There are no or limited amount of data from the use of vosoritide in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity. As a precautionary measure, it is preferable to avoid the use of vosoritide during pregnancy.
Available pharmacodynamic/toxicological data in animals have shown excretion of vosoritide in milk. A risk to newborns/infants cannot be excluded. Vosoritide should not be used during breast-feeding.
No impairment of male or female fertility has been observed in nonclinical studies.
Vosoritide has moderate influence on the ability to drive, cycle and use machines. Vosoritide may cause transient decreases in blood pressure that are usually mild but syncope, pre-syncope, and dizziness, as well as other signs and symptoms of decreased blood pressure have been reported as adverse reactions with vosoritide. The patient’s response to treatment should be considered and if appropriate, advised not to drive, cycle or use machines for at least 60 minutes after injection.
The most common adverse reactions to vosoritide were injection site reactions (85%), vomiting (27%), and decreased blood pressure (13%).
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.
Adverse reactions in patients treated with vosoritide:
| System organ class | Very common | Common |
|---|---|---|
| Nervous system disorders | Syncope Pre-syncope Dizziness | |
| Vascular disorders | Hypotensiona | |
| Gastrointestinal disorders | Vomiting | Nausea |
| General disorders and administration site conditions | Injection site reactionb | Fatigue |
| 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.
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 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.
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.
The safety profile of vosoritide in clinical studies involving children aged 2 to < 5 years was similar to that observed in older children.
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