Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most common adverse reactions to vosoritide were injection site reactions (85%), vomiting (27%), and decreased blood pressure (13%).

Tabulated list of adverse reactions

Adverse reactions in patients treated with vosoritide are tabulated below.
Adverse reactions are listed below by MedDRA system organ class and by frequency. Frequencies are 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); not known (cannot be estimated from available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2: Adverse reactions in patients treated with Voxzogo

System organ class            Very common              Common
Nervous system                                          Syncope disorders                                             Pre-syncope
Dizziness
Vascular disorders            Hypotensiona
Gastrointestinal               Vomiting                  Nausea disorders
General disorders and          Injection site            Fatigue administration site              reactionb conditions
Investigations                                       Increased alkaline phosphatase a.
Hypotension includes both asymptomatic and symptomatic adverse reactions.
b.
Injection site reactions include the preferred terms; injection site erythema, injection site reaction, injection site swelling, injection site urticaria, injection site pain, injection site bruising, injection site pruritus, injection site haemorrhage, injection site discolouration, and injection site induration.

Description of selected adverse reactions

Hypotension
In ACH study 111-301, 13% of patients treated with vosoritide reported events of decreases in blood pressure which were transient and resolved without intervention. The median time to onset from injection was 31 (18 to 120) minutes with resolution within 31 (5 to 90) minutes. The reported events were identified predominantly during periods of frequent vital signs monitoring at clinical visits after dosing over a 52-week treatment period. 2% of patients had a symptomatic episode with dizziness and vomiting.

Injection site reactions
Injection site reactions were reported in 85% patients treated with vosoritide compared to 82% patients on placebo. Patients receiving this medicinal product who experienced injection site reactions reported a median of 76 events, compared to patients receiving placebo who reported a median of 7.5 events over a 52-week period. The most common injection site reactions (occurring in at least 10% of patients treated with vosoritide) were injection site reaction (73%), injection site erythema (68%), injection site swelling (38%), and injection site urticaria (13%). All injection site reactions were Grade 1 (mild) in severity, with the exception of 5 events in two patients that were Grade 2 (moderate). Reported Grade 2 events included; two patients who reported two events of injection site urticaria, and one event of injection site vesicles.

Immunogenicity

Of 131 patients with achondroplasia who were treated with vosoritide 15 µg/kg/day and evaluable for the presence of anti-drug antibodies (ADA) for up to 240 weeks, ADA were detected in 35% of patients. The earliest time to ADA development was day 85. All ADA-positive patients tested negative for anti-vosoritide neutralising antibodies. There was no correlation between the number, duration, or severity of hypersensitivity adverse reactions or injection site reactions and ADA positivity or mean ADA titre. There was no association between ADA positivity or mean ADA titre and change from baseline in annual growth velocity (AGV) or height Z-score at Month 12. There was no impact of serum ADA detected on the plasma PK measurements of vosoritide.

Paediatric population

The safety profile of vosoritide in clinical studies involving children aged 2 to < 5 years was similar to that observed in older children (see section 5.1).

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/.