VOXZOGO 1.2mg powder + solvent for injection medication leaflet

Each vial of powder contains 0.4 mg of vosoritide*.

After reconstitution, each vial contains 0.4 mg vosoritide in 0.5 mL of solution, corresponding to aconcentration of 0.8 mg/mL.

Each vial of powder contains 0.56 mg of vosoritide*.

After reconstitution, each vial contains 0.56 mg vosoritide in 0.7 mL of solution, corresponding to aconcentration of 0.8 mg/mL.

Each vial of powder contains 1.2 mg of vosoritide*.

After reconstitution, each vial contains 1.2 mg vosoritide in 0.6 mL of solution, corresponding to aconcentration of 2 mg/mL.

*produced in Escherichia coli cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder and solvent for solution for injection.

The powder is white to yellow and the solvent is clear and colourless.

Voxzogo is indicated for the treatment of achondroplasia in patients 4 months of age and older whoseepiphyses are not closed. The diagnosis of achondroplasia should be confirmed by appropriate genetictesting.

Treatment with vosoritide should be initiated and directed by a physician appropriately qualified in themanagement of growth disorders or skeletal dysplasias.

Voxzogo is given as a daily subcutaneous injection. The recommended dose is based on the patient'sweight and is approximately between 15-30 µg/kg, where the higher dose is given to smallest children,see Table 1.

The dose can be administered using either mL graduated syringes or Unit (U) graduated syringes (see

Table 1). The measurements for the Unit graduated syringes are equivalent to mL as follows: 0.1 mL =10 Units. For practicality reasons and to account for weight-related PK changes (see section 5.2), thefollowing dosing is recommended.

Table 1: Single dose volumes by body weight in mL and Units (U) volumes

Body Vosoritide 0.4 mg Vosoritide 0.56 mg Vosoritide 1.2 mgweight Dose solvent (water for solvent (water for solvent (water for(kg) (mg) injections): 0.5 mL injections): 0.7 mL injections): 0.6 mLconcentration: 0.8 mg/mL concentration: 0.8 mg/mL concentration: 2 mg/mL

Daily injection volumemL Units mL Units mL Units4 0.12 mg 0.15 mL 15 U5 0.16 mg 0.20 mL 20 U6-7 0.20 mg 0.25 mL 25 U8-11 0.24 mg 0.30 mL 30 U12-16 0.28 mg 0.35 mL 35 U17-21 0.32 mg 0.40 mL 40 U22-32 0.40 mg 0.50 mL 50 U33-43 0.50 mg 0.25 mL 25 U44-59 0.60 mg 0.30 mL 30 U60-89 0.70 mg 0.35 mL 35 U≥ 90 0.80 mg 0.40 mL 40 U

Treatment with this medicinal product should be stopped upon confirmation of no further growthpotential, indicated by a growth velocity of < 1.5 cm/year and closure of epiphyses.

If a dose of vosoritide is missed, it can be administered within 12 hours. If more than 12 hours havepassed since the original dosing schedule, the missed dose should NOT be administered.

Patients/caregivers should be advised to continue with the next scheduled dose the following day.

Patients should be monitored and assessed regularly every 3-6 months to check body weight, growthand physical development. Dose should be adjusted according to the patient’s body weight(see Table 1).

The safety and efficacy of vosoritide in patients with renal or hepatic impairment has not beenevaluated.

The safety and efficacy of Voxzogo in children aged less than 4 months of age is limited. Currentlyavailable data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can bemade.

Voxzogo is for subcutaneous single use only. This medicinal product must be administered within3 hours of reconstitution.

Prior to injecting, a healthcare professional should:

* train caregivers on the preparation and subcutaneous injection of this medicinal product.

* train caregivers and patients to recognise signs and symptoms of decreased blood pressure.

* inform caregivers and patients what to do in the event of symptomatic decreases in bloodpressure.

Patients and caregivers should be instructed to rotate sites for subcutaneous injections. Recommendedinjection sites on the body include the front middle of the thighs, the lower part of the abdomen exceptfor 5 cm directly around the navel, top of the buttocks or the back of the upper arms. The sameinjection area should not be used on two consecutive days. Voxzogo should not be injected into sitesthat are red, swollen, or tender.

Patients should be well hydrated at the time of injection. It is recommended patients eat a light snackand drink an adequate amount of fluid (e.g., water, milk, juice, etc.) about 30 minutes before injecting.

This is to reduce the signs and symptoms of potential decreases in blood pressure (dizziness, fatigueand/or nausea) (see section 4.4, Blood pressure effects).

If possible, this medicinal product should be injected at approximately the same time each day.

For instructions on reconstitution of the medicinal product before administration, see section 6.6.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

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

Patients with significant cardiac or vascular disease and patients on anti-hypertensive medicinalproducts 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 4.2and 4.8).

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

In vitro cytochrome P450 (CYP) inhibition and induction studies and in vitro transporter inhibitionstudies have been performed. Results suggested that vosoritide is unlikely to cause CYP- ortransporter-mediated drug-drug interactions in humans when the medicinal product is administeredconcomitantly 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.

There are no or limited amount of data from the use of vosoritide in pregnant women. Animal studiesdo 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.

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 duringbreast-feeding.

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 causetransient decreases in blood pressure that are usually mild but syncope, pre-syncope, and dizziness, aswell as other signs and symptoms of decreased blood pressure have been reported as adverse reactionswith Voxzogo. The patient’s response to treatment should be considered and if appropriate, advisednot 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 aredefined 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 availabledata). Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Table 2: Adverse reactions in patients treated with Voxzogo

System organ class Very common Common Uncommon

Nervous system disorders Syncope

Pre-syncope

Dizziness

Vascular disorders Hypotensiona

Gastrointestinal disorders Vomiting Nausea

Skin and subcutaneous tissue Hypertrichosisdisorders

General disorders and Injection site reactionb Fatigueadministration site conditions

Investigations Increased alkalinephosphatase

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, injectionsite pruritus, injection site haemorrhage, injection site discolouration, and injection site induration.

In ACH study 111-301, patients aged ≥ 5 years, 13% of patients treated with vosoritide compared to5% of patients treated with placebo, experienced events of decreases in blood pressure which weretransient and resolved without intervention. The median time to onset from injection was31 (18 to 120) minutes with resolution within 31 (5 to 90) minutes. The reported events wereidentified predominantly during periods of frequent vital signs monitoring at clinical visits after dosingover a 52-week treatment period. 2% of patients had a symptomatic episode with dizziness andvomiting.

In study 111-206, events of decrease in blood pressure occurred in 2 patients (5%) aged < 5 yearstreated with vosoritide compared to 2 patients (6%) on placebo. In patients > 2 years to < 5 years ofage, events of decrease in blood pressure were reported in 1 patient (5%) treated with vosoritidecompared to 1 patient (6 %) on placebo. In patients 6 months to < 2 years of age, events of decrease inblood pressure were reported in 0 patients treated with vosoritide compared to 1 patient (13%) onplacebo. 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, resolvedwithout intervention and were not treatment limiting.

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 medicinalproduct who experienced injection site reactions reported a median of 76 events, compared to patientsreceiving placebo who reported a median of 7.5 events over a 52-week period. The most commoninjection site reactions (occurring in at least 10% of patients treated with vosoritide) were injection sitereaction (73%), injection site erythema (68%), injection site swelling (38%), and injection siteurticaria (13%). All injection site reactions were Grade 1 (mild) in severity, with the exception of 5events in two patients that were Grade 2 (moderate). Reported Grade 2 events included; two patientswho 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 patientstreated with vosoritide compared to 53% patients on placebo. Patients receiving vosoritide whoexperienced injection site reactions reported a median of 224 events, compared to patients receivingplacebo 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 yearsof age, events of injection site reactions were reported in 83% patients treated with vosoritidecompared to 50% patients on placebo. In patients < 6 months of age, injection site reactions werereported 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.

Of 131 patients aged 5 years of age and older with achondroplasia who were treated with vosoritide15 µg/kg/day and evaluable for the presence of anti-drug antibodies (ADA) for up to 240 weeks, ADAwere 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 correlationbetween the number, duration, or severity of hypersensitivity adverse reactions or injection sitereactions and ADA positivity or mean ADA titre. There was no association between ADA positivity ormean 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 ofvosoritide.

In patients under 5 years of age, 19% (8/43) of vosoritide-treated patients tested positive for ADA andall placebo-treated patients tested negative for ADA. The earliest time to ADA development was week26. All of the ADA-positive patients tested negative for neutralising anti-drug antibodies (NAb) at alltime points. There was no impact of ADA development on safety, efficacy or PK of vosoritide.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

In clinical trials, doses of vosoritide were explored up to 30 μg/kg/day. Two patients received up to3 times the recommended daily dose of 15 μg/kg/day for up to 5-weeks. No signs, symptoms oradverse reactions associated with the higher than intended dose were observed.

In the event a patient takes more than they should, the patient should contact their healthcareprofessional.

Pharmacotherapeutic group: Drugs for treatment of bone diseases, other drugs affecting bone structureand mineralisation, ATC code: M05BX07

Vosoritide is a modified type C natriuretic peptide (CNP). In patients with achondroplasia,endochondral bone growth is negatively regulated due to a gain of function mutation in fibroblastgrowth factor receptor 3 (FGFR3). Binding of vosoritide to natriuretic peptide receptor-B (NPR-B)antagonises FGFR3 downstream signalling by inhibiting the extracellular signal-regulated kinases 1and 2 (ERK1/2) in the mitogen-activated protein kinase (MAPK) pathway at the level of rapidlyaccelerating fibrosarcoma serine/threonine protein kinase (RAF-1). As a result, vosoritide, like CNP,acts as a positive regulator of endochondral bone growth as it promotes chondrocyte proliferation anddifferentiation.

Exposure-dependent (AUC and Cmax) increases from baseline in urinary cyclic guanosinemonophosphate (cGMP, a biomarker for NPR-B activity) concentrations and serum collagen type Xmarker (CXM, a biomarker for endochondral ossification) were observed on treatment with vosoritide.

Increase in the urinary cGMP concentrations from pre-dose baseline took place within the first fourhours post-dose. Median serum CXM concentration increased over baseline by day 29 of dailyadministration of this medicinal product. This effect was maintained beyond 24 months of treatment.

Vosoritide activity as measured by urine cGMP was near saturation while maximal increase in growthplate activity indicated by CXM was achieved at the dose of 15 μg/kg administered subcutaneouslyonce daily.

The efficacy and safety of vosoritide in patients with achondroplasia with confirmed FGFR3 mutationwere assessed in a randomised, double-blind, placebo-controlled 52-week study (ACH study 111-301).

In ACH study 111-301, patients were randomised to either vosoritide (n=60) or placebo (n=61) andthe dose of vosoritide was 15 μg/kg administered subcutaneously once daily. Prior to randomisation,all patients enrolled in an observational study (ACH study 111-901) for paediatric patients withachondroplasia for at least a 6-month period during which baseline standing height and otherpre-treatment growth assessments were collected. Patients with limb-lengthening surgery in the prior18 months or who planned to have limb-lengthening surgery during the study period were excluded.

The study comprised a 52-week placebo-controlled treatment phase followed by an open-labeltreatment extension study in which all patients received vosoritide. The primary efficacy endpoint wasthe change from baseline in AGV at Week 52 compared with placebo.

Patients with achondroplasia were also treated with vosoritide 15 μg/kg/day in an open label, dose-escalation study and in its long-term extension study (ACH study 111-205). Data was collected fromobservational studies in patients to characterise the natural history of achondroplasia. Height data fromuntreated patients with achondroplasia in the same age range as the clinical studies was used as anhistorical control to assess the effect on height after up to 5 years of vosoritide treatment.

Patient demographics and baseline characteristics are shown in Table 3.

Table 3: Patient demographics and characteristics in ACH study 111-301 and ACH study 111-205

ACH study 111-301 ACH study 111-205b15 μg/kg/day 15 μg/kg/day

Placebo Voxzogo Voxzogo

Parameter (N=61) (N=60) (N=10)

Age at day 1 (years)

Mean (SD) 9.06 (2.47) 8.35 (2.43) 8.54 (1.54)

Min, max 5.1, 14.9 5.1, 13.1 6.3, 11.1

Age at day 1, n (%)a≥ 5 to < 8 years 24 (39.3) 31 (51.7) 4 (40.0)≥ 8 to < 11 years 24 (39.3) 17 (28.3) 5 (50.0)≥ 11 to < 15 years 13 (21.3) 12 (20.0) 1 (10.0)

Tanner stage b, n (%)a

I 48 (78.7) 48 (80.0) 10 (100.0)> I 13 (21.3) 12 (20.0)

Sex, n (%)a

Male 33 (54.1) 31 (51.7) 4 (40.0)

Female 28 (45.9) 29 (48.3) 6 (60.0)

Weight (kg)

Mean (SD) 24.62 (9.07) 22.88 (7.96) 25.13 (5.74)

Min, max 11.6, 68.9 13.6, 53.0 18.2, 36.4max, maximum; min, minimum; SD, standard deviation.

a Percentages were calculated using the total number of patients in the full analysis set (N for eachtreatment group) as the denominatorb Analysis from 10 out of 35 patients who only received 15 µg/kg/day in an open label, dose-escalationstudy and continued into the long-term extension ACH study 111-205

In ACH study 111-301, improvements in AGV and height Z-score from baseline were observed inpatients treated with Voxzogo 15 µg/kg/day compared with placebo. Efficacy results are shown in

Table 4.

Table 4: Results from placebo-controlled clinical trial

Placebo Voxzogo 15 µg/kg daily Voxzogo vs.(N=61) (N=60c) placebo

Baseline Week 52 Change Baseline Week 52 Change LS Mean differencein changes(95% CI)

Annualised growth velocity (cm/year)

Mean 4.06 3.94 -0.12 4.26 5.61 1.35 1.57a± SD ± 1.20 ± 1.07 ± 1.74 ± 1.53 ± 1.05 ± 1.71 (1.22, 1.93)(p = < 0.0001)b

Height Z-score

Mean -5.14 -5.14 0.00 -5.13 -4.89 0.24 0.28a± SD ± 1.07 ± 1.09 ± 0.28 ± 1.11 ± 1.09 ± 0.32 (0.17, 0.39)(p = < 0.0001)b

AGV, annualised growth velocity; 95% CI, 95% confidence interval; LS, least-square; SD, standarddeviation.a Difference is 15 µg/kg Voxzogo minus placebo.b Two-sided p-value.c Two patients in the Voxzogo group discontinued from the study before Week 52. The values forthese 2 patients were imputed for this analysis.

LS mean estimated from the ANCOVA (analysis of covariance) model adjusted for baselinedifferences between the two arms, analysis of covariance.

The benefit of improvement in AGV in favour of Voxzogo was consistent across all predefinedsubgroups analysed including sex, age group, Tanner stage, baseline height Z-score, and baseline

AGV. In the subgroup of males Tanner stage > I, the point estimate of treatment effect was in favourof vosoritide however there were only 8 subjects in this subgroup (3 and 5 subjects in vosoritide andplacebo arms, respectively).

The observed increase in growth occurred proportionally in both the spine and the lower limbs. Therewas no difference in bone mineral density after treatment with Voxzogo compared to placebo. Duringtreatment with this medicinal product, the mean increase in bone age was comparable to the meanincrease in chronological age, indicating no acceleration of bone maturation.

Figure 1 shows the effect of Voxzogo over the two-year period in the Voxzogo treatment group, aswell as the effect in the placebo control group after receiving daily subcutaneous injections of

Voxzogo for 52 weeks in the open label extension study. Improvements in AGV were maintainedduring continued Voxzogo therapy, with no evidence of tachyphylaxis.

Figure 1: Mean (±SD) 12-Month Interval AGV Over Time

The figure includes all subjects enrolled in the pivotal trial who had a height assessment at week 52 inthe extension study. Solid lines represent treatment with vosoritide 15 ug/kg; dashed lines representplacebo. Baseline is defined as the last assessment before the first dose of active study drug(i.e. vosoritide) or Placebo in 111-301.12-Month AGV at post-baseline visits is derived over the previous 12 months. For example, 12-Month

Interval AGV at Week 52 111-302 = [(Height at Week 52 111-302 Visit- Height at Week 52 111-301

Visit)/(Date of Week 52 111-302 Visit - Date of Week 52 111-301 Visit)] x 365.25.

In the long-term extension study (ACH study 111-205), 10 patients were treated with Voxzogo15 µg/kg/day dose continuously for up to 5 years. The mean (SD) improvement in AGV compared tobaseline at 60 months was 1.34 (1.31) cm/year.

The gain in height after 5 years of treatment with 15 µg/kg/day of Voxzogo was compared with an ageand sex matched historical control. The 5-year cross-sectional comparative analysis adjusted forbaseline height differences, demonstrated, there was a statistically significant mean (95% CI)difference in height in favour of Voxzogo (9.08 [5.77, 12.38] cm; p=0.0002) compared with untreatedpatients with achondroplasia.

Paediatric population <5 years

A total of 75 patients aged 4.4 months to 59.8 months at day 1 of dosing were enrolled in arandomized, double-blind, placebo-controlled 52-week study. At least 6 months of baseline growthdata were collected in the observational study for patients who were aged 6 months and over atrandomization, and at least 3-months baseline data for those subjects aged under 6 months atrandomization. A total of 64 patients were randomised to receive vosoritide treatment or placebo and11 patients received open-label treatment. At 52 weeks, patients treated with vosoritide had animprovement in Height Z-score +0.30 SDS (95% CI 0.07, 0.54) compared to placebo.

Nine children aged >24 to <60 months were treated with vosoritide for 3 years and showed animprovement in Height Z-score of + 1.22 SDS (95% CI 0.78, 1.66) and a LS mean difference in heightof 5.73 cm (95%CI 3.54, 7.93) compared with an age and sex matched historical control of untreatedpatients with achondroplasia.

Eleven children aged >6 to <24 months were treated with vosoritide for 2 years and showed animprovement in Height Z-score of + 0.79 SDS (95% CI 0.29, 1.28) and a LS mean difference in heightof 2.69 cm (95%CI 1.00, pct. 4.38) compared with an age and sex matched historical control of untreatedpatients with achondroplasia.

Vosoritide is a modified recombinant human CNP. The 39 amino acid peptide analogue includes the37 C terminal amino acids of the human CNP53 sequence plus the addition of 2 amino acids (Pro Gly)to convey resistant to neutral endopeptidase (NEP) degradation, resulting in prolonged half-life incomparison to endogenous CNP.

The pharmacokinetics of vosoritide were evaluated in a total of 58 patients aged 5 to 18 years withachondroplasia who received subcutaneous injections of vosoritide 15 µg/kg once daily for 52 weeks.

The pharmacokinetic exposure of vosoritide in 15 patients aged 2 to < 5 years old were comparablewith older children.

In 8 patients aged 6 months to < 2 years old, receiving 30 µg/kg once daily the pharmacokineticexposure of vosoritide was 65% to 70% higher than the older children (> 2 years old) receiving15 µg/kg once daily. In 9 patients < 6 months of age receiving 30 µg/kg once daily, thepharmacokinetic exposure of vosoritide was 57% to 105% higher than the older children (> 2 yearsold) receiving 15 µg/kg once daily.

Vosoritide was absorbed with a median Tmax of 15 minutes. The mean (± SD) peak concentration(Cmax) and area under the concentration-time curve from time zero to the last measurableconcentration (AUC0-t) observed after 52 weeks of treatment was 5 800 (±3 680), and 290 000(± 235 000) pg-min/mL respectively. The bioavailability of vosoritide was not assessed in clinicalstudies.

The mean (± SD) apparent volume of distribution after 52 weeks of treatment was2 910 (± 1 660) mL/kg.

The metabolism of vosoritide is expected to occur via catabolic pathways and be degraded into smallpeptide fragments and amino acids.

The mean (± SD) apparent clearance after 52 weeks of treatment was 79.4 (53.0) mL/min/kg. Themean (± SD) half-life was 27.9 (9.9) minutes.

The inter-subject variability (coefficient of variation) in apparent clearance was 33.6 %.

The increase in plasma exposure (AUC and Cmax) with dose was greater than dose proportional acrossthe dose range of 2.5 (0.17 times the recommended dose) to 30.0 μg/kg/day (twice the approved dose).

No clinically significant differences in the vosoritide pharmacokinetics was observed based on age(0.9 to 16 years), sex, race or ethnicity.

Body weight is the only significant covariate for vosoritide clearance or volume of distribution. Theapparent clearance and volume of distribution of vosoritide increased with increasing body weight inpatients with achondroplasia (9 to 74.5 kg). The proposed posology (see section 4.2) takes account ofthis deviation and recommends the use of doses above (in patients between 10 and 16 kg bodyweight), or below (in those above a body weight of 44 kg) the 15 µg/kg “standard dose” in order toenable a similar level of exposure across all weight-ranges.

The safety and efficacy of vosoritide in patients with renal or hepatic impairment has not beenevaluated. Based on the elimination mechanism, renal or hepatic impairment is not expected to alterthe pharmacokinetics of vosoritide.

In vitro cytochrome P450 (CYP) inhibition and induction studies indicated that vosoritide did notinhibit CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, or 3A4/5, nor induce CYP 1A2, 2B6, or 3A4/5 atclinically relevant concentrations. In vitro interaction studies also indicated that the potential forinteraction with the drug-transporters OAT1, OAT3, OCT 1, OCT 2, OATP1B1, OATP1B3, MATE 1,

KATE2-K, BCRP, P-gp, and BSEP is low at clinically relevant concentrations.

Adverse reactions not observed in clinical studies but seen in animals at exposure levels similar toclinical exposure levels, and with possible relevance to clinical use.

Transient decreases in blood pressure and increases in heart rate were observed in healthy monkeysacross multiple studies in doses of 28 to 300 μg/kg in a dose-related manner. Peak effects weretypically observed within the first hour post dose and were generally asymptomatic. In some monkeysreceiving higher doses of vosoritide, brief bouts of sternal/lateral recumbency or hypoactivity, wereobserved. These effects could be related to decreased blood pressure.

Adverse effects on body posture, bone shape, mobility, and bone strength were observed in normalanimals in repeat-dose toxicity studies in rats and monkeys. In monkeys, the NOAEL for vosoritide is25 μg/kg (mean Cmax value of 1 170 pg/mL; approximately equivalent to the recommended humandose in a 20 kg human) when administered daily via subcutaneous injection for 44 weeks.

Carcinogenicity/mutagenicity

Carcinogenicity and genotoxicity studies have not been performed with vosoritide. Based on themechanism of action, vosoritide is not expected to be tumorigenic.

In a fertility and reproductive study in male and female rats at dose levels up to 540 μg/kg/day,vosoritide had no effect on mating performance, fertility, or litter characteristics.

Vosoritide was not associated with effects on reproductive performance, in utero or developmentalparameters measured in rats and rabbits to investigate fertility, or embryo-foetal development in pre-and post-natal development studies.

Vosoritide was detected in the breast milk in rats.

Citric acid (E 330)

Sodium citrate (E 331)

Trehalose dihydrate

Mannitol (E 421)

Methionine

Polysorbate 80 (E 433)

Water for injections

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

Unopened vials4 years

Chemical and physical stability has been demonstrated for 3 hours at 25°C.

From a microbiological point of view, unless the method of reconstitution precludes the risk ofmicrobial contamination, the solution should be used immediately.

If not used immediately, Voxzogo must be administered within 3 hours of reconstitution (seesection 4.2).

Store in a refrigerator (2 °C - 8 °C). Do not freeze.

Store in the original package in order to protect from light.

Voxzogo may be stored at room temperature below 30 °C for a single period up to 90 days, but notbeyond the expiry date. Do not return Voxzogo to refrigerator after storage at room temperature.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Vosoritide 0.4 mg powder and solvent for solution for injection

Powder2 mL vial (glass) with rubber stopper (bromobutyl) and white flip cap.

Pre-filled syringe (glass) with plunger (bromobutyl) and tip cap with a luer lock and tamper evidentseal containing 0.5 mL of water for injections.

Vosoritide 0.56 mg powder and solvent for solution for injection

Powder2 mL vial (glass) with rubber stopper (bromobutyl) and magenta flip cap.

Pre-filled syringe (glass) with plungers (bromobutyl) and tip cap with a luer lock and tamper evidentseal containing 0.7 mL of water for injections.

Vosoritide 1.2 mg powder and solvent for solution for injection

Powder2 mL vial (glass) with rubber stopper (bromobutyl) and grey flip cap.

Pre-filled syringe (glass) with plungers (bromobutyl) and tip cap with a luer lock and tamper evidentseal containing 0.6 mL of water for injections

Each carton contains:

* 10 vials of Voxzogo

* 10 pre-filled syringes of water for injections

* 10 individual single use needles (23 gauge, for reconstitution)

* 10 individual single use syringes (30 gauge, for administration)

* The correct Voxzogo strength and correct pre-filled syringe of solvent (reconstitution volume)should be confirmed based on the patient’s body weight (see Table 1).

* All necessary ancillary supplies must be in place before starting.

o Alcohol padso Gauze or bandageso Sharps container

* The Voxzogo vial and solvent in a pre-filled syringe (water for injections) should be removedfrom the refrigerator and allowed to reach room temperature before reconstituting Voxzogo.

* The solvent needle must be attached to the solvent in the pre-filled syringe (water forinjections).

* The entire solvent volume must be injected into the vial.

* The solvent in the vial should be gently swirled until the white powder is completely dissolved.

The vial should not be shaken.

* The dosing volume of the reconstituted solution should be slowly withdrawn from the single usevial into a syringe.

* Once reconstituted this medicinal product is a clear, colourless to yellow liquid. The solutionshould not be used if discoloured or cloudy, or if particles are present.

* After reconstitution, Voxzogo can be held in the vial at a room temperature up to 25 °C for amaximum of 3 hours. The medicinal product contains no preservative.

* For administration, the required dose volume must be extracted from the vial using the suppliedadministration syringe (see Table 1).

* Each vial and pre-filled syringe are for single use only.

* Only the administration syringe provided should be used.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

All needles and syringes should be disposed of in a sharps disposal container.

BioMarin International Limited

Shanbally, Ringaskiddy

County Cork, P43 R298

Ireland

EU/1/21/1577/001 10 x 0.4 mg Powder and solvent for solution for injection

EU/1/21/1577/002 10 x 0.56 mg Powder and solvent for solution for injection

EU/1/21/1577/003 10 x 1.2 mg Powder and solvent for solution for injection

Date of first authorisation: 26 August 2021

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.