Elaprasea 6 mg/3 mL Solution

ELAPRASE is indicated for patients with Hunter syndrome (Mucopolysaccharidosis II, MPS II).

ELAPRASE treatment should be supervised by a medical practitioner or other health care professional experienced in the management of patients with Hunter syndrome (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 preparation and administration instructions see section 6.6. Infusion of ELAPRASE at home may be considered for patients who are tolerating their infusions well. Home infusions should be performed under the surveillance of a doctor or other health care professional.

Special populations:

• 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. The safety and efficacy of ELAPRASE has not been established in paediatric patients less than 16 months of age.

Method of administration: For preparation and administration instructions before use, see section 6.6.

Hypersensitivity to the active substance or to any of the excipients (see section 6.1).

RISK OF HYPERSENSITIVITY REACTIONS Anaphylactoid/anaphylactic reactions, which have the potential to be life threatening, have been observed in some patients treated with ELAPRASE. Patients with compromised respiratory function or acute respiratory disease may be at risk of serious exacerbation of their respiratory dysfunction due to infusion related reactions. These patients require additional monitoring. Late-emergent anaphylactoid/anaphylactic reactions have been observed after ELAPRASE administration. Patients who have experienced severe and refractory anaphylactoid/anaphylactic reactions may require prolonged observation times.

Due to the potential for severe infusion reactions appropriate medical support measures should be readily available when ELAPRASE is administered. Patients treated with ELAPRASE 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 or 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. Consideration should be given to delay 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. Paediatric patients with the complete deletion/large rearrangement genotype have a high probability of developing antibodies, including neutralising antibodies, in response to exposure to ELAPRASE. 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.

Anaphylactoid/anaphylactic reactions, which have the potential to be life threatening, have been observed in some patients treated with ELAPRASE 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 of ELAPRASE should be suspended immediately and appropriate treatment and observation should be 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 ELAPRASE. Appropriately trained personnel and equipment for emergency resuscitation (including epinephrine (adrenaline)) should be available during infusions. Severe or potentially life-threatening hypersensitivity is a contraindication to rechallenge.

Sodium ELAPRASE 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.

No formal interaction studies have been conducted with ELAPRASE. Based on its metabolism in cellular lysosomes, idursulfase would not be affected by cytochrome P450 mediated interactions.

Safety during pregnancy and lactation has not been established.

Pregnancy There are no or limited data available from the use of ELAPRASE in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3). ELAPRASE is not recommended for use during pregnancy.

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

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

ELAPRASE may influence the patientu2019s ability to drive and use machines.

Adverse reactions that were reported for the 32 patients treated with 0,5 mg/kg ELAPRASE weekly in the Phase II/III 53-week placebo-controlled study, are listed in the table below with information presented by system organ class and frequency. Frequency is given as very common (u2265 1/10, u2265 10 %), common (u2265 1/100, < 1/10, between 1 % and 10 %) or uncommon (u2265 1/1 000, < 1/100, between 0,1 % and 1 %). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. Adverse 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 reactions. The most common reactions are infusion-related reactions including cutaneous reactions (rash, pruritus, urticaria and erythema), pyrexia, flushing, wheezing, dyspnoea, headache, vomiting, abdominal pain, nausea and chest pain.

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

* Side effects reported post-marketing.

Across studies, serious adverse reactions were reported in a total of 5 patients out of 64 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 resulting in a 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 corticosteroids, antihistamines, and beta-agonist nebulisation. The fifth patient, who had pre-existing cardiomyopathy, was diagnosed with ventricular premature complexes and pulmonary embolism during the study.

Post-marketing There have been post-marketing reports of anaphylactoid/anaphylactic reactions. Patients with complete deletion/large rearrangement genotype have a higher probability of developing infusion related adverse events.

Please see section 4.4 for further information.

Immunogenicity Across 4 clinical studies (TKT008, TKT018, TKT024 and TKT024EXT), 53/107 patients (50 %) developed anti-idursulfase IgG antibodies at some point. The overall neutralising 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 0,5 mg/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 neutralising antibodies at least once and 13 % (8/63) tested positive for neutralising 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 neutralising antibodies at least once and half of the patients tested positive for neutralising 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 neutralising 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 neutralising 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 paediatric population were, in general, similar to those reported in adults.

Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of ELAPRASE is important. It allows continued monitoring of the benefit/risk balance of ELAPRASE. Health care providers are asked to report any suspected adverse reactions to: u2022 The Pharmacovigilance Unit at Sanofi: [email protected] (email) or 011 256 3700 (tel), or u2022 SAHPRA via the u201c6.04 Adverse Drug Reaction Reporting Formu201d, found online under SAHPRAu2019s publications: https://www.sahpra.org.za/Publications/Index/8.

There is limited information regarding overdose with ELAPRASE. Evidence suggests that some patients may experience an anaphylactoid reaction due to overdose. See section 4.3, 4.4 and 4.8. Treatment should be symptomatic and supportive if needed.