Adverse reactions : תופעות לוואי

4.8    Undesirable effects

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).

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              Increased appetite                       Common disorders                             Decreased appetite                       Not known Psychiatric disorders                 Psychotic behaviour                      Common Initial insomnia                         Common
Agitation                                Not known
Encopresis                               Not known
Psychotic disorder                       Not known
System organ class               Adverse reaction            Frequency Nervousness                 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
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
Respiratory, thoracic and        Epistaxis                   Common mediastinal disorders            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
Skin and subcutaneous tissue     Urticaria(1)                Common disorders                        Hyperhidrosis(1)            Common
Angioedema                  Not known
Erythema                    Not known
Rash                        Not known
Musculoskeletal and connective   Arthralgia                  Common tissue disorders                 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             Pyrexia(1)                  Very common administration site conditions   Chills(1)                   Common
Catheter site pain          Common
Feeling hot(1)              Common
Fatigue                     Common
Malaise(1)                  Common
Asthenia                    Not known
Investigations                   Weight increase             Very common System organ class                     Adverse reaction                       Frequency Injury, poisoning and procedural       Procedural headache                    Common complications                          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. All were mild or moderate in severity and 2 were reported as a serious adverse reaction (see section 5.1). All patients who experienced IRRs recovered.

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. The patient recovered within few seconds and was taken to the hospital, where she/he received sodium chloride 9 mg/mL (0.9%) 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.


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 (19 out of 33) with alpha-mannosidosis receiving velmanase alfa in clinical studies were aged 6 to 17 years at the start of the study.

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/
Additionally, any suspected adverse events should also be reported to Kamada Ltd., by e-mail: pharmacovigilance@kamada.com