Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The majority of the related adverse events in the clinical trials were classified as infusion-associated reactions (IARs), experienced by 53% of the patients in the Phase 3 study (treated for up to 4 years) and 35% of the patients in the under 5 study (up to 1 year of treatment). Some of the IARs were severe. Over time the number of these reactions decreased. The most frequent adverse drug reactions (ADRs) were: headache, nausea, abdominal pain, rash, arthralgia, backpain, pain at extremity, flushing, pyrexia, infusion site reactions, blood pressure increased, oxygen saturation decreased, tachycardia and chills. Post-marketing experience of infusion-associated reactions revealed reporting of cyanosis, hypoxia, tachypnoea, pyrexia, vomiting, chills and erythema, in which some of these reactions were severe.

Tabulated list of adverse reactions
ADRs to Aldurazyme reported during the Phase 3 study and its extension in a total of 45 patients age 5 years and older and treated up to 4 years are listed below using the following categories of frequency: very common (≥1/10); common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000) and not known (cannot be estimated from the available data). Due to the small patient population, an ADR reported in a single patient is classified as common.

MedDRA                   Very common                 Common                      Not known System Organ Class
Immune system                                        Anaphylactic reaction disorders
Psychiatric disorders                                Restlessness
Nervous system           Headache                    Paraesthesia, dizziness disorders
Cardiac disorders                                    Tachycardia
Vascular disorders       Flushing                    Hypotension, pallor, peripheral coldness
Respiratory, thoracic                                Respiratory distress,       Cyanosis, hypoxia, and mediastinal                                      dyspnoea, cough             tachypnoea, disorders                                                                        bronchospasm, respiratory arrest
Gastrointestinal         Nausea, abdominal pain Vomiting, diarrhoea disorders
Skin and subcutaneous Rash                           Angioneurotic edema,        Erythema, facial edema, tissue disorders                                     swelling face, urticaria,   laryngeal edema, edema pruritus, cold sweat,       peripheral alopecia, hyperhidrosis
Musculoskeletal and      Arthropathy, arthralgia,    Musculoskeletal pain connective tissue        back pain, pain in disorders                extremity
General disorders and    Pyrexia, infusion site      Chills, feeling hot,        Extravasation administration site      reaction                    feeling cold, fatigue, conditions                                           influenza like illness Investigations                                       Body temperature increased, oxygen saturation decreased

A single patient with pre-existing airway compromise developed a severe reaction three hours from the start of the infusion (at week 62 of treatment) consisting of urticaria and airway obstruction, requiring tracheostomy. This patient tested positive for IgE.


Additionally, a few patients who had a prior history of severe MPS I- related upper airway and pulmonary involvement, experienced severe reactions including bronchospasm, respiratory arrest, and facial oedema (see section 4.4).


Paediatric population
ADRs to Aldurazyme reported during a Phase 2 study in a total of 20 patients, under 5 years of age and mainly of the severe phenotype, treated up to 12 months are listed below. ADRs were all mild to moderate in severity.

MedDRA                                MedDRA
Frequency
System Organ Class                       Preferred term
Cardiac disorders                        tachycardia                  Very common General disorders and administration site             pyrexia                    Very common conditions                                chills                   Very common blood pressure increased           Very common
Investigations oxygen saturation decreased         Very common

In a phase 4 study 33 MPS I patients received 1 of 4 dose regimens: 100 U/kg IV every week (recommended dose), 200 U/kg IV every week, 200 U/kg IV every 2 weeks or 300 U/kg IV every 2 weeks. The recommended dose group had the fewest number of patients who experienced ADRs and
IARs. The type of IARs was similar to those seen in other clinical studies.

Description of selected adverse reactions

Immunogenicity
Almost all patients developed IgG antibodies to laronidase. Most patients seroconverted within 3 months of initiation of treatment; although seroconversion in patients under 5 years old with a more severe phenotype occurred mostly within 1 month (mean 26 days versus 45 days in patients 5 years and older). By the end of the Phase 3 study (or at time of early study withdrawal), 13/45 patients had no detectable antibodies by radioimmunoprecipitation (RIP) assay, including 3 patients that had never seroconverted. Patients with absent to low antibody levels showed a robust reduction in urinary GAG level, whereas patients with high antibody titers showed variable reduction in urinary GAG. The clinical significance of this finding is unknown since there were no consistent relationships between IgG antibody level and clinical efficacy endpoints.

In addition 60 patients in the Phase 2 and 3 studies were tested for in-vitro neutralising effects. Four patients (three in the Phase 3 study and one in the Phase 2 study) showed marginal to low level in vitro inhibition of laronidase enzymatic activity, which did not appear to impact clinical efficacy and/or urinary GAG reduction.

The presence of antibodies did not appear to be related to the incidence of IARs, although the onset of IARs typically coincided with the formation of IgG antibodies. The occurrence of IgE antibodies was not fully explored.

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/