VOXZOGO Powder and solvent for solution for injection Ref.[49897] Active ingredients: Vosoritide

Traceability

In order to improve the traceability of biological medicinal products, the name and the batch number of the administered medicinal product should be clearly recorded.

Blood pressure effects

Patients with significant cardiac or vascular disease and patients on anti-hypertensive medicinal products were excluded from participation in premarketing clinical trials.

To reduce the risk of a potential decrease in blood pressure and associated symptoms (dizziness, fatigue and/or nausea), patients should be well hydrated at the time of injection (see sections 4.2 and 4.8).

Sodium

This medicinal product contains less than 1 mmol sodium (23 mg) per unit volume, that is to say essentially ‘sodium-free’.

In vitro cytochrome P450 (CYP) inhibition and induction studies and in vitro transporter inhibition studies have been performed. Results suggested that vosoritide is unlikely to cause CYP- or transporter-mediated drug-drug interactions in humans when the medicinal product is administered concomitantly with other medicinal products.

No other interaction studies have been performed. Because it is a recombinant human protein, vosoritide is an unlikely candidate for drug-drug interactions.

Pregnancy

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 (see section 5.3). As a precautionary measure, it is preferable to avoid the use of vosoritide during pregnancy.

Breast-feeding

Available pharmacodynamic/toxicological data in animals have shown excretion of vosoritide in milk (see section 5.3). A risk to newborns/infants cannot be excluded. Vosoritide should not be used during breast-feeding.

Fertility

No impairment of male or female fertility has been observed in nonclinical studies (see section 5.3).

Voxzogo 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 Voxzogo. 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.

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:

^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, patients aged ≥5 years, 13% of patients treated with vosoritide compared to 5% of patients treated with placebo, experienced 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.

In study 111-206, events of decrease in blood pressure occurred in 2 patients (5%) aged <5 years treated with vosoritide compared to 2 patients (6%) on placebo. In patients >2 years to <5 years of age, events of decrease in blood pressure were reported in 1 patient (5%) treated with vosoritide compared to 1 patient (6%) on placebo. In patients 6 months to <2 years of age, events of decrease in blood pressure were reported in 0 patients treated with vosoritide compared to 1 patient (13%) on placebo. In patients <6 months of age, events of decrease in blood pressure were reported in 1 patient (8%) treated with vosoritide compared to 0 patients on placebo. All events were transient, resolved without intervention and were not treatment limiting.

Injection site reactions

In ACH study 111-301, in patients aged ≥5 years, 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. In study 111-206, patients aged <5 years, injections site reactions were reported in 86% of patients treated with vosoritide compared to 53% patients on placebo. Patients receiving vosoritide who experienced injection site reactions reported a median of 224 events, compared to patients receiving placebo who reported a median of 114 events over a 52-week period, all of which were Grade 1 (mild) in severity. In patients >2 years to <5 years of age, injection site reactions were reported in 84% patients treated with vosoritide compared to 44% patients on placebo. In patients 6 months to <2 years of age, events of injection site reactions were reported in 83% patients treated with vosoritide compared to 50% patients on placebo. In patients <6 months of age, injection site reactions were reported in 92% patients treated with vosoritide compared to 75% patients on placebo.

Across all age groups, injection site reactions were transient, and not treatment limiting.

Immunogenicity

Of 131 patients aged 5 years of age and older 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.

In patients under 5 years of age, 19% (8/43) of vosoritide-treated patients tested positive for ADA and all placebo-treated patients tested negative for ADA. The earliest time to ADA development was week 26. All of the ADA-positive patients tested negative for neutralising anti-drug antibodies (NAb) at all time points. There was no impact of ADA development on safety, efficacy or PK of vosoritide.

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.

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.