4.1. Therapeutic indications

Elaprase is indicated for the long-term treatment of patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II).

Heterozygous females were not studied in the clinical trials.

4.2. Posology and method of administration

This treatment should be supervised by a physician or other healthcare professional experienced in the management of patients with MPS II disease or other inherited metabolic disorders.

Posology

Elaprase is administered at a dose of 0.5 mg/kg body weight every week by intravenous infusion over a 3 hour period, which may be gradually reduced to 1 hour if no infusion-associated reactions are observed (see section 4.4).

For instructions for use, see section 6.6.

Infusion at home may be considered for patients who have received several months of treatment in the clinic and who are tolerating their infusions well. Home infusions should be performed under the surveillance of a physician or other healthcare professional.

Special populations

Elderly patients

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

Patients with renal or hepatic impairment

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

Special care should be taken when administering an infusion in patients with severe underlying airway disease. These patients should be closely monitored and infused in an appropriate clinical setting. Caution must be exercised in the management and treatment of such patients by limitation or careful monitoring of antihistamine and other sedative medicinal product use. Institution of positive-airway pressure may be necessary in some cases.

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

Anaphylactoid/anaphylactic reactions

Anaphylactoid/anaphylactic reactions, which have the potential to be life threatening, have been observed in some patients treated with idursulfase up to several years after initiating treatment. Late emergent symptoms and signs of anaphylactoid/anaphylactic reactions have been observed as long as 24 hours after an initial reaction. If an anaphylactoid/anaphylactic reaction occurs the infusion should be immediately suspended and appropriate treatment and observation initiated. The current medical standards for emergency treatment are to be observed. Patients experiencing severe or refractory anaphylactoid/anaphylactic reactions may require prolonged clinical monitoring. Patients who have experienced anaphylactoid/anaphylactic reactions should be treated with caution when re-administering idursulfase, appropriately trained personnel and equipment for emergency resuscitation (including epinephrine) should be available during infusions. Severe or potentially life-threatening hypersensitivity is a contraindication to rechallenge, if hypersensitivity is not controllable (see section 4.3).

Patients with the complete deletion/large rearrangement genotype

Paediatric patients with the complete deletion/large rearrangement genotype have a high probability of developing antibodies, including neutralizing antibodies, in response to exposure to idursulfase. Patients with this genotype have a higher probability of developing infusion-related adverse events and tend to show a muted response as assessed by decrease in urinary output of glycosaminoglycans, liver size and spleen volume compared to patients with the missense genotype. Management of patients must be decided on an individual basis (see section 4.8).

Sodium

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

Traceability

In order to improve the traceability of biological medicinal products, the name and batch number of the administered product should be clearly recorded.

4.5. Interaction with other medicinal products and other forms of interaction

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

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

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no data or limited amount of data from the use of idursulfase in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). As a precautionary measure, it is preferable to avoid the use of idursulfase during pregnancy.

Breast-feeding

It is not known whether idursulfase is excreted in human breast milk. Available data in animals have shown excretion of idursulfase in milk (see section 5.3). A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from idursulfase therapy taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

Adverse reactions that were reported for the 32 patients treated with 0.5 mg/kg idursulfase weekly in the TKT024 phase II/III 52-week placebo-controlled study were almost all mild to moderate in severity. The most common were infusion-related reactions, 202 of which were reported in 22 out of 32 patients following administration of a total of 1580 infusions. In the placebo treatment group 128 infusion-related reactions were reported in 21 out of 32 patients following administration of a total of 1612 infusions. Since more than one infusion-related reaction may have occurred during any single infusion, the above numbers are likely to overestimate the true incidence of infusion reactions. Related reactions in the placebo group were similar in nature and severity to those in the treated group. The most common of these infusion-related reactions included cutaneous reactions (rash, pruritus, urticaria, and erythema), pyrexia, flushing, wheezing, dyspnoea, headache, vomiting, abdominal pain, nausea, and chest pain. The frequency of infusion-related reactions decreased over time with continued treatment.

Tabulated list of adverse reactions

Adverse reactions are listed in table 1 with information presented by system organ class and frequency. Frequency is given as very common (≥1/10), common (≥1/100 to <1/10) or uncommon (≥1/1,000 to <1/100). The occurrence of an adverse reaction in a single patient is defined as common in view of the number of patients treated. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Adverse reactions only reported during the post marketing period are also included in the table with a frequency “not known” (cannot be estimated from the available data).

Table 1: Adverse reactions from clinical trials and post-marketing experience in patients treated with Elaprase.

System organ class

Adverse reaction (preferred term)

Very common

Common

Uncommon

Not known

Immune system disorders

Anaphylactoid/anaphylactic reaction

Nervous system disorders

Headache

Dizziness, tremor

Cardiac disorders

Cyanosis, arrhythmia, tachycardia

Vascular disorders

Flushing

Hypertension, Hypotension

Respiratory, thoracic and mediastinal disorders

Wheezing, dyspnoea

Hypoxia, bronchospasm, cough

Tachypnoea

Gastrointestinal disorders

Abdominal pain, nausea, diarrhoea, vomiting

Swollen tongue, dyspepsia

Skin and subcutaneous tissue disorders

Urticaria, rash, pruritus, erythema

Musculoskeletal and connective disorders

Arthralgia

General disorders and administration site conditions

Pyrexia, chest pain

Infusion-site swelling, face oedema, oedema peripheral

Injury, poisoning and procedural complications

Infusion-related reaction

Description of selected adverse reactions

Across clinical studies, serious adverse reactions were reported in a total of 5 patients who received 0.5 mg/kg weekly or every other week. Four patients experienced a hypoxic episode during one or several infusions, which necessitated oxygen therapy in 3 patients with severe underlying obstructive airway disease (2 with a pre-existing tracheostomy). The most severe episode occurred in a patient with a febrile respiratory illness and was associated with hypoxia during the infusion, resulting in a short seizure. In the fourth patient, who had less severe underlying disease, spontaneous resolution occurred shortly after the infusion was interrupted. These events did not recur with subsequent infusions using a slower infusion rate and administration of pre-infusion medicinal products, usually low-dose steroids, antihistamine, and beta-agonist nebulisation. The fifth patient, who had pre-existing cardiopathy, was diagnosed with ventricular premature complexes and pulmonary embolism during the study.

There have been post-marketing reports of anaphylactoid/anaphylactic reactions (see section 4.4).

Patients with complete deletion/large rearrangement genotype have a higher probability of developing infusion related adverse events (see section 4.4).

Immunogenicity

Across 4 clinical studies (TKT008, TKT018, TKT024 and TKT024EXT), 53/107 patients (50%) developed anti-idursulfase IgG antibodies at some point. The overall neutralizing antibody rate was 26/107 patients (24%).

In the post-hoc immunogenicity analysis of data from TKT024/024EXT studies, 51% (32/63) patients treated with 0.5mg/kg weekly idursulfase had at least 1 blood sample that tested positive for anti-idursulfase antibodies, and 37 % (23/63) tested positive for antibodies on at least 3 consecutive study visits. Twenty-one percent (13/63) tested positive for neutralizing antibodies at least once and 13 % (8/63) tested positive for neutralizing antibodies on at least 3 consecutive study visits.

Clinical study HGT-ELA-038 evaluated immunogenicity in children 16 months to 7.5 years of age. During the 53-week study, 67.9% (19 of 28) of patients had at least one blood sample that tested positive for anti-idursulfase antibodies, and 57.1% (16 of 28) tested positive for antibodies on at least three consecutive study visits. Fifty-four percent of patients tested positive for neutralizing antibodies at least once and half of the patients tested positive for neutralizing antibodies on at least three consecutive study visits.

All patients with the complete deletion/large rearrangement genotype developed antibodies, and the majority of them (7/8) also tested positive for neutralizing antibodies on at least 3 consecutive occasions. All patients with the frameshift/splice site mutation genotype developed antibodies and 4/6 also tested positive for neutralizing antibodies on at least 3 consecutive study visits. Antibody-negative patients were found exclusively in the missense mutation genotype group (see sections 4.4 and 5.1).

Paediatric population

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

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).