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 System Organ Class MedDRA Preferred Term Frequency Immune system disorders Anaphylaxis, shock Unknown Infections and infestations Pharyngitis1, gastroenteritis1 Very common Areflexia1, headache Very common Tremor Common Nervous system disorders 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 Hypertension1 Very common Hypotension Common Vascular disorders Pallor Unknown Dyspnoea1, nasal congestion1 Very common Apnoea1, cough, respiratory distress, asthma, bronchospasm Common Respiratory, thoracic, and mediastinal disorders Laryngeal oedema, hypoxia, tachypnoea Unknown Gastrointestinal disorders Abdominal pain1, umbilical hernia1, vomiting, nausea Very common Angioeodema1, rash1, urticaria, pruritus Very CommonSkin and subcutaneous tissue disorders Erythema Common General disorders and administration site conditions Pain1, chest pain1, rigors1, malaise1, pyrexia Very Common Musculoskeletal and Connective Tissue Disorders Arthralgia Very common 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 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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.