Elaprase

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 

 

SUMMARY OF PRODUCT CHARACTERISTICS 

 



2 

▼This medicinal product is subject to additional monitoring. This will allow quick identification of 

new safety information. Healthcare professionals are asked to report any suspected adverse reactions. 

See section 4.8 for how to report adverse reactions. 

 

 

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. 

 



3 

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 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 



4 

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. 

 



5 

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 



6 

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. Healthcare 

professionals are asked to report any suspected adverse reactions via the national reporting system 

listed in Appendix V. 

 

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. 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


7 

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 (FEV1), 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 



8 

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 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 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% (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 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/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 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 



9 

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. 

 

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 

 

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 



10 

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) 

Cmax (μg/mL) 

Mean ± SD 

1.3 ± 0.8 1.6 ± 0.7 1.4 ± 0.3 1.9 ± 0.5 

AUC0-∞ 

(min*μg/mL) 

Mean ± SD 

224.3 ± 76.9 238 ± 103.7 196 ± 40.5 262 ± 74.5 

CL 

(mL/min/kg) 

Mean ± SD 

2.4 ± 0.7 2.7 ± 1.3 2.8 ± 0.7 2.2 ± 0.7 

Vss (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 < 30 

(n=18) 

≥ 30 and < 40 

(n=9) 

≥ 40 and < 50 

(n=5) 

≥ 50 

(n=6) 

Cmax (μg/mL)  

Mean ± SD 

1.2 ± 0.3 1.5 ± 1.0 1.7 ± 0.4 1.7 ± 0.7 1.7 ± 0.7 

AUC0-∞ 

(min*μg/mL) 

206.2 ± 33.9 234.3 ± 103.0 231.1 ± 681.0 260.2 ± 113.8 251.3 ± 86.2 

CL 

(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 

Vss 

(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. 

 



11 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 

 

Polysorbate 20 

Sodium chloride 

Dibasic sodium phosphate heptahydrate 

Monobasic sodium phosphate monohydrate 

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 

 

3 years. 

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 sizes of 1, 4 and 10 vials. Not all pack sizes may be marketed. 

 

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. 

 



12 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Shire Human Genetic Therapies AB 

Vasagatan 7 

111 20 Stockholm 

Sweden 

 

 

8. MARKETING AUTHORISATION NUMBER(S)  

 

EU/1/06/365/001-003 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 

 

Date of first authorisation: 08 January 2007 

Date of latest renewal:  

 

 

10. DATE OF REVISION OF THE TEXT 

 

 

 

Detailed information on this medicinal product is available on the website of the European Medicines 

Agency http://www.ema.europa.eu.

http://www.ema.europa.eu/


13 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE 

SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR 

BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 

E. SPECIFIC OBLIGATION TO COMPLETE POST-

AUTHORISATION MEASURES FOR THE MARKETING 

AUTHORISATION UNDER EXCEPTIONAL 

CIRCUMSTANCES 



14 

A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND 

MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer of the biological active substance 

 

Shire (TK3) 

205 Alewife Brook Parkway 

Cambridge, MA 02138 

USA 

 

Shire 

300 Shire Way 

Lexington MA 02421 

USA 

 

Name and address of the manufacturer responsible for batch release 

 

Shire Pharmaceuticals Ireland Limited 

Block 2 & 3 Miesian Plaza 

50 – 58 Baggot Street Lower 

Dublin 2 

Ireland 

 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 

Characteristics, 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

• Periodic safety update reports (PSURs)  
 

The requirements for submission of PSURs for this medicinal product are set out in the list of Union 

reference dates (EURD list) provided for under Article 107c(7) of Directive 2001/83/EC and any 

subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT  

 

• Risk management plan (RMP) 
 

The marketing authorization holder (MAH) shall perform the required pharmacovigilance 

activities and interventions detailed in the agreed RMP presented in Module 1.8.2 of the 

marketing authorisation and any agreed subsequent updates of the RMP. 

 

An updated RMP should be submitted: 

• At the request of the European Medicines Agency;  

• Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 

 



15 

E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES 

FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL 

CIRCUMSTANCES 

 

This being an approval under exceptional circumstances and pursuant to Article 14(8) of Regulation 

(EC) No 726/2004, the MAH shall conduct, within the stated timeframe, the following measures: 

 

Description Due date 

Specific Obligation 1 – Hunter Outcome Survey (HOS): available data and 

updates will be provided within Annual Reassessments. 

31 March 

every year 

Specific Obligation 4 – To submit data regarding immunogenicity after re-

exposure to idursulfase within Annual Reassessments. 

31 March 

every year 

Specific Obligation 5 – To evaluate the following long term clinical endpoints 

primarily through the HOS. These data will be re-evaluated annually and 

outcomes reported and discussed within the Annual Reassessments. 

 

- Assessment of long term pulmonary morbidity (e.g., incidence of infections, 
pulmonary function status) and mortality 

- Assessment of long term cardiovascular morbidity (e.g., incidence of 
events, and echocardiography data, where available) and mortality 

- Assessment of long term urinary GAG excretion patterns 
- Assessment of long term antibody levels, isotype and correlation to other 

therapeutic parameters 

31 March 

every year 

 



16 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 



17 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 



18 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

OUTER CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Elaprase 2 mg/ml concentrate for solution for infusion 

idursulfase  

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

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

 

 

3. LIST OF EXCIPIENTS 

 

Polysorbate 20 

Sodium chloride  

Dibasic sodium phosphate heptahydrate 

Monobasic sodium phosphate monohydrate 

Water for injections 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Concentrate for solution for infusion 

3 ml  

4 x 3 ml 

10 x 3 ml 

 

6 mg/3 ml 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

For single use only 

Read the package leaflet before use 

Intravenous use 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP  



19 

9. SPECIAL STORAGE CONDITIONS 

 

Store in a refrigerator  

Do not freeze 

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Shire Human Genetic Therapies AB 

Vasagatan 7 

111 20 Stockholm 

Sweden 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/06/365/001 

EU/1/06/365/002 

EU/1/06/365/003 

 

 

13. BATCH NUMBER 

 

Lot  

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Justification for not including Braille accepted  

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included 

 

 

18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 



20 

 

MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 

 

VIAL  

 

 

1. NAME OF THE MEDICINAL PRODUCT AND ROUTE(S) OF ADMINISTRATION 

 

Elaprase 2 mg/ml sterile concentrate 

idursulfase 

IV 

 

 

2. METHOD OF ADMINISTRATION 

 

 

3. EXPIRY DATE 

 

EXP  

 

 

4. BATCH NUMBER 

 

Lot  

 

 

5. CONTENTS BY WEIGHT, BY VOLUME OR BY UNIT 

 

6 mg/3 ml 

 

 

6. OTHER 

 

Store in a refrigerator  

Do not freeze 

 

 



21 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



22 

Package leaflet: Information for the user 

 

Elaprase 2 mg/ml concentrate for solution for infusion 

idursulfase 

 

▼This medicine is subject to additional monitoring. This will allow quick identification of new safety 

information. You can help by reporting any side effects you may get. See the end of section 4 for how 

to report side effects. 

 

Read all of this leaflet carefully before you start using this medicine because it contains 

important information for you. 

 

- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor, pharmacist or nurse. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible 
side effects not listed in this leaflet. See section 4. 

 

What is in this leaflet:  

 

1. What Elaprase is and what it is used for 

2. What you need to know before you use Elaprase 

3. How to use Elaprase 

4. Possible side effects 

5 How to store Elaprase  

6. Contents of the pack and other information 

 

 

1. What Elaprase is and what it is used for 

 

Elaprase is used as enzyme replacement therapy to treat children and adults with Hunter syndrome 

(Mucopolysaccharidosis II) when the level of the enzyme iduronate-2-sulfatase in the body is lower 

than normal, helping improve the symptoms of the disease. If you suffer from Hunter syndrome, a 

carbohydrate called glycosaminoglycan which is normally broken down by your body, is not broken 

down and slowly accumulates in various organs in your body. This causes cells to function 

abnormally, thereby causing problems for various organs in your body which can lead to tissue 

destruction and organ malfunction and failure. Typical organs where glycosaminoglycan accumulates 

are spleen, liver, lungs, heart, and connective tissue. In some patients glycosaminoglycan accumulates 

also in the brain. Elaprase contains an active substance called idursulfase which works by acting as a 

replacement for the enzyme that is at a low level, thereby breaking down this carbohydrate in affected 

cells. 

 

Enzyme replacement therapy is usually administered as a long-term treatment. 

 

 

2. What you need to know before you use Elaprase 

 

Do not use Elaprase 

 

If you have experienced severe or potentially life-threatening allergic-type reactions to idursulfase or 

any of the other ingredients of this medicine (listed in section 6) and these cannot be controlled with 

appropriate medical treatment. 

 

Warnings and precautions 

 

Talk to your doctor or nurse before using this medicine. 



23 

 

If you are treated with Elaprase you may experience side effects during or following an infusion (see 

section 4 Possible side effects). The most common symptoms are itching, rash, hives, fever, headache, 

increased blood pressure, and flushing (redness). Most of the time you can still be given this medicine 

even if these symptoms occur. If you experience an allergic side effect following administration of this 

medicine, you should contact your doctor immediately. You may be given additional medicines such 

as antihistamines and corticosteroids to treat or help prevent allergic-type reactions. 

 

If severe allergic reactions occur, your doctor will stop the infusion immediately, and start giving you 

suitable treatment. You may need to stay in hospital. 

 

The nature of your genotype (a genetic make up of all active genes in human cells, which determines 

one’s specific, individual characteristics) may influence your therapeutic response to this medicine, as 

well as your risk of developing antibodies and infusion-related side effects. In individual cases, so-

called ‘neutralising antibodies’ may develop, which may diminish activity of Elaprase and your 

response to treatment. The longer term effects of antibody development on response to treatment have 

not been established. Please consult your doctor for additional information. 

 

Keeping a record 

 

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

the administered product should be clearly recorded by your healthcare professional. Speak with your 

healthcare professional if you are not sure. 

 

Other medicines and Elaprase 

 

There is no known interaction of this medicine with other medicines. 

 

Tell your doctor, pharmacist or nurse if you are taking, have recently taken or might take any other 

medicines. 

 

Pregnancy and breast-feeding 

 

If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 

your doctor or pharmacist for advice before taking this medicine. 

 

Driving and using machines 

 

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

 

Elaprase contains sodium 

 

This medicine contains 11.1 mg sodium (main component of cooking/table salt) in each vial. This is 

equivalent to 0.6% of the recommended maximum daily dietary intake of sodium for an adult. 

 

3. How to use Elaprase 

 

Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not 

sure. 

 

This medicine will be given to you under the supervision of a doctor or nurse who is knowledgeable in 

the treatment of Hunter syndrome or other inherited metabolic disorders. 

 

The recommended dose is an infusion of 0.5 mg (half a milligram) for every kg you weigh 

 



24 

Elaprase has to be diluted in sodium chloride 9 mg/ml (0.9%) solution for infusion before use. After 

dilution this medicine is given through a vein (drip feed). The infusion will normally last for 1 to 

3 hours and will be given every week. 

 

Use in children and adolescents 

 

The recommended dosage in children and adolescents is the same as in adults. 

 

If you use more Elaprase than you should 

 

Consult your doctor if you have an overdose of this medication. 

 

If you forget to use Elaprase 

 

If you have missed an Elaprase infusion, please contact your doctor. 

 

If you have any further questions on the use of this medicine, ask your doctor or nurse. 

 

 

4. Possible side effects 

 

Like all medicines, this medicine can cause side effects, although not everybody gets them.  

 

Most side effects are mild to moderate and associated with the infusion, however some side effects 

may be serious. Over time the number of these infusion-associated reactions decreases. 

 

If you have problems breathing, with or without bluish skin, tell your doctor straight away and 

seek immediate medical assistance. 

 

Very common side effects (may affect more than 1 in 10 people) are: 

• Headache 

• Flushing (redness) 

• Shortness of breath, wheezing 

• Abdominal pain, nausea, vomiting, frequent and/or loose stools 

• Chest pain 

• Hives, rash, itching, redness of the skin 

• Fever 

• Infusion-related reaction (see section entitled “Warnings and precautions”) 

 

Common side effects (may affect up to 1 in 10 people) are: 

• Dizziness, tremor 

• Rapid heartbeat, irregular heartbeat, bluish skin 

• Increased blood pressure, decreased blood pressure 

• Difficulty breathing, cough, low oxygen levels in your blood 

• Swollen tongue, indigestion 

• Pain in the joints 

• Infusion-site swelling, swelling of the extremities, facial swelling 

 

Uncommon side effects (may affect up to 1 in 100 people) are: 

• Quickened breathing 

 

Side effects for which frequency is not known (cannot be estimated from available data) are: 

• Serious allergic reactions 

 



25 

Reporting of side effects 

 

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 

effects not listed in this leaflet. You can also report side effects directly via the national reporting 

system listed in Appendix V. By reporting side effects you can help provide more information on the 

safety of this medicine. 

 

5. How to store Elaprase  
 

Keep this medicine out of the sight and reach of children. 

 

Do not use this medicine after the expiry date which is stated on the label and carton after EXP. The 

expiry date refers to the last day of that month. 

Store in a refrigerator (2C – 8C) 

Do not freeze 

 

Do not use this medicine if you notice that there is discolouration or presence of foreign particles. 

 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help protect the environment. 

 

 

6. Contents of the pack and other information 

 

What Elaprase contains 

 

The active substance is idursulfase, which is a form of the human enzyme iduronate-2-sulfatase. 

Idursulfase is produced in a human cell line by genetic engineering technology (it involves the 

introduction of genetic information into human cells in the lab, which will then produce the desired 

product). 

 

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

 

The other ingredients are Polysorbate 20, sodium chloride, dibasic sodium phosphate, heptahydrate, 

monobasic sodium phosphate, monohydrate and water for injections. 

 

What Elaprase looks like and contents of the pack 

 

This medicine is a concentrate for solution for infusion. It is supplied in a glass vial as a clear to 

slightly opalescent, colourless solution. 

 

Each vial contains 3 ml of concentrate for solution for infusion. 

 

Elaprase is supplied in pack sizes of 1, 4 and 10 vials per carton. Not all pack sizes may be marketed. 

 

Marketing Authorisation Holder  

 

Shire Human Genetic Therapies AB 

Vasagatan 7 

111 20 Stockholm 

Sweden 

Tel: +44(0)1256 894 959 

E-mail: medinfoEMEA@shire.com 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc
mailto:medinfoEMEA@shire.com


26 

Manufacturer 

 

Shire Pharmaceuticals Ireland Limited 

Block 2 & 3 Miesian Plaza 

50 – 58 Baggot Street Lower 

Dublin 2 

Ireland 

 

This leaflet was last revised in. 

 

This medicine has been authorised under “exceptional circumstances”. This means that because of the 

rarity of this disease it has been impossible to get complete information on this medicine. 

 

The European Medicines Agency will review any new information on the medicine every year and this 

leaflet will be updated as necessary. 

 

Other sources of information 

 

Detailed information on this medicine is available on the European Medicines Agency web site: 

http://www.ema.europa.eu. There are also links to other websites about rare diseases and treatments. 

 

This leaflet is available in all EU/EEA languages on the European Medicines Agency website. 

 

-------------------------------------------------------------------------------------------------------------------------- 

 

The following information is intended for healthcare professionals only: 

 

Instructions for use, handling and disposal 

 

1. Calculate the total dose to be administered and number of Elaprase vials needed. 
 

2. Dilute the total volume of Elaprase concentrate for solution for infusion required in 100 ml of 
sodium chloride 9 mg/ml (0.9%) solution for infusion . It is recommended to deliver the total 

volume of the infusion using a 0.2 µm in line filter. 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. 

 

3. The solution should be inspected visually for particulate matter and discolouration prior to 
administration. Do not shake. 

 

4. It is recommended that administration is started as soon as possible. The chemical and physical 
stability of the diluted solution has been demonstrated for 8 hours at 25°C. 

 

5. Do not infuse Elaprase concomitantly in the same intravenous line with other medicinal 
products. 

 

6. For single use only. Any unused product or waste material should be disposed of in accordance 
with local requirements. 

 

http://www.ema.europa.eu/

	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER OF THE BIOLOGICAL ACTIVE SUBSTANCE AND MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	E. SPECIFIC OBLIGATION TO COMPLETE POST-AUTHORISATION MEASURES FOR THE MARKETING AUTHORISATION UNDER EXCEPTIONAL CIRCUMSTANCES
	A. LABELLING
	B. PACKAGE LEAFLET