a documented

deficiency in iduronate-2-sulfatase enzyme activity, a percent predicted FVC <80%, and a broad

spectrum of disease severity.

The primary efficacy endpoint was a two-component composite score based on the sum of the

ranks of the change from baseline to the end of the study in the distance walked during six

minutes (6-minute walk test or 6MWT) as a measure of endurance, and % predicted forced vital

capacity (FVC) as a measure of pulmonary function. This endpoint differed significantly from

placebo for patients treated weekly (p=0.0049).

Additional clinical benefit analyses were performed on individual components of the primary

endpoint composite score, absolute changes in FVC, changes in urine GAG levels, liver and

spleen volumes, measurement of forced expiratory volume in 1 second (FEV

), and changes in

left ventricular mass (LVM). The results are presented in Table 2.

Table 2. Results from pivotal clinical study at 0.5 mg/kg per week (Study TKT024).

Endpoint

52 weeks of treatment

0.5 mg/kg weekly

Marginally weighted (OM)

mean (SE)

Mean treatment

difference

compared with

placebo (SE)

P-value

(compared with

placebo)

Idursulfase

Placebo

Composite

(6MWT and

%FVC)

74.5 (4.5)

55.5 (4.5)

19.0 (6.5)

0.0049

6MWT (m)

43.3 (9.6)

8.2 (9.6)

35.1 (13.7)

0.0131

% Predicted FVC

4.2 (1.6)

-0.04 (1.6)

4.3 (2.3)

0.0650

FVC absolute

volume (L)

0.23 (0.04)

0.05 (0.04)

0.19 (0.06)

0.0011

Urine GAG levels

(μg GAG/mg

creatinine)

-223.3 (20.7)

52.23 (20.7)

-275.5 (30.1)

<0.0001

% Change in liver

volume

-25.7 (1.5)

-0.5 (1.6)

-25.2 (2.2)

<0.0001

% Change in

spleen volume

-25.5 (3.3)

7.7 (3.4)

-33.2 (4.8)

<0.0001

A total of 11 of 31 (36%) patients in the weekly treatment group versus 5 of 31 (16%) patients in

the placebo group had an increase in FEV

of at least 0.2 l at or before the end of the study,

indicating a dose-related improvement in airway obstruction. The patients in the weekly

treatment group experienced a clinically significant 15% mean improvement in FEV

at the end

of the study.

Urine GAG levels were normalized below the upper limit of normal (defined as 126.6 µg

GAG/mg creatinine) in 50% of the patients receiving weekly treatment.

Of the 25 patients with abnormally large livers at baseline in the weekly treatment group, 80%

patients) had reductions in liver volume to within the normal range by the end of the study.

Of the 9 patients in the weekly treatment group with abnormally large spleens at baseline, 3 had

spleen volumes that normalized by the end of the study.

Approximately half of the patients in the weekly treatment group (15 of 32; 47%) had left

ventricular hypertrophy at baseline, defined as LVM index

>

103 g/m

. Of these 6 (40%) had

normalised LVM by the end of the study.

All patients received weekly idursulfase up to 3.2 years in an extension to this study

(TKT024EXT).

Among patients who were originally randomised to weekly idursulfase in TKT024, mean

maximum improvement in distance walked during six minutes occurred at Month 20 and mean

percent predicted FVC peaked at Month 16.

Among all patients, statistically significant mean increases from treatment baseline (TKT024

baseline for TKT024 idursulfase patients and Week 53 baseline for TKT024 placebo patients)

were seen in the distance walked 6MWT at the majority of time points tested, with significant

mean and percent increases ranging from 13.7m to 41.5m (maximum at Month 20) and from

6.4% to 13.3% (maximum at Month 24) respectively. At most time points tested, patients who

were from the original TKT024 weekly treatment group improved their walking distance to a

greater extent that patients in the other 2 treatment groups.

Among all patients, mean % predicted FVC was significantly increased at Month 16, although

by Month 36, it was similar to the baseline. Patients with the most severe pulmonary impairment

at baseline (as measured by % predicted FVC) tended to show the least improvement.

Statistically significant increases from treatment baseline in absolute FVC volume were seen at

most visits for all treatment groups combined and for each of the prior TKT024 treatment

groups. Mean changes from 0.07 l to 0.31 l and percent ranged from 6.3% to 25.5% (maximum

at Month 30). The mean and percent changes from treatment baseline were greatest in the group

of patients from the TKT024 study who had received the weekly dosing, across all time points.

At their final visit 21/31 patients in the TKT024 Weekly group, 24/32 in the TKT024 EOW

group and 18/31 patients in the TKT024 placebo group had final normalised urine GAG levels

that were below the upper limit of normal. Changes in urinary GAG levels were the earliest

signs of clinical improvement with idursulfase treatment and the greatest decreases in urinary

GAG were seen within the first 4 months of treatment in all treatment groups; changes from

Month 4 to 36 were small. The higher the urinary GAG levels at baseline, the greater the

magnitude of decreases in urinary GAG with idursulfase treatment.

The decreases in liver and spleen volumes observed at the end of study TKT024 (week 53) were

maintained during the extension study (TKT024EXT) in all patients regardless of the prior

treatment they had been assigned. Liver volume normalised by Month 24 for 73% (52 out of 71)

of patients with hepatomegaly at baseline. In addition, mean liver volume decreased to a near

maximum extent by Month 8 in all patients previously treated, with a slight increase observed at

Month 36. The decreases in mean liver volume were seen regardless of age, disease severity,

IgG antibody status or neutralising antibody status. Spleen volume normalised by Months 12 and

24 for 9.7% of patients in the TKT024 Weekly group with splenomegaly.

Mean cardiac LVMI remained stable over 36 months of idursulfase treatment within each

TKT024 treatment group.

In a post-hoc analysis of immunogenicity in studies TKT024 and TKT024EXT (see section 4.8),

patients were shown to have either the mis-sense mutation or the frameshift / nonsense mutation.

After 105 weeks of exposure to idursulfase, neither antibody status nor genotype affected

reductions in liver and spleen size or distance walked in the 6-minute walk test or forced vital

capacity measurements. Patients who tested antibody-positive displayed less reduction in urinary

output of glycosaminoglycans than antibody-negative patients. The longer-term effects of

antibody development on clinical outcomes have not been established.

Study HGT-ELA-038

This was an open-label, multicenter, single-arm study of idursulfase infusions in male Hunter

syndrome patients between the age of 16 months and 7.5 years.

Idursulfase treatment resulted in up to 60% reduction in urine output of glycosaminoglycans and

in reductions of liver and spleen size: results were comparable to those found in study TKT024.

Reductions were evident by week 18 and were maintained to week 53. Patients who developed a

high titre of antibodies displayed less response to idursulfase as assessed by urine output of

glycosaminoglycans and by liver and spleen size.

Analyses of genotypes of patients in study HGT-ELA-038

Patients were classified into the following groups: missense (13), complete deletion/large

rearrangement (8), and frameshift/ splice site mutations (5). One patient was unclassified /

unclassifiable.

The complete deletion/ large rearrangement genotype was most commonly associated with

development of high titre of antibodies and neutralising antibodies to idursulfase and was most

likely to display a muted response to the medicinal product. It was not possible, however, to

accurately predict individual clinical outcome based on antibody response or genotype.

No clinical data exist demonstrating a benefit on the neurological manifestations of the disorder.

5.2

Pharmacokinetic properties

Idursulfase is taken up by selective receptor-mediated mechanisms involving binding to

mannose 6-phosphate receptors. Upon internalization by cells, it is localized within cellular

lysosomes, thereby limiting distribution of the protein. Degradation of idursulfase is achieved by

generally well understood protein hydrolysis mechanisms to produce small peptides and amino

acids, consequently renal and liver function impairment is not expected to affect the

pharmacokinetics of idursulfase.

Pharmacokinetic parameters measured during the first infusion at week 1 of studies TKT024

(0.5 mg/kg weekly arm) and HGT-ELA-038 are displayed in table 3 and table 4 below as a

function of age and body weight, respectively.

Table 3. Pharmacokinetic parameters at week 1 as a function of age in Studies TKT024

and HGT-ELA-038

Study

HGT-ELA-038

TKT024

Age (years)

1.4 to 7.5

(n=27)

5 to 11

(n=11)

12 to 18

(n=8)

> 18

(n=9)

(μg/mL)

Mean ± SD

1.3 ± 0.8

1.6 ± 0.7

1.4 ± 0.3

1.9 ± 0.5

0-∞

(min*μg/mL)

Mean ± SD

224.3 ± 76.9

238 ± 103.7

196 ± 40.5

262 ± 74.5

(mL/min/kg)

Mean ± SD

2.4 ± 0.7

2.7 ± 1.3

2.8 ± 0.7

2.2 ± 0.7

(mL/kg)

Mean ± SD

394 ± 423

217 ± 109

184 ± 38

169 ± 32

Patients in the TKT024 and HGT-ELA-038 studies were also stratified across five weight

categories; as shown in the following table:

Table 4. Pharmacokinetic parameters at week 1 as a function of body weight in studies

TKT024 and HGT-ELA-038

Weight (kg)

<20

(n=17)

≥ 20 and <

(n=18)

≥ 30 and <

(n=9)

≥ 40 and <

50 (n=5)

≥ 50

(n=6)

(μg/mL)

Mean ± SD

1.2 ± 0.3

1.5 ± 1.0

1.7 ± 0.4

1.7 ± 0.7

1.7 ± 0.7

0-∞

(min*μg/mL)

206.2 ± 33.9

234.3 ±

103.0

231.1 ±

681.0

260.2 ±

113.8

251.3 ±

86.2

(mL/min/kg)

Mean ± SD

2.5 ± 0.5

2.6 ± 1.1

2.4 ± 0.6

2.4 ± 1.0

2.4 ± 1.1

(mL/kg)

321 ± 105

397 ± 528

171 ± 52

160 ± 59

181 ± 34

A higher volume of distribution at steady state (Vss) was observed in the lowest weight groups.

Overall, there was no apparent trend in either systemic exposure or clearance rate of idursulfase

with respect to either age or body weight.

5.3

Preclinical safety data

Nonclinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, single dose toxicity, repeated dose toxicity, toxicity to reproduction and

development and to male fertility.

Animal studies do not indicate direct or indirect harmful effects with respect to pregnancy,

embryonal/ foetal development, parturition or postnatal development.

Animal studies have shown excretion of idursulfase in breast milk.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Sodium

chloride

Sodium phosphate monobasic, monohydrate

Sodium phosphate dibasic, heptahydrate

Polysorbate 20

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

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

Chemical and physical in-use stability has been demonstrated for 8 hours at 25°C.

After dilution

From a microbiological safety point of view, the diluted product should be used immediately. If

not used immediately, in-use storage times and conditions prior to use are the responsibility of

the user and should not be longer than 24 hours at 2 to 8°C.

6.4

Special precautions for storage

Store in a refrigerator (2

C – 8

Do not freeze.

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

6.5

Nature and contents of container

5 ml vial (type I glass) with a stopper (fluoro-resin coated butyl rubber), one piece seal and blue

flip-off cap. Each vial contains 3 ml of concentrate for solution for infusion.

Pack size of 1 vial.

6.6

Special precautions for disposal and other handling

Each vial of Elaprase is intended for single use only and contains 6 mg of idursulfase in 3 ml of

solution. Elaprase is for intravenous infusion and must be diluted in sodium chloride 9 mg/ml

(0.9%) solution for infusion prior to use. It is recommended to deliver the total volume of

infusion using a 0.2 µm in line filter. Elaprase should not be infused with other medicinal

products in the infusion tubing.

The number of vials to be diluted should be determined based on the individual patient’s

weight and the recommended dose of 0.5 mg/kg.

The solution in the vials should not be used if it is discoloured or if particulate matter is

present. The solution should not be shaken.

The calculated volume of Elaprase should be withdrawn from the appropriate number of

vials.

The total volume required of Elaprase should be diluted in 100 ml of 9 mg/ml (0.9%)

sodium chloride solution for infusion. Care must be taken to ensure the sterility of the

prepared solutions since Elaprase does not contain any preservative or bacteriostatic

agent; aseptic technique must be observed. Once diluted, the solution should be mixed

gently, but not shaken.

Any unused medicinal product or waste material should be disposed of in accordance with local

requirements.

7. Manufacturer

Shire Human Genetic Therapies Inc., USA

8. License holder

Takeda Israel Ltd.,25 Efal st.,Petach Tikva 4951125

9

.

Registration

Number

138-94-31772

-Revised on July 2020