Adverse reactions : תופעות לוואי

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,             Hypoxia,              Tachypnoea dyspnoea              bronchospasm,
cough
Gastrointestinal disorders
Abdominal pain,       Swollen tongue,
nausea, diarrhoea, dyspepsia vomiting
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.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il