2.1 Important Instructions Prior to Administration of VOXZOGO

To reduce the risk of low blood pressure and its associated signs and symptoms, instruct the caregiver and patient that the patient should [see Warnings and Precautions (5.1)]:

• Have adequate food intake prior to VOXZOGO administration.
• Drink approximately 240 to 300 mL of fluid in the hour prior to VOXZOGO administration.

2.2 Recommended Dosage and Administration

The recommended dosage of VOXZOGO is based on the patient's actual body weight (see Table 1). VOXZOGO is administered by subcutaneous injection once daily [see Dosage and Administration (2.4)].

Inject VOXZOGO at approximately the same time each day, if possible. The volume of VOXZOGO to be administered (injection volume) is based on the patient's actual body weight and the concentration of reconstituted VOXZOGO (0.8 mg/mL or 2 mg/mL) (see Table 1). VOXZOGO must be reconstituted prior to use [see Dosage and Administration (2.4)].

2.3 Growth Monitoring

Monitor and assess patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust the dosage according to the patient's actual body weight [see Dosage and Administration (2.2)].

Permanently discontinue VOXZOGO upon confirmation of no further growth potential, indicated by closure of epiphyses.

2.4 Preparation and Administration

Reconstitute VOXZOGO before administration using the provided diluent syringe containing Sterile Water for Injection, USP (see Reconstitution Instructions below).

Caregivers may inject VOXZOGO subcutaneously after proper training by a healthcare professional on the preparation and administration of VOXZOGO [see Instructions for Use].

5.1 Risk of Low Blood Pressure

Transient decreases in blood pressure were observed in clinical studies of VOXZOGO. Subjects with significant cardiac or vascular disease and patients on anti-hypertensive medicinal products were excluded from participation in VOXZOGO clinical trials. To reduce the risk of a decrease in blood pressure and associated symptoms (dizziness, fatigue and/or nausea), instruct patients to be well hydrated and have adequate food intake prior to administration of VOXZOGO [see Dosage and Administration (2.1) and Adverse Reactions (6.1)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

The safety and effectiveness of VOXZOGO have been established in pediatric patients for the improvement in linear growth in patients with achondroplasia with open epiphyses.

Use of VOXZOGO for this indication is supported by evidence from an adequate and well-controlled study in 121 pediatric patients aged 5 to 15 years with achondroplasia, pharmacokinetic data in pediatric patients aged 4.5 months to 15 years, and additional safety data in pediatric patients aged 4.4 months to <5 years [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14)].

8.6 Renal Impairment

The effect of renal impairment on the pharmacokinetics of VOXZOGO has not been evaluated. No dosage adjustment is needed for patients with eGFR ≥ 60 mL/min/1.73 m2. VOXZOGO is not recommended for patients with eGFR < 60 mL/min/1.73 m2.

12.1 Mechanism of Action

In patients with achondroplasia, endochondral bone growth is negatively regulated due to a gain of function mutation in fibroblast growth factor receptor 3 (FGFR3). Binding of vosoritide to natriuretic peptide receptor-B (NPR-B) antagonizes FGFR3 downstream signaling by inhibiting the extracellular signal-regulated kinases 1 and 2 (ERK1/2) in the mitogen-activated protein kinase (MAPK) pathway at the level of rapidly accelerating 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 and differentiation.

In animal models with open growth plates, vosoritide administration resulted in the promotion of chondrocyte proliferation and differentiation that led to a widening of the growth plate and subsequent increase in skeletal growth. In the mouse models of FGFR3-related chondrodysplasia, a partial or complete normalization of the dwarfism phenotype was observed.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

The area under the concentration-time curve (AUC) and peak concentration (Cmax) of vosoritide increased greater than proportionally following subcutaneous administration to pediatric subjects with achondroplasia in the dose range of 7.5 to 30.0 mcg/kg. The pharmacokinetics of vosoritide were evaluated in 58 subjects aged 5 to 13 years with achondroplasia who received subcutaneous injections of vosoritide 15 mcg/kg once daily for 52 weeks. The mean (± SD) Cmax and area under the concentration-time curve from time zero to the last measurable concentration (AUC0-t) observed across 52 weeks of treatment ranged from 4.71 (± 2.32) to 7.18 (± 9.65) ng/mL, and 161 (± 98.1) to 290 (± 235) ng-min/mL, respectively. No drug accumulation was observed following 15 mcg/kg once daily dosing. The exposure of vosoritide increased with the duration of treatment. The mean AUC0-t at week 52 increased approximately 20% compared to that at day 1.

12.6 Immunogenicity

The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of vosoritide.

Of 131 subjects aged 5 years and older who were treated with VOXZOGO 15 mcg/kg/day and evaluable for the presence of anti-drug antibodies (ADA) for up to 240 weeks, ADA were detected in 35% (46/131). The earliest time to ADA development was day 85. All ADA-positive subjects tested negative for anti-vosoritide neutralizing 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 titer. There was no association between ADA positivity or mean ADA titer 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 subjects under 5 years of age, 33% (20/61) of vosoritide-treated subjects tested positive for ADA and all placebo-treated subjects tested negative for ADA for up to 44 months. The earliest time to ADA development was week 26. All of the ADA-positive subjects tested negative for neutralizing antibodies at all time points. There was no impact of ADA development on safety, efficacy or PK of vosoritide up to Month 12.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term carcinogenicity studies and genotoxicity studies with vosoritide have not been performed.

14.1 Pediatric Patients 5 Years of Age and Older

The safety and effectiveness of VOXZOGO in patients with achondroplasia were assessed in one 52-week, multi-center, randomized, double-blind, placebo-controlled, phase 3 study - Study 1 (NCT03197766).

Study 1 was conducted in 121 subjects with genetically-confirmed achondroplasia, who were randomized to either VOXZOGO (N=60) or placebo (N=61). The dosage of VOXZOGO was 15 mcg/kg administered subcutaneously once daily. Baseline standing height, weight Z-score, body mass index (BMI) Z-score, and upper to lower body ratio were collected for at least 6 months prior to randomization. Subjects with limb-lengthening surgery in the prior 18 months or who planned to have limb-lengthening surgery during the study period were excluded. The study included a 52-week placebo-controlled treatment phase followed by an open-label treatment extension study period in which all subjects received VOXZOGO. The primary efficacy endpoint was the change from baseline in annualized growth velocity (AGV) at Week 52 compared with placebo.

The subjects' ages ranged from 5.1 to 14.9 years with a mean of 8.7 years. Sixty four (53%) subjects were male and 57 (47%) were female. Overall, 86 (71%) subjects were White, 23 (19%) were Asian, 5 (4%) were Black or African American, and 7 (6%) were classified as "multiple" race. The subjects had a mean baseline height standard deviation score (SDS) of -5.13.

Treatment with VOXZOGO for 52 weeks resulted in a treatment difference in the change from baseline in AGV of 1.57 cm/year after 52 weeks of treatment (Table 5).

The improvement in AGV in favor of VOXZOGO was consistent across all predefined subgroups analyzed including sex, age group, Tanner stage, baseline height Z-score, and baseline AGV.

How Supplied

VOXZOGO for injection is a white to yellow lyophilized powder for reconstitution and is provided as a co-pack which includes ten:

• Sterile, single-dose 2 mL glass vials containing VOXZOGO
• Diluent (Sterile Water for Injection, USP) in a single-dose prefilled syringe
• Diluent transfer needles (23 gauge)
• Single-dose administration syringes (30 gauge) both with needle retraction safety devices

The following items to be obtained separately; alcohol aseptic wipes, gauze, bandages and sharps container.

Storage

Refrigerate VOXZOGO vials and prefilled diluent syringes at 2°C to 8°C (36°F to 46°F). Do not freeze.

VOXZOGO can be stored at room temperature 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) for 90 days. Do not return VOXZOGO to the refrigerator once stored at room temperature.

After reconstitution, VOXZOGO can be held in the vial at room temperature 20°C to 25°C (68°F to 77°F) for a maximum of 3 hours [see Dosage and Administration (2.4)].

Record the starting date of room-temperature storage clearly on the unopened product carton.

Do not use beyond expiration date on the label.

Store in the original package to protect from light.

Handling

Reconstituted VOXZOGO must be administered within 3 hours of reconstitution [see Dosage and Administration (2.4)].

Preparation and Administration

Instruct caregivers on proper preparation and administration of VOXZOGO. Ensure caregivers have demonstrated the ability to perform a subcutaneous injection [see Dosage and Administration (2.4)].

Instruct caregivers in the technique of proper syringe and needle disposal, and advise them not to reuse these items. Instruct caregivers to dispose needles and syringes in a puncture-resistant container.

Risk of Low Blood Pressure

Inform caregivers and patients that VOXZOGO may lower blood pressure after administration. Instruct caregivers and patients that prior to VOXZOGO administration, the patient should have adequate food intake and within the hour prior to administration, the patient should drink approximately 8-10 ounces (240-300 mL) of fluid [see Dosage and Administration (2.1) and Warnings and Precautions (5.1)].