Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
Serious adverse reactions reported in patients treated with Xenpozyme were an event of extrasystoles in the context of a history of cardiomyopathy in 1 (2.5%) adult patient, and anaphylactic reaction, urticaria, rash, hypersensitivity, and alanine aminotransferase level increase, each in 1 (5%) paediatric patient. The incidence of serious hypersensitivity-related IARs were higher in paediatric patients compared to adults

The most frequently reported adverse drug reactions (ADRs) were headache (31.7%), pyrexia (25%), urticaria (21.7%), nausea (20%), vomiting (16.7%), abdominal pain (15%), myalgia (11.7%), pruritus (10%) and C-reactive protein increased (10%).


Tabulated list of adverse reactions

The pooled safety analysis from 4 clinical studies (a tolerability study in adult patients, ASCEND, ASCEND-Peds, and an extension study in adult and paediatric patients) included a total of 60 patients (40 adult and 20 paediatric patients) treated with Xenpozyme at doses up to 3 mg/kg every 2 weeks.

Adverse reactions reported in the pooled safety analysis of clinical studies are listed in Table 5 per System Organ Class, presented by frequency categories: 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).

Table 5: Adverse drug reactions in patients treated with Xenpozyme in pooled analysis of clinical studies

System Organ Class                                        Frequency
Very common                       Common
Immune system disorders                                          Anaphylaxis and hypersensitivity Nervous system disorders                  Headache
Ocular hyperaemia, ocular
Eye disorders discomfort, eye pruritus
Cardiac disorders                                                 Palpitations, tachycardia Vascular disorders                                            Hypotension, hot flush, flushing Pharyngeal oedema, pharyngeal
Respiratory, thoracic, and                                           swelling, throat tightness, mediastinal disorders                                             wheezing, larynx irritation, dyspnoea, throat irritation
Diarrhoea, abdominal pain upper,
Nausea, abdominal pain,
Gastrointestinal disorders                                             abdominal discomfort, vomiting gastrointestinal pain
Hepatobiliary disorders                                                    Hepatic pain Angioedema, fixed eruption, rash,
rash papular, rash macular, rash
Skin and subcutaneous tissue
Urticaria, pruritus        maculopapular, rash erythematous,
disorders rash pruritic, rash morbilliform,
papule, macule, erythema
Musculoskeletal and
Myalgia                Bone pain, arthralgia, back pain connective tissue disorders
Pain, chills, catheter site pain,
General disorders and                                             catheter site related reaction, Pyrexia administration site conditions                                     catheter site pruritus, catheter site swelling, fatigue, asthenia
C-reactive protein             Alanine aminotransferase increased                     increased, aspartate aminotransferase increased, serum
Investigations ferritin increased, C-reactive protein abnormal, body temperature increased

Description of selected adverse reactions

Infusion-associated reactions (IARs), including hypersensitivity/anaphylactic reactions 
IARs were reported in 55% of adult and 65% of paediatric patients. IAR symptoms reported most frequently in adult patients were headache (22.5%), nausea (15%), urticaria (12.5%), arthralgia (10%), myalgia (10%), pyrexia (10%), pruritus (7.5%), vomiting (7.5%), and abdominal pain (7.5%). IAR symptoms reported most frequently in paediatric patients were pyrexia (40%), urticaria (35%), 
vomiting (30%), headache (20%), nausea (20%), and rash (15%). IARs typically occurred between the time of infusion and 24 hours after infusion end.

Hypersensitivity-related IARs, including anaphylaxis, occurred in 26.7% patients, 17.5% adult and 45% paediatric patients in clinical studies. The most frequently reported hypersensitivity-related IAR symptoms were urticaria (20%), pruritus (6.7%), erythema (6.7%), and rash (5%).

One paediatric patient in the clinical studies incurred a severe anaphylactic reaction. Also, independent of the clinical study program, a 16-month-old patient with ASMD type A treated with Xenpozyme experienced 2 anaphylactic reactions. Anti-olipudase alfa IgE antibodies were detected in both patients.

In 2 adults and 3 paediatric patients, IAR symptoms were associated with changes in laboratory parameters (e.g C-reactive protein, ferritin value) indicative of acute phase reaction.

Transaminase elevations

Transient transaminase (ALT or AST) elevations within 24 to 48 hours after an infusion occurred in some patients treated with Xenpozyme during the dose escalation phase in the clinical studies. These elevations generally returned to the previous pre-infusion transaminase levels by the next scheduled infusion.
Overall, after 52 weeks of treatment with Xenpozyme, mean ALT decreased 45.9% and mean AST decreased 40.2%, compared to baseline. In adult patients, all 16 patients with an elevated baseline ALT had an ALT within the normal range and 10 of 12 patients with an elevated baseline AST had an AST within the normal range.

Immunogenicity

Overall, 16 out of 40 (40%) adult patients and 13 out of 20 (65%) paediatric patients treated with Xenpozyme developed treatment-emergent antidrug antibodies (ADA). The median time to seroconversion from first Xenpozyme infusion was approximately 33 weeks in adults and 10 weeks in paediatric patients. The majority of ADA-positive patients (11 out of 16 adult and 8 out of 13 paediatric patients) had a low ADA response (≤ 400) or reverted to ADA-negative. Four out of the 16 adult ADA-positive patients and 5 out of the 13 paediatric ADA-positive patients had Neutralizing Antibodies (NAb) that inhibited the olipudase alfa activity. Six patients developed NAbs at a single time point and 3 patients had an intermittent response. One paediatric patient had a treatment boosted ADA response. One paediatric patient experienced an anaphylactic reaction and developed IgE ADA, and IgG ADA with a peak titer of 1600.

No effect of ADA was observed on pharmacokinetics and efficacy of Xenpozyme in adult and paediatric populations. There was a higher percentage of patients with treatment-emergent IARs (including hypersensitivity reactions) in patients who developed treatment-emergent ADA versus those who did not (75.9% versus 41.9%).

Paediatric population

Except for a higher incidence of hypersensitivity-related IARs in paediatric patients compared to adults, the safety profile of Xenpozyme in paediatric and adult patients was similar.

Long-term use

Overall, the pattern of adverse events observed in adult and paediatric patients in longer term use was consistent with that observed during the first year of treatment.

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/