Vosoritide is a C type natriuretic peptide (CNP) analog approved for increasing linear growth in pediatric patients with achondroplasia with open epiphyses. Achondroplasia is a genetic condition that causes short stature and disproportionate growth. The average height of an adult with achondroplasia is approximately 4 feet. In a multi-center, randomized, double-blind, placebo-controlled, phase 3 clinical trial of 121 patients with achondroplasia, vosoritide efficacy was determined by the change from baseline in annualized growth velocity (AGV) after 52 weeks. At the end of the 52-week treatment period, the treatment difference in the change from baseline in AGV was 1.57 cm per year in patients receiving daily vosoritide compared to those receiving placebo. At the end of the study, 58 patients enrolled in an open-label extension. The improvement in AGV was maintained in patients who had 2 years of follow-up since randomization. The most common adverse reactions were injection site reactions, vomiting, and decreased blood pressure. To reduce the risk of decreased blood pressure, ensure patients are well hydrated and have adequate food intake prior to vosortide administration.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
Route-Specific Administration
Injectable Administration
-Administer vosoritide by subcutaneous injection. Do NOT administer by intramuscular injection or intravenously.
-Discontinue therapy if epiphyseal fusion occurs.
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
-Vosoritide is a white to yellow lyophilized powder. After reconstitution, the solution should be a clear, colorless to yellow liquid. Do not use if the solution is discolored, cloudy, or contains particulate matter.
Subcutaneous Administration
-Vosoritide may be administered by caregivers after appropriate training on the preparation and administration.
-Vosoritide is available in 3 vial sizes; selection of the appropriate vial is based on the patient's actual body weight (kg).
-Vosoritide must be reconstituted using the provided diluent syringe containing Sterile Water for Injection.
-The injection volume is based on the patient's actual body weight and the concentration of reconstituted vosoritide. The vosoritide reconstituted concentration of the 0.4 mg vial, after adding 0.5 mL reconstitution volume, is 0.8 mg/mL. The reconstituted concentration of the 0.56 mg vial, after adding 0.7 mL of reconstitution volume, is 0.8 mg/mL. The reconstituted concentration of the 1.2 mg vial, after adding 0.6 mL of reconstitution volume, is 2 mg/mL.
-Remove vosoritide vial and prefilled diluent syringe from the refrigerator and allow both to reach room temperature before reconstitution.
-Attach the diluent needle to the diluent prefilled syringe and inject the entire diluent prefilled syringe volume into the vial.
-Gently swirl the diluent in the vial until the white powder is completely dissolved, but do not shake.
-Slowly withdraw the appropriate dose from the vial using the supplied administration syringe.
-Missed dose: Administer a missed dose as soon as possible, but not more than 12 hours after the missed dose. If more than 12 hours have passed since the missed dose, skip the dose and administer the next dose according to the usual dosing schedule.
-Storage: After reconstitution, vosoritide can remain in the vial at room temperature (68 to 77 degrees F [20 to 25 degrees C]) for a maximum of 3 hours. Discard any unused portion. Do not pool unused portions from the vials. Do not administer more than 1 dose from a vial. Do not mix with other medications.
Subcutaneous Injection
-Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration) to reduce the risk of low blood pressure and its signs and symptoms.
-Administer at approximately the same time each day, if possible.
-Rotate sites for subcutaneous injections. The recommended injection sites are the front middle of the thighs, the lower part of the abdomen at least 2 inches away from the navel, top of the buttocks, or the back of the upper arms. Do not use the same injection area on 2 consecutive days. Do not inject into sites that are red, swollen, or tender.
Local injection site reaction (85% to 86%), including erythema (75%), swelling (62%), and urticaria (25%), was the most commonly reported adverse reaction after vosoritide administration during clinical trials in pediatric patients. Rash (28%), injection site pain, bruising (hematoma), pruritus, hemorrhage, site discoloration, and site induration were also reported. During the 52-week treatment period, vosoritide treated patients experienced a total of 6,983 events of injection site reactions (120.4 events per person/year exposure) compared to 1,776 events of injection site reactions (29.2 events per person/year exposure) in patients receiving placebo. Two patients receiving vosoritide discontinued treatment due to adverse reactions of pain and anxiety with injections.
Vomiting (27% vs. 20%, placebo), gastroenteritis (13% vs. 8%, placebo), and diarrhea (10% vs. 3%, placebo) were reported in pediatric patients 5 to 14 years receiving vosoritide during a clinical trial.
Arthralgia (15% vs. 7%, placebo); dizziness, including presyncope, procedural dizziness, and vertigo (10% vs. 3%, placebo); and fatigue, including lethargy and malaise (8% vs. 3%, placebo), were reported in pediatric patients 5 to 14 years receiving vosoritide during a clinical trial.
Decreased blood pressure (hypotension) occurred in 13% of vosoritide treated patients compared to 5% of patients receiving placebo. Of the 8 patients who experienced a decrease in blood pressure, a total of 11 events of transient decrease in blood pressure occurred. The median time to onset from injection was 31 (18 to 120) minutes with resolution within 31 (5 to 90) minutes in vosoritide treated patients. Two (3%) patients each had 1 symptomatic episode of decreased blood pressure with vomiting and/or dizziness compared to 0 patients receiving placebo. Ensure patients are well hydrated and have adequate food intake prior to vosoritide administration to reduce the risk of decreased blood pressure and associated symptoms.
Otalgia (10% vs. 5%, placebo), influenza (10% vs. 5%, placebo), seasonal allergy (7% vs. 2%, placebo), and xerosis (5% vs. 0%, placebo) were reported in pediatric patients 5 to 14 years receiving vosoritide during a clinical trial. Additionally, an increase in alkaline phosphatase levels (17% vs. 7% of placebo), was reported in vosoritide treated pediatric patients during clinical trials.
As with all peptides, there is a potential for immunogenicity with vosoritide treatment. Anti-drug antibody formation was detected in 35% (46/131) of pediatric patients age 5 years and older treated with vosoritide for up to 240 weeks. All anti-drug antibody (ADA)-positive patients tested negative for anti-vosoritide neutralizing antibodies. No association was found between the number, duration, or severity of hypersensitivity adverse reactions or injection site reactions and ADA positivity or mean ADA titer. No association was found between ADA positivity or mean ADA titer and change from baseline in annual growth velocity (AGV) or height Z-score at month 12. In patients younger than 5 years, 33% (20/61) of patients receiving vosoritide tested positive for ADA for up to 44 months. All ADA-positive subjects tested negative for anti-vosoritide neutralizing antibodies. There was no impact of serum ADA development on safety, efficacy, or pharmacokinetics of vosoritide up to month 12.
Ensure patients are well hydrated and have adequate food intake prior to vosoritide administration to reduce the risk of hypotension and associated symptoms (dizziness, fatigue, and/or nausea). Transient decreases in blood pressure were observed in vosoritide clinical trials. Patients with significant vascular or cardiac disease and patients on antihypertensive medications were excluded from clinical trials.
There are no available data on the use of vosoritide in human pregnancy to evaluate a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, no embryo-fetal toxicity or congenital malformations occurred in pregnant rats and rabbits administered doses up to 14 times and 200 times, respectively, the exposure at the maximum recommended human dose (MRHD).
There are no data on the presence of vosoritide in human milk, effects on the breast-fed infant, or effects on milk production. Vosoritide is present in rat milk and is likely present in human milk. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally administered drug, health care providers are encouraged to report the adverse effect to the FDA.
For the treatment of growth failure in patients with achondroplasia:
Subcutaneous dosage:
Children and Adolescents weighing 90 kg or more: 0.8 mg (0.4 mL) subcutaneously once daily using the 1.2 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Children and Adolescents weighing 60 to 89 kg: 0.7 mg (0.35 mL) subcutaneously once daily using the 1.2 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Children and Adolescents weighing 44 to 59 kg: 0.6 mg (0.3 mL) subcutaneously once daily using the 1.2 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Children and Adolescents weighing 33 to 43 kg: 0.5 mg (0.25 mL) subcutaneously once daily using the 1.2 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Children and Adolescents weighing 22 to 32 kg: 0.4 mg (0.5 mL) subcutaneously once daily using the 0.56 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Children and Adolescents weighing 17 to 21 kg: 0.32 mg (0.4 mL) subcutaneously once daily using the 0.56 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly every 3 to 6 months. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Infants, Children, and Adolescents weighing 12 to 16 kg: 0.28 mg (0.35 mL) subcutaneously once daily using the 0.56 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Infants and Children weighing 8 to 11 kg: 0.24 mg (0.3 mL) subcutaneously once daily using the 0.4 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Infants and Children weighing 6 to 7 kg: 0.2 mg (0.25 mL) subcutaneously once daily using the 0.4 mg vial. Ensure the patient has had adequate food and fluid intake (approximately 240 to 300 mL of fluid within the hour prior to administration). Monitor patient body weight, growth, and physical development regularly. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Neonates and Infants weighing 5 kg: 0.16 mg (0.2 mL) subcutaneously once daily using the 0.4 mg vial. Ensure the patient has had adequate food and fluid intake within the hour prior to administration. Monitor patient body weight, growth, and physical development regularly. Adjust dosage according to the patient's actual body weight. Discontinue therapy once epiphyseal fusion has occurred.
Neonates and infants weighing 4 kg: 0.12 mg (0.15 mL) subcutaneously once daily using the 0.4 mg vial. Ensure the patient has had adequate food and fluid intake within the hour prior to administration. Monitor patient body weight, growth, and physical development regularly. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Neonates and Infants weighing 3 kg: 0.096 mg (0.12 mL) subcutaneously once daily using the 0.4 mg vial. Ensure the patient has had adequate food and fluid intake within the hour prior to administration. Monitor patient body weight, growth, and physical development regularly. Adjust dosage according to the patient's actual body weight. Discontinue vosoritide therapy once epiphyseal fusion has occurred.
Maximum Dosage Limits:
-Adults
Safety and efficacy have not been established.
-Geriatric
Safety and efficacy have not been established.
-Adolescents
weighing 90 kg or more: 0.8 mg/day subcutaneously.
weighing 60 to 89 kg: 0.7 mg/day subcutaneously.
weighing 44 to 59 kg: 0.6 mg/day subcutaneously.
weighing 33 to 43 kg: 0.5 mg/day subcutaneously.
weighing 22 to 32 kg: 0.4 mg/day subcutaneously.
weighing 17 to 21 kg: 0.32 mg/day subcutaneously.
weighing 12 to 16 kg: 0.28 mg/day subcutaneously.
-Children
weighing 60 to 89 kg: 0.7 mg/day subcutaneously.
weighing 44 to 59 kg: 0.6 mg/day subcutaneously.
weighing 33 to 43 kg: 0.5 mg/day subcutaneously.
weighing 22 to 32 kg: 0.4 mg/day subcutaneously.
weighing 17 to 21 kg: 0.32 mg/day subcutaneously.
weighing 12 to 16 kg: 0.28 mg/day subcutaneously.
weighing 8 to 11 kg: 0.24 mg/day subcutaneously.
weighing 6 to 7 kg: 0.2 mg/day subcutaneously.
-Infants
weighing 12 to 16 kg: 0.28 mg/day subcutaneously.
weighing 8 to 11 kg: 0.24 mg/day subcutaneously.
weighing 6 to 7 kg: 0.2 mg/day subcutaneously.
weighing 5 kg: 0.16 mg/day subcutaneously.
weighing 4 kg: 0.12 mg/day subcutaneously.
weighing 3 kg: 0.096 mg/day subcutaneously.
-Neonates
weighing 5 kg: 0.16 mg/day subcutaneously.
weighing 4 kg: 0.12 mg/day subcutaneously.
weighing 3 kg: 0.096 mg/day subcutaneously.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
eGFR 60 mL/minute/1.73 m2 or more: No dosage adjustment needed.
eGFR less than 60 mL/minute/1.73 m2: Use is not recommended.
*non-FDA-approved indication
There are no drug interactions associated with Vosoritide products.
Vosoritide is a human C type natriuretic peptide (CNP) analog. Patients with achondroplasia have endochondral bone growth that is negatively regulated due to a function mutation in fibroblast growth factor receptor 3 (FGFR3). Vosoritide binds to natriuretic peptide receptor-B (NPR-B) and 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/theonine protein kinase (RAF-1). 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 therapy resulted in chondrocyte proliferation and differentiation that led to a widening of the growth plate and increase in skeletal growth. In mouse models of FGFR3-related chondrodysplasia, a partial or complete normalization of the dwarfism phenotype was observed.
Vosoritide is administered by subcutaneous injection. The mean apparent volume of distribution of vosoritide 15 mcg/kg/dose subcutaneously once daily for 52 weeks ranged from 2,880 (+/- 2,450) to 3,020 (+/- 1,980) mL/kg. The mean apparent clearance ranged from 79.4 (+/- 53) to 104 (+/- 98.8) mL/minute/kg and the mean half-life ranged from 21 (+/- 4.7) to 27.9 (+/- 9.9) minutes. Vosoritide is thought to be metabolized via catabolic pathways with degradation into small peptide fragments and amino acids.
After vosoritide administration to pediatric patients with achondroplasia, urinary cyclic guanosine monophosphate (cGMP) concentrations increased from pre-dose baseline within the first 4 hours post-dose, with a maximum concentration at 2 hours post-dose. Daily administration of vosoritide also led to an increase from baseline in serum collagen type X marker (CXM), an endochondral ossification biomarker that remained elevated beyond 24 months. In patients 5 to 14 years old at screening, exposure-response analyses showed that vosoritide activity (measured by urinary cGMP) was near saturation at 15 mcg/kg/dose once daily, while maximal increase in growth plate activity (indicated by CXM) was achieved at this dose.
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: none
In vitro studies showed that vosoritide, at therapeutic concentrations, does not inhibit or induce CYP450 enzymes. Based on in vitro studies, vosoritide is unlikely to inhibit the human drug uptake or efflux transporters such as OAT1, OAT3, OCT1, OCT2, OATP1B1, OATP1B3, MATE1, MATE2-K, BCRP, P-gp, and BSEP at clinically relevant concentrations and therefore, no effect of vosoritide is anticipated on concomitantly administered drugs that are substrates of these transporters. Clinical studies evaluating the drug-drug interaction potential of vosoritide have not been conducted.
-Route-Specific Pharmacokinetics
Subcutaneous Route
Vosoritide AUC and Cmax increased more than proportionally after subcutaneous administration to pediatric patients with achondroplasia receiving 7.5 to 30 mcg/kg/dose. The mean Cmax and AUC ranged from 4.71 (+/- 2.32) ng/mL to 7.18 (+/- 9.65) ng/mL and 161 (+/- 98.1) ng x minute/mL to 290 (+/- 235) ng x minute/mL, respectively, in patients 5 to 13 years with achondroplasia who received subcutaneous injections of vosoritide 15 mcg/kg/dose once daily for 52 weeks. No drug accumulation was observed after 15 mcg/kg/dose once daily. Vosoritide exposure increased with the duration of treatment; the mean AUC at week 52 increased approximately 20% compared to that at day 1. After subcutaneous injection, the absolute bioavailability was not determined. Vosoritide was absorbed with a median Tmax of 15 minutes after dosing.
-Special Populations
Hepatic Impairment
The effect of hepatic impairment on the pharmacokinetics of vosoritide is unknown.
Renal Impairment
The effect of renal impairment on the pharmacokinetics of vosoritide is unknown.
Pediatrics
No clinically significant differences in vosoritide pharmacokinetics were observed based on age (0.4 to 15 years).
Gender Differences
No clinically significant differences in vosoritide pharmacokinetics were observed based on gender.
Ethnic Differences
No clinically significant differences in vosoritide pharmacokinetics were observed based on ethnicity.
Obesity
During population pharmacokinetic analyses, body weight was a significant covariate for vosoritide clearance and volume of distribution. The apparent clearance and volume of distribution of vosoritide increased with increasing body weight (5 to 74.5 kg) in patients with achondroplasia.