Elapraza

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ELAPRASE (ELAPRASE)

Composition:

Active substance: idursulfase;

1 ml contains idursulfase 2 mg;

Excipients: sodium chloride, sodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, polysorbate 20, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear or slightly opalescent, colorless solution.

Pharmacotherapeutic group.

Agents affecting the digestive system and metabolism. Enzymes. Idursulfase. ATC code A16A B09.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Hunter syndrome is an X-linked disorder caused by deficient levels of the lysosomal enzyme iduronate-2-sulfatase in the body. The function of iduronate-2-sulfatase is the catabolism of glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate by cleaving sulfate groups from oligosaccharide-bound positions. Due to the absence or presence of defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, glycosaminoglycans progressively accumulate within cells, leading to cellular engorgement, organomegaly, tissue destruction, and organ dysfunction.

Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase produced in a human cell line, providing a glycosylation profile similar to that of the natural enzyme. Idursulfase is secreted as a 525-amino acid glycoprotein and contains 8 N-linked glycosylated sites bearing complex hybrid oligosaccharide chains as well as oligosaccharides with high mannose content. The molecular weight of idursulfase is approximately 76 kDa.

Idursulfase administered intravenously to patients with Hunter syndrome provides exogenous enzyme delivery to cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow the enzyme to specifically bind to M6P receptors on the cell surface, resulting in cellular internalization of the enzyme targeted to intracellular lysosomes, and subsequent catabolism of accumulated GAGs.

Clinical Efficacy and Safety

The safety and efficacy of Elaprase were demonstrated in three clinical studies: two randomized, placebo-controlled clinical trials (TKT008 and TKT024) involving adults and children aged 5 years and older, and one open-label safety study (HGT-ELA-038) involving children aged 16 months to 7.5 years.

Overall, 108 male patients with Hunter syndrome and a broad range of symptoms were included in the two randomized, placebo-controlled clinical trials; 106 of them continued treatment during two open-label extension studies.

Study TKT024

In a 52-week randomized, double-blind, placebo-controlled study, 96 patients aged 5 to 31 years received Elaprase at a dose of 0.5 mg/kg once weekly (n = 32), or 0.5 mg/kg once every two weeks (n = 32), or placebo (n = 32). Patients included in the study had documented deficiency of iduronate-2-sulfatase enzyme activity, a forced vital capacity (FVC) <80% of predicted, and a wide range of clinical disease severity.

The primary efficacy endpoint was a two-part composite measure based on the sum of ranks of change from baseline to end of study in the distance walked during the 6-minute walk test (6-MWT), as a measure of endurance, and the percentage of predicted FVC as a measure of lung function. This endpoint differed significantly between patients receiving weekly treatment and those in the placebo group (p = 0.0049).

Additional analyses of clinical efficacy were performed on individual components of the primary composite endpoint, absolute changes in FVC, changes in urinary GAG concentration and liver and spleen size, forced expiratory volume in one second (FEV1), and left ventricular mass (LVM) dynamics. Data are presented in Table 1.

Table 1. Results of the clinical study of Elaprase administered at a dose of 0.5 mg/kg body weight weekly (TKT024).

Overall, an increase in FEV1 of at least 0.2 L was observed in 11 out of 31 patients (36%) in the weekly treatment group compared to 5 out of 31 patients (16%) in the placebo group during or by the end of the study, indicating a dose-dependent reduction in airway obstruction. In patients receiving weekly therapy, FEV1 significantly improved by an average of 15% at the end of the study.

Urinary GAG concentration decreased below the LLOQ (defined as 126.6 µg GAG/mg creatinine) in 50% of patients receiving weekly treatment.

In 80% (20 out of 25) of patients with hepatomegaly at baseline who received weekly treatment, liver size decreased to normal by the end of the study.

Of the 9 patients in the weekly treatment group who had splenomegaly at baseline, spleen size normalized by the end of the study in 3 patients.

Left ventricular hypertrophy, defined as a LVMI > 103 g/m², was present at baseline in approximately half of the patients in the weekly treatment group (15 out of 32; 47%). LVMI normalized by the end of the study in 6 (40%) of these patients.

All patients received weekly idursulfase for up to 3.2 years in an open-label extension study (TKT024EXT).

In patients receiving weekly idursulfase in study TKT024, the average maximum improvement in 6-minute walk distance occurred at month 20, and the percentage of predicted FVC reached its peak on average at month 16.

All patients showed a statistically significant mean increase in 6-minute walk distance at most assessment time points from the start of treatment (for patients receiving idursulfase, the start was the beginning of study TKT024; for placebo patients, the start was week 53), with mean and percentage increases in walking distance ranging from 13.7 m to 41.5 m (maximum at month 20) and from 6.4% to 13.3% (maximum at month 24), respectively. At most time points, patients initially receiving weekly treatment in study TKT024 showed greater improvement in walking distance than the two other treatment groups.

The mean percentage of predicted FVC significantly increased by month 16 in all patients, although by month 36 it was similar to baseline values. Minimal improvement was observed in patients with the most severe pulmonary disease at baseline (as measured by percentage of predicted FVC).

Statistically significant increases in absolute FVC from baseline were observed at most visits across all combined treatment groups and each prior treatment group in study TKT024. Mean changes in FVC ranged from 0.07 L to 0.31 L, and percentage changes ranged from 6.3% to 25.5% (maximum at month 30). Mean and percentage changes in FVC at each time point from treatment initiation were greatest in the weekly treatment group in study TKT024.

At the final visit in study TKT024, normalization of urinary GAG concentration below the LLOQ was observed in 21 out of 31 patients in the weekly treatment group, 24 out of 32 patients in the every-other-week treatment group, and 18 out of 31 patients in the placebo group. Changes in urinary GAG concentration were the earliest signs of clinical improvement during idursulfase therapy, with the greatest reduction observed during the first 4 months of treatment across all treatment groups; changes from month 4 to month 36 were minimal. The higher the urinary GAG concentration at baseline, the greater the reduction during idursulfase treatment.

Reductions in liver and spleen size observed at the end of study TKT024 (week 53) were maintained during the extension study (TKT024EXT) in all patients regardless of prior treatment group assignment. Liver size normalized by month 24 in 73% (52 out of 71) of patients who had hepatomegaly at baseline. Additionally, liver size reduction peaked on average by month 8 in all previously treated patients, with a slight increase in liver size observed by month 36. Reduction in liver size was independent of age, disease severity, presence of IgE antibodies, or neutralizing antibodies. In study TKT024, spleen size normalized by month 12 and month 24 in 9.7% of patients with splenomegaly receiving weekly therapy.

During study TKT024, mean LVMI remained stable over 36 months of idursulfase therapy across all treatment groups.

A retrospective immunogenicity analysis based on data from studies TKT024 and TKT024EXT (see section "Adverse Reactions") showed that patients had either a missense mutation or a frameshift/nonsense mutation. After 105 weeks of idursulfase treatment, neither antibody status nor genotype influenced reductions in liver and spleen size, 6-minute walk distance, or forced vital capacity measurements. Patients who tested positive for antibodies showed a smaller reduction in urinary glycosaminoglycan levels compared to patients who tested negative for antibodies. The long-term clinical impact of antibody development has not been established.

Study HGT-ELA-038

An open-label, multicenter study was conducted in a single group of boys with Hunter syndrome aged 16 months to 7.5 years receiving idursulfase infusions.

Treatment with Elaprase resulted in nearly a 60% reduction in urinary glycosaminoglycan levels and reductions in liver and spleen size: results from this study were comparable to those from study TKT024. Reductions in these parameters were observed by week 18 and continued through week 53. Patients who developed high antibody titers showed a reduced response to idursulfase based on urinary glycosaminoglycan levels and liver and spleen size measurements.

Genotype analysis of patients in study HGT-ELA-038

Patients were classified into the following groups: missense mutation (13), complete deletion/major rearrangement (8), and frameshift/splice site mutations (5). One patient was unclassified/not classified.

Complete deletion/major rearrangement genotypes were most frequently associated with the development of high antibody titers and neutralizing antibodies to idursulfase. A diminished response to this medicinal product is most likely in this patient category. However, individual clinical response cannot be precisely predicted based on antibody response or genotype.

There are no clinical data demonstrating benefits with regard to neurological manifestations of the disease.

Pharmacokinetics

The mechanism of idursulfase uptake is mediated by selective binding to mannose-6-phosphate receptors. After cellular internalization, it localizes to cellular lysosomes, thereby limiting protein distribution. Idursulfase degradation occurs via well-understood protein hydrolysis mechanisms, resulting in small peptide fragments and amino acids. Therefore, impaired renal or hepatic function does not affect the pharmacokinetic parameters of idursulfase.

Pharmacokinetic parameters determined at week 1 of studies TKT024 (treatment group receiving 0.5 mg/kg weekly) and HGT-ELA-038 after the first intravenous infusion of Elaprase are presented in Tables 2 and 3 as a function of age and body weight.

Table 2. PK parameters at week 1 as a function of age: studies TKT024 and HGT-ELA-038.

Patients enrolled in studies TKT024 and HGT-ELA-038 were also stratified by five body weight categories (see table).

Table 3. PK parameters at Week 1 as a function of body weight: studies TKT024 and HGT-ELA-038.

A higher volume of distribution at steady state (Vss) was observed in patient groups with lower body weight.

Overall, when assessing age or body weight, no clear trend was observed either for systemic exposure or for the clearance rate of Elaprazole.

Clinical characteristics

Indications.

Elaprase is indicated for long-term treatment of patients with Hunter syndrome (mucopolysaccharidosis type II (MPS II)).

Women who are heterozygous carriers were not included in clinical trials.

Contraindications.

Severe or life-threatening hypersensitivity to the active substance or to any of the excipients, when hypersensitivity cannot be controlled.

Special precautions.

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

Interaction with other medicinal products and other forms of interaction.

Formal studies of idursulfase interaction with other medicinal products have not been conducted.

However, due to the metabolism of the drug in cellular lysosomes, idursulfase is not expected to interact with drugs that are metabolized in the body via the cytochrome P450 system.

Special precautions for use.

Infusion reactions

Infusion reactions may occur in patients receiving idursulfase (see section "Adverse reactions"). During clinical trials, the most common infusion reactions included skin reactions (rash, pruritus, urticaria), hyperthermia, headache, hypertension, and facial flushing. Infusion reactions were managed or reduced by slowing the infusion rate, temporarily stopping the infusion, or by administration of medications such as antihistamines, antipyretics, low-dose corticosteroids (prednisolone or methylprednisolone), or inhaled beta-agonists. During clinical studies, no patient discontinued treatment due to infusion reactions.

Infusion therapy should be administered with particular caution in patients with severe underlying respiratory disease. This patient population requires careful monitoring and administration of infusion therapy under appropriate clinical conditions. These patients should be prescribed disease control and treatment medications cautiously, with limitation or careful monitoring of antihistamines and other sedative medicinal products. In some cases, provision of positive airway pressure may be required.

For patients with acute febrile respiratory illness, consideration should be given to postponing infusion therapy. For patients receiving supplemental oxygen therapy, oxygen should be available during infusion therapy in case an infusion reaction occurs.

Anaphylactoid/anaphylactic reactions

Anaphylactoid/anaphylactic reactions, which may be life-threatening, have been observed in some patients receiving idursulfase, even after several years of treatment initiation. Delayed symptoms of anaphylactoid/anaphylactic reactions have been observed within 24 hours following the initial reaction. If an anaphylactoid/anaphylactic reaction occurs, the infusion must be stopped immediately and appropriate treatment and monitoring initiated. Current standards of emergency therapy should be followed. Patients with severe or refractory anaphylactoid/anaphylactic reactions may require prolonged clinical observation. Re-administration of idursulfase to patients with a history of anaphylactoid/anaphylactic reactions to the drug should be undertaken with caution. Therefore, infusions should be administered by appropriately trained personnel in settings equipped with resuscitation equipment and medications (including epinephrine). Severe or potentially life-threatening hypersensitivity is a contraindication to re-administration of the drug if hypersensitivity cannot be controlled (see section "Contraindications").

Patients with complete gene deletion/significant genotype rearrangement

Children with complete gene deletion/significant genotype rearrangement are at high risk of developing antibodies, including neutralizing antibodies, in response to idursulfase. Patients with this genotype generally have a higher risk of infusion-related adverse reactions and a more attenuated response to treatment, as determined by the degree of reduction in urinary glycosaminoglycan levels, liver size, and spleen volume, compared to patients with a missense genotype. Evaluation and treatment of these patients should be individualized (see section "Adverse reactions").

Sodium content

The medicinal product contains 0.482 mmol of sodium (or 11.1 mg) per vial, which is equivalent to 0.6% of the WHO recommended maximum daily intake of sodium for adults of 2 g.

Traceability

To enhance traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

Use during pregnancy or breastfeeding

Pregnancy

Data on the use of idursulfase in pregnant women are lacking or limited. Animal studies have not shown any direct or indirect adverse effects with regard to reproductive toxicity. As a precautionary measure, it is advisable to avoid using idursulfase during pregnancy.

Breastfeeding

It is unknown whether idursulfase is excreted in human breast milk. Animal studies have confirmed excretion of idursulfase into breast milk. A risk to newborns/infants cannot be excluded. Therefore, the decision to discontinue breastfeeding or to discontinue/abstain from idursulfase therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility

Reproductive studies did not reveal any effect on fertility in male rats.

Ability to affect reaction speed when driving or operating machinery

Idursulfase has no or negligible influence on the ability to drive or operate machinery.

Administration and Dosage

Elaprase is administered under the supervision of a physician or nurse experienced in the treatment of MPS II or other inherited metabolic disorders.

The recommended dose is 0.5 mg/kg body weight administered once weekly as an intravenous infusion over a 3-hour period. This infusion time may be gradually reduced to 1 hour, provided the patient does not experience infusion-related reactions (see section "Special Precautions").

Each vial of Elaprase is for single use only and contains 6 mg of idursulfase in 3 mL of solution. Elaprase is intended for intravenous infusion and must be diluted prior to administration in 0.9% sodium chloride solution (9 mg/mL). It is recommended to administer the total infusion volume using a linear filter with a pore size of 0.2 μm. Elaprase should not be co-administered with other medicinal products in the same infusion line.

Preparation Instructions

• Determine the number of vials required based on the patient's body weight and the recommended dose of 0.5 mg/kg.
• Do not use the medication if the solution in the vial has changed color or if particulate matter is present. Do not shake the vial.
• Withdraw the calculated volume of Elaprase from the required number of vials.
• Dilute the total dose of Elaprase in 100 mL of 0.9% sodium chloride solution (9 mg/mL) for infusion. Care must be taken to maintain sterility of the prepared solution, as Elaprase does not contain preservatives or bacteriostatic agents; aseptic techniques must be followed. After dilution, gently mix the solution by inversion; do not shake.

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

Home infusion may be considered for patients who have received treatment in a medical facility for several months and have demonstrated adequate tolerance to infusions. Home infusions must be performed under the supervision of a physician.

Special Patient Groups

Elderly Patients

There is no clinical experience with the use of Elaprase in patients over 65 years of age.

Patients with Renal or Hepatic Impairment

There is no clinical experience with the use of Elaprase in patients with renal or hepatic impairment (see section "Pharmacokinetics").

Children

The same dosage regimen as in adults (0.5 mg/kg body weight once weekly) is recommended for children and adolescents.

Overdose

Information regarding overdose with Elaprase is limited. An anaphylactoid reaction may occur in some patients due to overdose (see sections "Contraindications", "Special Precautions").

Adverse Reactions

Adverse reactions were observed in 32 patients who received idursulfase at a dose of 0.5 mg/kg weekly during a 52-week placebo-controlled Phase II/III study (study TKT024). In nearly all cases, these reactions were mild or moderate in severity. The most commonly observed events were infusion reactions, with 202 such reactions reported in 22 out of 32 patients following a total of 1,580 infusions. In the placebo group, 128 infusion reactions were reported in 21 out of 32 patients following a total of 1,612 infusions. Since multiple infusion reactions could occur during a single infusion, the numbers stated above likely overestimate the true incidence of infusion reactions. The nature and severity of these reactions were similar between the placebo and active treatment groups. The most common infusion reactions included cutaneous reactions (rash, pruritus, urticaria, erythema), hyperthermia, flushing, wheezing, dyspnea, headache, vomiting, abdominal pain, nausea, and chest pain. The frequency of infusion reactions decreased over time with continued treatment.

The adverse reactions listed below are categorized by organ system and frequency according to the following criteria: very common (≥ 1/10), common (≥ 1/100 to <1/10), or uncommon (≥ 1/1,000 to <1/100). The frequency of an adverse event per patient is determined based on the number of patients who received treatment. Within each frequency category, adverse reactions are listed in order of decreasing severity. Also included are adverse reactions reported after marketing authorization, categorized as "unknown frequency" (frequency cannot be estimated from available data).

Table 1. Adverse reactions observed in clinical trials and post-marketing experience in patients receiving Elaprase.

Description of some adverse reactions

Serious adverse reactions were generally observed in 5 patients receiving the drug at a dose of 0.5 mg/kg weekly or every other week. Hypoxia developed during one or several infusions in 4 patients, requiring oxygen administration in 3 patients with severe obstructive respiratory diseases (2 of whom had previously undergone tracheotomy). The most severe infusion reaction, manifested by transient seizures, was observed in 1 patient during an exacerbation of febrile respiratory disease and was accompanied by hypoxia during infusion. In the fourth patient with a milder course of the underlying disease, the adverse reaction spontaneously resolved after discontinuation of the drug. Subsequently, when a slower infusion rate and premedication (administration of low-dose corticosteroids, antihistamines, beta-agonist inhalations) were used, these events did not recur. In the fifth patient with previously diagnosed cardiopathy, premature ventricular complexes and pulmonary artery thromboembolism were recorded during the study.

Post-marketing data include information on anaphylactoid/anaphylactic reactions (see section "Special precautions").

Patients with complete gene deletion/significant genotype rearrangement have a higher risk of infusion-related adverse reactions (see section "Special precautions").

Immunogenicity

During 4 clinical trials (TKT008, TKT018, TKT024, and TKT024EXT), anti-IgG antibodies to idursulfase were detected in 53 out of 107 patients (50%) at some point. The overall incidence of neutralizing antibodies was 24% (26 out of 107 patients).

In a retrospective analysis of immunogenicity data from the TKT024/024EXT studies, 51% (32 out of 63) of patients receiving idursulfase at a dose of 0.5 mg/kg weekly had at least one blood sample testing positive for antibodies to idursulfase, and 37% (23 out of 63) tested positive for antibodies during at least 3 consecutive visits: 21% (13 out of 63) tested positive for neutralizing antibodies at least once, and 13% (8 out of 63) tested positive for neutralizing antibodies during at least 3 visits.

Immunogenicity was evaluated in children aged 16 months to 7.5 years during the clinical trial HGT-ELA-038. During the 53-week study, 67.9% of patients (19 out of 28) had at least one blood sample testing positive for antibodies to idursulfase, and 57.1% of patients (16 out of 28) tested positive for antibodies during at least three consecutive visits. 54% of patients tested positive for neutralizing antibodies at least once, and half of the patients tested positive for neutralizing antibodies during at least three consecutive visits.

All patients with complete gene deletion/significant genotype rearrangement developed antibodies, and most of these patients (7 out of 8) also tested positive for neutralizing antibodies at least three consecutive times. All patients with frameshift mutation/splice site mutation genotypes developed antibodies, and 4 out of 6 patients also tested positive for neutralizing antibodies during at least three consecutive visits. Patients with negative antibody test results belonged exclusively to the missense mutation genotype group (see sections "Special precautions" and "Pharmacodynamics").

Experience with use in children

Adverse reactions identified in the pediatric population were generally similar to those in adults.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the drug. Medical and pharmaceutical professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Incompatibility.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Shelf life. 3 years.

Do not use after the expiry date.

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

Storage conditions.

Store in the original packaging at 2–8 °C.

Do not freeze.

From a microbiological standpoint, the diluted product should be used immediately. If not used immediately, the storage conditions and duration prior to use are the responsibility of the user and should not exceed 24 hours at 2–8 °C.

Keep out of the reach of children.

Packaging.

3 ml concentrate for solution for infusion in a 5 ml vial (Type I glass) with a stopper (butyl rubber coated with fluoropolymer), a seal, and a blue flip-off cap.

1 vial in a cardboard box.

Prescription status.

Prescription only.

Manufacturer. Shire Pharmaceuticals Ireland Limited.

Manufacturer's location and address of place of business.

Blocks 2/3 Meathian Plaza, 50-58 Lower Baggot Street, Dublin 2, D02 Y754, Ireland

INSTRUCTION

for medical use of the medicinal product

ELAPRASE

(ELAPRASE)

Composition:

Active substance: idursulfase;

1 ml contains idursulfase 2 mg;

Excipients: sodium chloride, sodium hydrogen phosphate heptahydrate, sodium dihydrogen phosphate monohydrate, polysorbate 20, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical characteristics: clear or slightly opalescent, colorless solution.

Pharmacotherapeutic group.

Agents affecting the digestive system and metabolism. Enzymes. Idursulfase. ATC code A16AB09.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Hunter syndrome is an X-linked disorder caused by deficient levels of the lysosomal enzyme iduronate-2-sulfatase in the body. The function of iduronate-2-sulfatase is the catabolism of glycosaminoglycans (GAGs) dermatan sulfate and heparan sulfate by cleaving sulfate groups from oligosaccharide chains. Due to the absence or presence of defective iduronate-2-sulfatase enzyme in patients with Hunter syndrome, glycosaminoglycans progressively accumulate within cells, leading to cellular overload, organomegaly, tissue destruction, and impaired organ function.

Idursulfase is a purified form of the lysosomal enzyme iduronate-2-sulfatase produced in a human cell line, providing a glycosylation profile similar to that of the natural enzyme. Idursulfase is secreted as a 525-amino acid glycoprotein and contains 8 N-linked glycosylated sites bearing complex hybrid oligosaccharide chains as well as oligosaccharides with high mannose content. The molecular weight of idursulfase is approximately 76 kDa.

Idursulfase administered intravenously to patients with Hunter syndrome provides exogenous enzyme delivery to cellular lysosomes. Mannose-6-phosphate (M6P) residues on the oligosaccharide chains allow the enzyme to specifically bind to M6P receptors on the cell surface, resulting in cellular internalization of the enzyme targeted to intracellular lysosomes, and subsequent catabolism of accumulated GAGs.

Clinical Efficacy and Safety

The safety and efficacy of Elaprase were demonstrated in three clinical studies: two randomized, placebo-controlled clinical trials (TKT008 and TKT024) involving adults and children aged 5 years and older, and one open-label safety study (HGT-ELA-038) involving children aged 16 months to 7.5 years.

Overall, 108 male patients with Hunter syndrome and a broad spectrum of symptoms were enrolled in the two randomized, placebo-controlled clinical trials; 106 of them continued treatment during two open-label extension studies.

Study TKT024

In a 52-week randomized, double-blind, placebo-controlled study, 96 patients aged 5 to 31 years received Elaprase at a dose of 0.5 mg/kg once weekly (n = 32), or 0.5 mg/kg once every two weeks (n = 32), or placebo (n = 32). Patients enrolled in the study had documented deficiency of iduronate-2-sulfatase enzyme activity, a predicted forced vital capacity (FVC) <80%, and a wide range of clinical disease severity.

The primary efficacy endpoint was a two-component composite score based on the sum of ranks of change from baseline to end of study in the distance walked during the 6-minute walk test (6MWT), as a measure of endurance, and the percentage of predicted FVC as a measure of lung function. This endpoint differed significantly between patients receiving weekly treatment and those in the placebo group (p = 0.0049).

Additional analyses of clinical efficacy were performed based on individual components of the primary composite endpoint, absolute changes in FVC, changes in urinary GAG concentration, liver and spleen size, forced expiratory volume in one second (FEV1), and left ventricular mass (LVM). Data are presented in Table 1.

Table 1. Results of the clinical study of Elaprase administered at a dose of 0.5 mg/kg body weight weekly (TKT024).

Overall, in 11 out of 31 patients (36%) in the weekly treatment group compared to 5 out of 31 patients (16%) in the placebo group, FEV1 increased by at least 0.2 L during or before the end of the study, indicating a dose-dependent reduction in airway obstruction. In patients in the weekly treatment group, FEV1 significantly improved, on average by 15%, at the end of the study.

Urinary GAG concentration decreased below the lower limit of quantification (defined as 126.6 µg GAG/mg creatinine) in 50% of patients receiving weekly treatment.

In 80% (20 out of 25) of patients with hepatomegaly at baseline who received weekly treatment with the drug, liver size decreased to normal by the end of the study.

Of the 9 patients in the weekly treatment group who had splenomegaly at baseline, spleen size normalized in 3 patients by the end of the study.

Left ventricular hypertrophy, defined as a LVMI > 103 g/m², was detected at baseline in approximately half of the patients in the weekly treatment group (15 out of 32; 47%). LVMI normalized by the end of the study in 6 (40%) of these patients.

All patients received weekly idursulfase for up to 3.2 years in an open-label extension study (TKT024EXT).

In patients receiving weekly idursulfase in study TKT024, the mean maximum improvement in the 6-minute walk distance was observed at month 20, and the percent predicted FVC reached its maximum at a mean of month 16.

All patients showed a statistically significant mean increase in the 6-minute walk distance at most assessment time points from the start of treatment (for patients receiving idursulfase, the start was the beginning of study TKT024; for patients who received placebo, the start was week 53), with significant mean and percentage increases in walking distance ranging from 13.7 m to 41.5 m (maximum at month 20) and from 6.4% to 13.3% (maximum at month 24), respectively. At most time points, patients who initially received weekly treatment in study TKT024 showed greater improvement in walking distance than those in the other two treatment groups.

The mean percent predicted FVC significantly increased by month 16 in all patients, although it was similar to baseline values by month 36. Minimal improvement was observed in patients with the most severe pulmonary disease at baseline (as measured by percent predicted FVC).

Statistically significant increases in absolute FVC from baseline were observed at most visits in all combined treatment groups and in each prior treatment group in study TKT024. Changes in mean FVC values ranged from 0.07 L to 0.31 L, and percentage changes ranged from 6.3% to 25.5% (maximum at month 30). Changes in mean and percentage FVC values at each time point from the start of treatment were greatest in the weekly treatment group in study TKT024.

At the final visit in study TKT024, sustained normalization of urinary GAG concentration below the lower limit of quantification was observed in 21 out of 31 patients in the weekly treatment group, 24 out of 32 patients in the every-other-week treatment group, and 18 out of 31 patients in the placebo group. Changes in urinary GAG concentration were the earliest clinical signs of improvement with idursulfase therapy, with the greatest reduction observed during the first 4 months of treatment in all treatment groups; changes from months 4 to 36 were minimal. The higher the urinary GAG concentration at baseline, the greater the reduction during idursulfase treatment.

Reductions in liver and spleen size observed at the end of study TKT024 (week 53) were maintained during the extension study (TKT024EXT) in all patients, regardless of prior treatment group assignment. Liver size normalized by month 24 in 73% (52 out of 71) of patients who had hepatomegaly at baseline. Additionally, liver size reduction was maximal by a mean of month 8 in all previously treated patients, with a slight increase in liver size observed by month 36. Reduction in liver size was independent of age, disease severity, presence of IgE antibodies, or neutralizing antibodies. During study TKT024, spleen size normalized by month 12 and month 24 in 9.7% of patients with splenomegaly receiving weekly therapy.

During study TKT024, mean LVMI remained stable over 36 months of idursulfase therapy in all treatment groups.

A retrospective immunogenicity analysis based on data from studies TKT024 and TKT024EXT (see section "Adverse Reactions") showed that patients had either a missense mutation or a frameshift/nonsense mutation. After 105 weeks of idursulfase treatment, neither antibody status nor genotype influenced reductions in liver and spleen size, 6-minute walk distance, or forced vital capacity measurements. Patients who tested positive for antibodies showed less reduction in urinary glycosaminoglycan levels than patients with negative antibody tests. The long-term clinical impact of antibody development has not been established.

Study HGT-ELA-038

An open-label, multicenter study was conducted in a single group receiving idursulfase infusions in boys with Hunter syndrome aged from 16 months to 7.5 years.

Treatment with Elaprase resulted in nearly a 60% reduction in urinary glycosaminoglycan levels and reductions in liver and spleen size: results from this study were comparable to those from study TKT024. Reductions in these parameters were observed at week 18 and continued to be observed at week 53. Patients who developed high antibody titers showed a reduced response to idursulfase based on urinary glycosaminoglycan levels and liver and spleen size assessments.

Genotype analysis of patients in study HGT-ELA-038

Patients were classified into the following groups: missense mutation (13), complete deletion/significant rearrangement (8), and frameshift/splice site mutations (5). One patient was unclassified/not classified.

Complete deletion/significant rearrangement genotype was most frequently associated with the development of high titers of antibodies and neutralizing antibodies to idursulfase. A diminished response to the drug is most likely in this patient category. However, individual clinical response cannot be precisely predicted based on antibody response or genotype.

There are no clinical data demonstrating benefits with respect to neurological manifestations of the disease.

Pharmacokinetics

The mechanism of idursulfase uptake is mediated by selective binding to mannose-6-phosphate receptors. After cellular internalization, it localizes in cellular lysosomes, thereby limiting protein distribution. Degradation of idursulfase occurs via well-understood mechanisms of protein hydrolysis, resulting in small peptide fragments and amino acids. Therefore, impaired renal or hepatic function does not affect the pharmacokinetic parameters of idursulfase.

Pharmacokinetic parameters determined at week 1 of studies TKT024 (treatment group receiving 0.5 mg/kg weekly) and HGT-ELA-038 after the first intravenous administration of Elaprase are presented in Tables 2 and 3 as a function of age and body weight.

Table 2. PK parameters at week 1 as a function of age: studies TKT024 and HGT-ELA-038.

Patients enrolled in studies TKT024 and HGT-ELA-038 were also stratified by five body weight categories (see table).

Table 3. PK parameters at Week 1 as a function of body weight: studies TKT024 and HGT-ELA-038.

A higher volume of distribution at steady state (Vss) was observed in patient groups with lower body weight.

Overall, when assessing age or body weight, no clear trend was observed either for systemic exposure or for the clearance rate of Elaprazole.

Clinical characteristics

Indications.

Elaprase is indicated for long-term treatment of patients with Hunter syndrome (mucopolysaccharidosis type II (MPS II)).

Women who are heterozygous carriers were not included in clinical trials.

Contraindications.

Severe or life-threatening hypersensitivity to the active substance or to any of the excipients, when hypersensitivity cannot be controlled.

Special precautions.

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

Interaction with other medicinal products and other forms of interaction.

Formal studies of idursulfase interaction with other medicinal products have not been conducted.

However, due to the metabolism of the drug in cellular lysosomes, idursulfase is not expected to interact with drugs metabolized by the cytochrome P450 enzyme system.

Special precautions for use.

Infusion reactions

Infusion reactions may occur in patients receiving idursulfase (see section "Adverse reactions"). In clinical trials, the most common infusion reactions included skin reactions (rash, pruritus, urticaria), hyperthermia, headache, hypertension, and facial flushing. Infusion reactions were managed or mitigated by slowing the infusion rate, interrupting the infusion, or administering medications such as antihistamines, antipyretics, low-dose corticosteroids (prednisolone and methylprednisolone), or inhaled beta-agonists. During clinical studies, no patient discontinued treatment due to infusion reactions.

Infusion therapy should be administered with particular caution in patients with severe underlying respiratory disease. This patient population requires careful monitoring and infusion therapy should be conducted under appropriate clinical conditions. These patients should be prescribed disease control and treatment medications cautiously, limiting or carefully monitoring the use of antihistamines and other sedative medicinal products. In some cases, provision of positive airway pressure may be required.

For patients with acute febrile respiratory illness, consideration should be given to postponing infusion therapy. For patients receiving concomitant oxygen therapy, oxygen should be available during the infusion in case an infusion reaction occurs.

Anaphylactoid/anaphylactic reactions

Anaphylactoid/anaphylactic reactions, which may be life-threatening, have been observed in some patients receiving idursulfase, even after several years of treatment initiation. Delayed symptoms of anaphylactoid/anaphylactic reactions have been observed within 24 hours following the initial reaction. If an anaphylactoid/anaphylactic reaction occurs, the infusion must be stopped immediately and appropriate treatment and monitoring initiated. Current emergency treatment standards should be followed. Patients with severe or refractory anaphylactoid/anaphylactic reactions may require prolonged clinical observation. Re-administration of the drug should be approached with caution in patients who have previously experienced anaphylactoid/anaphylactic reactions to idursulfase. Therefore, infusions should be administered by properly trained personnel in settings equipped with resuscitation equipment and medications (including epinephrine). Severe or potentially life-threatening hypersensitivity is a contraindication to re-administration of the medicinal product if hypersensitivity cannot be controlled (see section "Contraindications").

Patients with complete gene deletion/significant genotype rearrangement

Children with complete gene deletion/significant genotype rearrangement are highly likely to develop antibodies, including neutralizing antibodies, in response to idursulfase. Patients with this genotype generally have a higher risk of developing infusion-related adverse reactions and a more attenuated response to treatment, as determined by the degree of reduction in urinary glycosaminoglycan levels, liver size, and spleen volume, compared to patients with a missense genotype. Evaluation and treatment of these patients should be individualized (see section "Adverse reactions").

Sodium content

The product contains 0.482 mmol of sodium (equivalent to 11.1 mg) per vial, which corresponds to 0.6% of the WHO recommended maximum daily intake of sodium for adults (2 g).

Traceability

To enhance traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

Use during pregnancy or breastfeeding.

Pregnancy

Data on the use of idursulfase in pregnant women are lacking or limited. Animal studies have not revealed any direct or indirect adverse effects of the drug with regard to reproductive toxicity. As a precautionary measure, it is advisable to avoid using idursulfase during pregnancy.

Breastfeeding

It is unknown whether idursulfase is excreted in human breast milk. Animal studies have confirmed excretion of idursulfase into milk. A risk to newborns/infants cannot be ruled out. Therefore, the decision to discontinue breastfeeding or to withhold/abandon idursulfase therapy should be made taking into account the benefits of breastfeeding for the child and the benefits of therapy for the mother.

Fertility

Reproductive studies did not reveal any effect on fertility in male rats.

Ability to affect reaction speed when driving or operating machinery.

Idursulfase has no or negligible influence on the ability to drive or operate machinery.

Administration and Dosage

Elaprase is administered under the supervision of a physician or nurse experienced in the treatment of MPS II or other inherited metabolic disorders.

The recommended dose is 0.5 mg/kg body weight administered once weekly as an intravenous infusion over a 3-hour period. This infusion duration may be gradually reduced to 1 hour if the patient does not experience infusion-related reactions (see section "Special Warnings and Precautions for Use").

Each vial of Elaprase is intended for single use only and contains 6 mg of idursulfase in 3 mL of solution. Elaprase is intended for intravenous infusion and must be diluted prior to administration in 0.9% sodium chloride solution (9 mg/mL). It is recommended to administer the total infusion volume using a low-protein-binding 0.2 µm in-line filter. Elaprase should not be co-administered with other medicinal products through the same infusion line.

Preparation of the Solution

• Determine the number of vials required based on the patient's body weight and the recommended dose of 0.5 mg/kg.
• Do not use the medication if the solution in the vial has changed color or contains particulate matter. Do not shake the vial.
• Withdraw the calculated volume of Elaprase from the appropriate number of vials.
• Dilute the total volume of Elaprase to be administered in 100 mL of 0.9% sodium chloride solution (9 mg/mL) for infusion. Care must be taken to ensure sterility of the prepared solution, as Elaprase contains no preservatives or bacteriostatic agents; aseptic techniques must be followed. After dilution, gently mix the solution by inverting the bag, but do not shake.

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

Home infusion may be considered for patients who have received treatment in a medical facility for several months and have demonstrated adequate tolerance to infusions. Home infusions must be conducted under the supervision of a physician.

Special Patient Populations

Elderly Patients

There is no clinical experience with the use of Elaprase in patients over 65 years of age.

Patients with Renal or Hepatic Impairment

There is no clinical experience with the use of Elaprase in patients with renal or hepatic impairment (see section "Pharmacokinetics").

Children

Elaprase may be administered to children and adolescents at the same dose as adults: 0.5 mg/kg body weight once weekly.

Overdose

Information regarding overdose with Elaprase is limited. Anaphylactoid reactions may occur in some patients due to overdose (see section "Contraindications", "Special Warnings and Precautions for Use").

Adverse Reactions

Adverse reactions were identified in 32 patients who received idursulfase at a dose of 0.5 mg/kg once weekly during a 52-week placebo-controlled phase II/III study (study TKT024). The majority of these reactions were mild or moderate in severity. The most commonly observed events were infusion reactions, with 202 such reactions reported in 22 out of 32 patients following a total of 1,580 infusions. In the placebo group, 128 infusion reactions were reported in 21 out of 32 patients following a total of 1,612 infusions. Since multiple infusion reactions could occur during a single infusion, the numbers stated above likely overestimate the true incidence of infusion reactions. The nature and severity of reactions were similar between the placebo group and the active treatment group. The most common infusion reactions included skin reactions (rash, pruritus, urticaria, erythema), hyperthermia, facial flushing, wheezing, dyspnea, headache, vomiting, abdominal pain, nausea, and chest pain. The frequency of infusion reactions decreased over time with continued treatment.

The adverse reactions listed below are categorized by organ systems according to the following frequency criteria: very common (≥ 1/10), common (≥ 1/100 to < 1/10), or uncommon (≥ 1/1,000 to < 1/100). The frequency of an adverse event per patient is determined based on the number of patients who received treatment. Within each frequency category, adverse reactions are listed in descending order of severity. Also included are adverse reactions reported after product registration with the frequency category of "unknown" (frequency cannot be estimated from available data).

Table 1. Adverse reactions observed in clinical studies and post-marketing experience in patients receiving Elaprase.

Description of some adverse reactions

Serious adverse reactions during clinical studies were generally observed in 5 patients receiving the drug at a dose of 0.5 mg/kg weekly or every other week. Hypoxia requiring oxygen administration occurred during one or more infusions in 4 patients, 3 of whom had severe obstructive airway disease (2 of these patients had previously undergone tracheostomy). The most severe infusion reaction, manifested by transient seizures, was observed in 1 patient during an exacerbation of febrile respiratory illness and was accompanied by hypoxia during infusion. In the fourth patient, who had a milder course of the underlying disease, the adverse reaction resolved spontaneously after discontinuation of the drug. Subsequently, when slower infusion rates and premedication (administration of low-dose corticosteroids, antihistamines, and beta-agonist inhalations) were used, these events did not recur. In the fifth patient, who had previously diagnosed cardiopathy, premature ventricular complexes and pulmonary artery thromboembolism were recorded during the study.

Post-marketing data include reports of anaphylactoid/anaphylactic reactions (see section "Special precautions").

Patients with complete gene deletion/significant genotype rearrangement have an increased risk of infusion-related adverse reactions (see section "Special precautions").

Immunogenicity

During 4 clinical trials (TKT008, TKT018, TKT024, and TKT024EXT), anti-IgG antibodies to idursulfase were detected at some point in 53 out of 107 patients (50%). The overall incidence of neutralizing antibodies was 24% (26 out of 107 patients).

In a retrospective analysis of immunogenicity data from studies TKT024/024EXT, anti-idursulfase antibodies were detected in 51% (32 out of 63) of patients receiving idursulfase at a dose of 0.5 mg/kg weekly, with positive antibody results in at least one blood sample, and in 37% (23 out of 63) of patients during at least 3 consecutive visits: 21% (13 out of 63) had positive results for neutralizing antibodies at least once, and 13% (8 out of 63) had positive results for neutralizing antibodies during at least 3 visits.

Immunogenicity was evaluated in children aged 16 months to 7.5 years during clinical trial HGT-ELA-038. During the 53-week study, 67.9% of patients (19 out of 28) had at least one blood sample with a positive test result for anti-idursulfase antibodies, and 57.1% of patients (16 out of 28) had positive results during at least three consecutive visits. Neutralizing antibodies were detected in 54% of patients at least once, and half of the patients showed positive reactions for neutralizing antibodies during at least three consecutive visits.

All patients with complete gene deletion/significant genotype rearrangement developed antibodies, and most of these patients (7 out of 8) also had positive results for neutralizing antibodies at least three times consecutively. All patients with frameshift mutation/splice site mutation genotypes developed antibodies, and 4 out of 6 patients had positive results for neutralizing antibodies during at least three consecutive visits. Patients with negative antibody test results belonged exclusively to the missense mutation genotype group (see sections "Special precautions" and "Pharmacodynamics").

Experience with use in pediatric patients

Adverse reactions observed in the pediatric population were generally similar to those observed in adults.

Reporting of suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmaceutical professionals, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Incompatibility.

This medicinal product must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Shelf life. 3 years.

Do not use after the expiry date.

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

Storage conditions.

Store in the original packaging at 2–8 °C.

Do not freeze.

From a microbiological standpoint, the diluted product should be used immediately. If not used immediately, the responsibility for storage conditions and duration lies with the user and must not exceed 24 hours at a temperature of 2–8 °C.

Keep out of reach of children.

Packaging.

3 ml concentrate for solution for infusion in a 5 ml vial (Type I glass) with stopper (butyl rubber coated with fluoropolymer), overseal, and blue flip-off cap.

1 vial in a cardboard box.

Prescription status.

By prescription only.

Manufacturer. Takeda Pharmaceuticals International AG Ireland Branch.

Manufacturer's address and place of business.

Block 2 Mezzanine Plaza, 50-58 Lower Baggot Street, Dublin 2, D02 HW68, Ireland