Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Due to the low number of patients in clinical trials, adverse event (AE) data from all Naglazyme studies have been pooled and reviewed in a single, clinical trial safety analysis.

All patients treated with NAGLAZYME (59/59) reported at least one AE. The majority (42/59; 71%) of patients experienced at least one Adverse Drug Reaction. The most common adverse reactions were pyrexia, rash, pruritus, urticaria, chills/rigors, nausea, headache, abdominal pain, vomiting and dypsnoea. Serious adverse reactions included laryngeal edema, apnoea, pyrexia, urticaria, respiratory distress, angioedema, asthma and anaphylactoid reaction.

Infusion reactions, defined as adverse reactions occurring during Naglazyme infusions or until the end of the infusion day, were observed in 33 (56%) of the 59 patients treated with Naglazyme across five clinical studies. Infusion reactions began as early as Week 1 and as late as Week 146 of Naglazyme treatment, and occurred during multiple infusions though not always in consecutive weeks. Very common symptoms of these infusion reactions were pyrexia, chills/rigors, rash, urticaria and dyspnoea. Common symptoms of infusion reactions were pruritus, vomiting, abdominal pain, nausea, hypertension, headache, chest pain, erythema, cough, hypotension, angioedema, respiratory distress, tremor, conjunctivitis, malaise, bronchospasm and arthralgia.

Adverse reactions are listed in Table 1 by System Organ Class.
The reactions are listed following the MedDRA frequency convention. Very common adverse reactions are those with a frequency of ≥1/10. Common reactions have a frequency of ≥1/100 to <1/10. Due to the small patient population, an adverse reaction in a single patient is classified as common.

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Adverse reactions reported during the Post Marketing period are included at a frequency category of “unknown”.

Overall, one case of sleep apnoea was experienced from all clinical studies.

Table 1: Frequency of adverse drug reactions with Naglazyme
MedDRA                                           MedDRA                                  Frequency System Organ Class                                 Preferred Term
Immune system disorders                             Anaphylaxis, shock                           Unknown 
Infections and infestations                    Pharyngitis1, gastroenteritis1                 Very common 
Nervous system disorders                         Areflexia1, headache                         Very common Tremor                                 Common
Paresthesia                              Unknown
Eye disorders                          Conjunctivitis1, corneal opacity1                 Very common Cardiac disorders                      Bradycardia, tachycardia, cyanosis                  Unknown Ear and labyrinth disorders                    Ear pain1, hearing impaired1                    Very common Vascular disorders                                Hypertension1                            Very common Hypotension                                Common
Pallor                               Unknown
Respiratory, thoracic, and mediastinal              Dyspnoea , nasal congestion1 1
Very common disorders
Apnoea1, cough, respiratory distress,                              Common asthma, bronchospasm
Laryngeal oedema, hypoxia,                                      Unknown tachypnoea
Gastrointestinal disorders      Abdominal pain1, umbilical hernia1,                             Very common vomiting, nausea
Skin and subcutaneous tissue     Angioeodema1, rash1, urticaria, pruritus                         Very Common disorders                            Erythema                                            Common General disorders and administration Pain1, chest pain1, rigors1, malaise1,                          Very Common site conditions                          pyrexia
Musculoskeletal and Connective                                Arthralgia                          Very common Tissue Disorders
1Reactions reported more frequently in the active arm of the placebo-controlled study than the placebo arm; frequency determined from 39 patients of the blinded Phase 3 study.
Other reactions with known frequency were reported from 59 patients treated with Naglazyme from all five clinical trials.
Reactions of unknown frequency were reported post-marketing.
In four patients <1 year of age, the overall safety profile of a higher dose (2 mg/kg/week) did not differ in a clinically meaningful manner from that of the recommended 1 mg/kg/week dose, and was consistent with the safety profile of Naglazyme in older children.

Immunogenicity

Out of the 59 patients treated with Naglazyme in the clinical studies, 54 were tested for IgG antibodies. 53/54 patients (98%) were positive for IgG antibodies to galsulfase.

A comprehensive antibody analysis based on data from three clinical studies has been carried out in 48 patients.

Although a larger proportion of subjects with high total antibody titres experienced recurrent infusion reactions, neither frequency nor severity could be predicted based on the anti-galsulfase antibody titre.
Likewise, antibody development is not predictive of decreased efficacy although subjects with limited response in endurance parameters or urinary glycosaminoglycans (GAGs) tended to have higher peak anti-galsulfase titres than those with good response.


Reporting of suspected adverse reactions

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/.