Summary of the safety profile The most common adverse reactions observed were weight increase (15%), IRRs (13%), diarrhoea (10%), headache (7%), arthralgia (7%), increased appetite (5%) and pain in extremity (5%). The majority of these adverse reactions were non-serious.
IRRs include hypersensitivity in 3 patients and anaphylactoid reaction in 1 patient. These reactions were mild to moderate in intensity. A total of 4 serious adverse reactions (loss of consciousness in 1 patient, acute renal failure in 1 patient, chills and hyperthermia in 1 patient) were observed.
In all cases the patients recovered without sequelae. Tabulated list of adverse reactions The adverse reactions reflecting exposure of 38 patients treated with velmanase alfa in clinical studies are listed in the table 1 below. Adverse reactions are classified by system organ class and preferred term according to the MedDRA frequency convention.
Within each frequency grouping, adverse reactions are presented in the order of decreasing seriousness. Frequency is defined as 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) or not known (cannot be estimated from the available data).
6 Table 1: Adverse reactions reported from clinical studies, post-authorization safety studies and spontaneous reporting in patients with alpha-mannosidosis treated with velmanase alfa System organ class Adverse reaction Frequency Infections and infestations Bacterial disease carrier Not known Endocarditis Not known Furuncle Not known Staphylococcal infection Not known Immune system disorders Hypersensitivity(1) Common Anaphylactoid reaction(1) Common Metabolism and nutrition disorders Increased appetite Common Decreased appetite Not known Psychiatric disorders Psychotic behaviour Common Initial insomnia Common Agitation Not known Encopresis Not known Psychotic disorder Not known Nervousness Not known Apathy(1) Not known Nervous system disorders Loss of consciousness(2) Common Tremor Common Confusional state Common Syncope Common Headache Common Dizziness Common Ataxia Not known Nervous system disorder Not known Somnolence Not known Hypotonia(1) Not known Eye disorders Eyelid oedema Common Eye irritation Common Ocular hyperaemia Common Lacrimation increased Not known Ear and labyrinth disorders Deafness Not known Cardiac disorders Cyanosis(1) Common Bradycardia Common Aortic valve incompetence Not known Palpitations Not known Tachycardia Not known Vascular disorders Hypotension Not known Vascular fragility Not known Pallor(1) Not known Respiratory, thoracic and mediastinal disorders Epistaxis Common Oropharyngeal pain Not known Pharyngeal oedema Not known Wheezing Not known Gastrointestinal disorders Diarrhoea Very common Vomiting(1) Common Abdominal pain upper Common Nausea(1) Common Abdominal pain Common Reflux gastritis Common Odynophagia Not known 7 System organ class Adverse reaction Frequency Skin and subcutaneous tissue disorders Urticaria(1) Common Hyperhidrosis(1) Common Angioedema Not known Erythema Not known Rash Not known Musculoskeletal and connective tissue disorders Arthralgia Common Pain in extremity Common Joint stiffness Common Myalgia Common Back pain Common Joint swelling Not known Joint warmth Not known Renal and urinary disorders Renal failure acute(2) Common General disorder and administration site conditions Pyrexia(1) Very common Chills(1) Common Catheter site pain Common Feeling hot(1) Common Fatigue Common Malaise(1) Common Asthenia Not known Investigations Weight increase Very common Injury, poisoning and procedural complications Procedural headache Common Infusion related reaction Not known (1) Preferred terms considered as IRR as described in the section below (2) Selected adverse reaction as described in the section below Description of selected adverse reactions Infusion-related reaction IRRs (including hypersensitivity, cyanosis, nausea, vomiting, pyrexia, chills, feeling hot, malaise, urticaria, anaphylactoid reaction and hyperhidrosis) were reported in 13% of the patients (5 out of 38 patients) in clinical studies.
1). All patients who experienced IRRs recovered. One patient experienced symptoms of apathy, pallor and hypotonia in the alpha-mannosidosis registry. Acute renal failure In the clinical studies, one patient experienced acute renal failure considered possibly related to the study treatment.
Acute renal failure was of moderate severity leading to temporary discontinuation of the study treatment and fully resolved within 3 months. Concomitant long-term treatment with high doses of ibuprofen was noted during the occurrence of the event.
Loss of consciousness In one patient, one event of loss of consciousness was reported during the treatment in the clinical trials. The event occurred 8 days after last infusion and after 14 months of treatment. A connection to the test drug could not be ruled out despite the long period from last infusion and until the event occurred.
9%) solution for infusion and was then discharged after 6-hour observation. The patient continued in the study with no change in dose level. No other related event of loss of consciousness has been reported either in the clinical either in the commercial setting.
8 Paediatric population Children age below 6 years old A total of 5 patients with alpha-mannosidosis below 6 years received velmanase alfa in a clinical study. The safety profile was similar to that observed in the previous studies, with similar frequency, type and severity of adverse events.
Children age group 6 to 17 years old The safety profile of velmanase alfa in clinical studies involving children and adolescents was similar to that observed in adult patients. Overall, 58% of patients […]