SUMMARY OF PRODUCT CHARACTERISTICS
1.

NAME OF THE MEDICINAL PRODUCTElaprase 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-associatedreactions 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 treatmentin the clinic and who are tolerating their infusions well. Home infusions should be performed
under the surveillance of a physician or other healthcare professional.

1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 (See 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 byadministration 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 clinicalsetting. Caution must be exercised in the management and treatment of such patients bylimitation 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 beconsidered. 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 theinfusion 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 clinicalmonitoring. Patients who have experienced anaphylactoid/anaphylactic reactions should betreated with caution when re-administering idursulfase, appropriately trained personnel andequipment for emergency resuscitation (including epinephrine) should be available duringinfusions. Severe or potentially life-threatening hypersensitivity is a contraindication torechallenge, 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 highprobability of developing antibodies, including neutralizing antibodies, in response to exposure
to idursulfase. Patients with this genotype have a higher probability of developing infusion2

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 themissense genotype. Management of patients must be decided on an individual basis (see section
4.8).
SodiumThis medicinal product contains 0.482 mmol sodium (or 11.1 mg) per vial. This is equivalent to0.6% 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 numberof 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 forcytochrome 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 ofidursulfase 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 forthe 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 tomoderate in severity. The most common were infusion-related reactions, 202 of which werereported in 22 out of 32 patients following administration of a total of 1580 infusions. In theplacebo 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 tooverestimate the true incidence of infusion reactions. Related reactions in the placebo groupwere similar in nature and severity to those in the treated group. The most common of theseinfusion-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.
3

Tabulated list of adverse reactions
Adverse reactions are listed in table 1 with information presented by system organ class andfrequency. 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 isdefined 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 “notknown” (cannot be estimated from the available data).
Table 1: Adverse reactions from clinical trials and post-marketing experience in patientstreated with Elaprase.
System organ class
Adverse reaction (preferred term)
Very common
CommonUncommonNot known
Immune system disorders
Anaphylactoid/
anaphylactic
reaction
Nervous system disorders
HeadacheDizziness, tremor
Cardiac disorders
Cyanosis,arrhythmia,
tachycardia
Vascular disorders
Flushing
Hypertension,
Hypotension
Respiratory, thoracic and mediastinal disorders
Wheezing,
Hypoxia,
Tachypnoea
dyspnoea
bronchospasm,
cough
Gastrointestinal disorders
Abdominal pain,
Swollen tongue,
nausea, diarrhoea, dyspepsia
vomiting
Skin and subcutaneous tissue disorders
Urticaria, rash,pruritus, erythema
Musculoskeletal and connective disorders
Arthralgia
General disorders and administration site conditions
Pyrexia, chest pain Infusion-siteswelling, faceoedema, 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 episodeduring 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
4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 andadministration of pre-infusion medicinal products, usually low-dose steroids, antihistamine, andbeta-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 (seesection 4.4).
Patients with complete deletion/large rearrangement genotype have a higher probability ofdeveloping 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 ofage. 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 forneutralizing 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, andthe 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 thosereported 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 somepatients may experience an anaphylactoid reaction due to overdose (see sections 4.3 and 4.4).

5

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Other alimentary tract and metabolism products – enzymes, ATCcode: 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 cellularengorgement, organomegaly, tissue destruction, and organ system dysfunction.
Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase, produced in ahuman 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 Nlinked glycosylation sites that are occupied by complex, hybrid, and high-mannose typeoligosaccharide 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 theoligosaccharide chains allow specific binding of the enzyme to the M6P receptors on the cellsurface, leading to cellular internalization of the enzyme, targeting to intracellular lysosomes andsubsequent 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 ageof 5 years and one open-label, safety study (HGT-ELA-038) in children between the age of 16months 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 openlabel, 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 theranks 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 fromplacebo 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 andspleen volumes, measurement of forced expiratory volume in 1 second (FEV1), and changes inleft ventricular mass (LVM). The results are presented in Table 2.

6

Table 2. Results from pivotal clinical study at 0.5 mg/kg per week (Study TKT024).
52 weeks of treatment
0.5 mg/kg weekly
Marginally weighted (OM)
Mean treatment
P-valuedifference(compared withmean (SE)compared withplacebo)Idursulfase
Placeboplacebo (SE)Endpoint
Composite
74.5 (4.5)
55.5 (4.5)
19.0 (6.5)
0.0049(6MWT and%FVC)
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)
0.0650FVC absolute
0.23 (0.04)
0.05 (0.04)
0.19 (0.06)
0.0011volume (L)Urine GAG levels-223.3 (20.7)
52.23 (20.7)-275.5 (30.1)<0.0001(μg GAG/mg
creatinine)% Change in liver-25.7 (1.5)-0.5 (1.6)-25.2 (2.2)<0.0001
volume% Change in-25.5 (3.3)
7.7 (3.4)-33.2 (4.8)<0.0001
spleen volume
A total of 11 of 31 (36%) patients in the weekly treatment group versus 5 of 31 (16%) patients inthe placebo group had an increase in FEV1 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 FEV1 at the endof 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%(20 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 hadspleen 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/m2. 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 agreater extent that patients in the other 2 treatment groups.
7

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 treatmentgroups. 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 groupof 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 fromMonth 4 to 36 were small. The higher the urinary GAG levels at baseline, the greater themagnitude of decreases in urinary GAG with idursulfase treatment.
The decreases in liver and spleen volumes observed at the end of study TKT024 (week 53) weremaintained during the extension study (TKT024EXT) in all patients regardless of the priortreatment 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 and24 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 ofantibody 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 andin 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 ahigh titre of antibodies displayed less response to idursulfase as assessed by urine output ofglycosaminoglycans 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, toaccurately predict individual clinical outcome based on antibody response or genotype.
8

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 tomannose 6-phosphate receptors. Upon internalization by cells, it is localized within cellularlysosomes, thereby limiting distribution of the protein. Degradation of idursulfase is achieved bygenerally well understood protein hydrolysis mechanisms to produce small peptides and aminoacids, consequently renal and liver function impairment is not expected to affect thepharmacokinetics 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 afunction 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
TKT024Age (years)
1.4 to 7.5
5 to 11
12 to 18
> 18
(n=27)(n=11)(n=8)(n=9)
Cmax (μg/mL)
1.3 ± 0.8
1.6 ± 0.7
1.4 ± 0.3
1.9 ± 0.5
Mean ± SD
AUC0-∞
224.3 ± 76.9
238 ± 103.7
196 ± 40.5
262 ± 74.5
(min*μg/mL)
Mean ± SD
CL
2.4 ± 0.7
2.7 ± 1.3
2.8 ± 0.7
2.2 ± 0.7
(mL/min/kg)
Mean ± SD
Vss (mL/kg)
394 ± 423
217 ± 109
184 ± 38169 ± 32
Mean ± SD
Patients in the TKT024 and HGT-ELA-038 studies were also stratified across five weightcategories; 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
≥ 20 and <≥ 30 and <≥ 40 and <≥ 50(n=17)
30
40
50 (n=5)(n=6)(n=18)(n=9)
Cmax (μg/mL)
1.2 ± 0.3
1.5 ± 1.0
1.7 ± 0.4
1.7 ± 0.7
1.7 ± 0.7
Mean ± SD
AUC0-∞
206.2 ± 33.9
234.3 ±
231.1 ±
260.2 ±
251.3 ±
(min*μg/mL)
103.0
681.0
113.8
86.2
CL
2.5 ± 0.5
2.6 ± 1.1
2.4 ± 0.6
2.4 ± 1.0
2.4 ± 1.1
(mL/min/kg)
Mean ± SD
Vss
321 ± 105397 ± 528
171 ± 52
160 ± 59
181 ± 34
(mL/kg)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 data9

Nonclinical data reveal no special hazard for humans based on conventional studies of safety
pharmacology, single dose toxicity, repeated dose toxicity, toxicity to reproduction anddevelopment 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 thosementioned 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°C).
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 ofsolution. 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 ofinfusion using a 0.2 µm in line filter. Elaprase should not be infused with other medicinal
products in the infusion tubing.
10-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 ispresent. The solution should not be shaken.
The calculated volume of Elaprase should be withdrawn from the appropriate number ofvials.
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 202011