Elaprase 2 mg/ml concentrate for solution for infusion.

Each vial of 3 ml contains 6 mg of idursulfase. Each ml contains 2 mg of idursulfase.

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

For a full list of excipients, see section 6.1.

Concentrate for solution for infusion.

A clear to slightly opalescent, colourless solution.

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.

Elaprase 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.

Infusion of Elaprase 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.

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 preparation and administration instructions see section 6.6.

Patients with renal or hepatic impairment

There is no clinical experience in patients with renal or hepatic insufficiency. See section 5.2.

Elderly patients

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

Paediatric patients

The dose for children and adolescents is 0.5 mg/kg body weight weekly.

For preparation and administration instructions see section 6.6.

There is no clinical experience in children under the age of 5.

Hypersensitivity to the active substance or to any of the excipients.

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 medicines, such as antihistamines, antipyretics, low-dose corticosteroids (prednisone and methylprednisolone), or beta-agonist nebulization. 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.

Consider delaying the infusion in patients who present with an acute febrile respiratory illness. Patients using supplemental oxygen should have this treatment readily available during infusion in the event of an infusion-related reaction.

Patients who develop IgM or IgG antibodies are at a higher risk of infusion reactions and other adverse reactions, however, IgE antibodies have not been observed.

Anaphylactoid reactions, which have the potential to be life threatening, have been observed in some patients treated with Elaprase, as with any intravenous protein product. Late emergent symptoms and signs of anaphylactoid reactions have been observed as long as 24 hours after an initial reaction. If an anaphylactoid 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 reactions may require prolonged clinical monitoring. Patients who have experienced anaphylactoid reactions should be treated with caution when re-administering Elaprase.

No formal drug interaction studies have been conducted with Elaprase.

Based on its metabolism in cellular lysosomes, idursulfase would not be a candidate for cytochrome P450 mediated interactions.

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

There are no 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 Elaprase during pregnancy.

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 suckling child cannot be excluded. A decision on whether to continue/discontinue breast-feeding or to continue/discontinue therapy with Elaprase should be made taking into account the benefit of breast-feeding to the child and the benefit of Elaprase therapy to the woman.

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

Adverse drug reactions that were reported for the 32 patients treated with 0.5 mg/kg Elaprase weekly in the 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 over estimate 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), pyrexia, headache, and hypertension. The frequency of infusion-related reactions decreased over time with continued treatment.

Adverse drug reactions are listed in the table below with information presented by system organ class and frequency. Frequency is given as very common (>1/10) or common (>1/100, <1/10). The occurrence of an event in a single patient is defined as common in view of the number of patients treated. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse drug reactions only reported during the post marketing period are also included in the table with a frequency of “not known”.

Adverse drug reactions were defined as treatment-emergent events with suspected causality and excluded non-serious events that were reported only once in a single patient; treatment emergent events with an excess incidence of at least 9% compared with placebo were also considered as adverse drug reactions.

Across 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 nebulization. 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 reactions. Please see section 4.4 for further information.

Across all studies, 53/107 patients (50%) developed anti-idursulfase IgG antibodies at some point. Nine of the IgG positive patients also tested positive for IgM antibodies, and four patients tested positive for IgA antibodies. In addition, one patient who was not IgG positive developed transient IgM antibodies and persistent IgA antibodies. The overall neutralizing antibody rate was 26/107 patients (24%). In the 52-week study, rates of seropositivity peaked by Weeks 18 to 27 and steadily declined thereafter for the remainder of this study.

In general, patients who tested positive for IgG antibodies were more likely to have infusion-related events than those who did not test positive. However, overall rates of infusion-related adverse events declined over time, regardless of antibody status. The reduction of urinary GAG excretion was somewhat less in patients for whom circulating anti-idursulfase antibodies were detected.

There is no experience with overdoses of Elaprase.

Pharmacotherapeutic group: Alimentary tract and metabolism products – enzymes, ATC code: A16AB09.

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 Elaprase 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.

A total of 108 male Hunter syndrome patients with a broad spectrum of symptoms were enrolled in two randomized, placebo-controlled clinical studies, 106 continued treatment in two open-label, extension studies.

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).

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 0.02L 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 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 0.07L to 0.31L 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.

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, 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.

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 (EMA) will review any new information which may become available every year and this SPC will be updated as necessary.

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.

Pharmacokinetics was eva luated in 10 patients at Week 1 and Week 27 following administration of 0.5 mg/kg weekly as a 3-hour infusion. There were no differences in pharmacokinetic parameters following 27 weeks of treatment.

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.

Polysorbate 20

Sodium chloride

Sodium phosphate dibasic, heptahydrate

Sodium phosphate monobasic, monohydrate

Water for Injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

2 years

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

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.

Store in a refrigerator (2°C – 8°C).

Do not freeze.

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

3 ml of concentrate for solution for infusion in a 5 ml vial (type I glass) with a stopper (fluoro-resin coated butyl rubber), one piece seal and blue flip-off cap.

Pack sizes of 1, 4 and 10 vials.

Not all pack sizes may be marketed.

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 product or waste material should be disposed of in accordance with local requirements.

Shire Human Genetic Therapies AB, Svärdvägen 11D, 182 33 Danderyd, Sweden

EU/1/06/365/001-003

08.01.2007

03/2010

Detailed information on this medicinal product is available on the website of the European Medicines Agency (EMA) http://www.ema.europa.eu.