Yuviwel Drug Information

YUVIWEL ® is indicated to increase linear growth in pediatric patients 2 years of age and older with achondroplasia with open epiphyses. This indication is approved under accelerated approval based on an improvement in annualized growth velocity. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trial(s).

Recommended Dosage and Administration

The recommended once-weekly dosage of YUVIWEL is based on the patient´s body weight (see Table 1 ). YUVIWEL is administered by subcutaneous injection. YUVIWEL must be reconstituted prior to use.

Table 1: Recommended YUVIWEL Weekly Dosage and Switching from Daily C-type Natriuretic Peptide (CNP) Analog Start once-weekly YUVIWEL on the day after completing the last dose of daily CNP therapy.

Monitor Growth

Periodically monitor the patient's growth and adjust the dosage according to the actual body weight. Discontinue YUVIWEL upon confirmation of no further growth potential, indicated by closure of the epiphyses.

Preparation of YUVIWEL for Administration Patients and caregivers who will administer YUVIWEL should receive appropriate training by a healthcare provider prior to use. Refer to the Instructions for Use for complete preparation and administration instructions with illustrations. Before administration, reconstitute YUVIWEL using the provided prefilled diluent syringe containing Sterile Water for Injection as described below.

Needles and syringes supplied with YUVIWEL are for single use only. If the product was refrigerated, allow the YUVIWEL vial and the prefilled diluent syringe to reach room temperature (about 30 minutes) before reconstitution. Screw a preparation needle onto the prefilled diluent syringe and inject the entire diluent volume into the vial.

Shake the vial up and down for 15 seconds. Do not swirl or roll. The reconstituted YUVIWEL vial should stand at room temperature for 5 minutes after shaking.

Dispose the diluent syringe with attached preparation needle immediately after injecting the diluent into the vial. YUVIWEL should be visually inspected for particles or discoloration prior to administration, whenever solution and container permit. Once reconstituted, YUVIWEL is a clear and colorless solution.

Do not use the solution if it is discolored, cloudy or contains visible particles. Air bubbles may be seen, and this is normal. Screw a new preparation needle onto the injection syringe and withdraw the prescribed injection volume from the reconstituted vial.

Remove air from the withdrawn dose volume before continuing and ensure the withdrawn dose volume is correct after removing any air. Remove and dispose the preparation needle from the injection syringe. Screw the injection needle onto the injection syringe before administration.

Two Kits are needed to achieve a complete dose for patients with body weight 56 kg or greater, where the prescribed injection volume is greater than 1 mL. Reconstituted YUVIWEL can be stored at room temperature up to 30°C (86°F) for up to 4 hours.

Using the prepared syringe, administer the prescribed injection volume. Administer YUVIWEL subcutaneously in the abdominal region (2 inches from the belly button) or thighs. If a caregiver is administering YUVIWEL, subcutaneous injection in the buttocks or back of the upper arm is also acceptable.

Rotate injection sites. Do not give an injection into sites other than described above. Avoid injecting where the skin is red, swollen, or scarred.

Administer YUVIWEL once weekly on the dosing day, at any time of day. All YUVIWEL components are for single use only. Do not draw up more than one injection volume, as specified in Table 1, from a vial.

For injection volumes greater than 1 mL, use two Kits to achieve a complete dose. The two injections must be given one after the other, using different injection sites. Discard the unused reconstituted solution.

Missed Dose If a dose of YUVIWEL is missed, administer the missed dose as soon as possible but not more than 2 days after the missed dosing day. To avoid missed doses, YUVIWEL can be taken up to 2 days before or 2 days after the scheduled dosing day. Resume once-weekly dosing for the next dose at the previously scheduled dosing day.

If more than 2 days have passed from the dosing day, skip the missed dose and administer the dose on the next regularly scheduled day. At least 5 days should elapse between doses.

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. The safety of YUVIWEL was evaluated in pediatric patients with achondroplasia in two randomized, placebo-controlled trials of navepegritide. Trial 1 included a 52-week, randomized, double-blind, placebo-controlled period, followed by a 52-week, single-arm, open-label extension (OLE) period.

Trial 2 included a randomized, double-blind, placebo-controlled dose-finding period. At Week 52, all participants transitioned to an OLE period during which they received navepegritide 0.1 mg/kg/week for 104 weeks. The adverse reaction rates for navepegritide were derived from pediatric participants with achondroplasia who received navepegritide 0.1 mg/kg/week or placebo during the double-blind period of Trials 1 and 2.

Cases presented as localized hair growth at injection sites or generalized increased body hair growth affecting limbs, back, or shoulders. To reduce the risk of local skin changes, rotate the site of injection with each dose.

Pregnancy Risk Summary There are no available data on the use of YUVIWEL in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, subcutaneous administration of navepegritide during the period of organogenesis in pregnant rats and rabbits resulted in no impact on embryo-fetal survival or congenital malformations at doses up to 10- and 7-fold, respectively, the exposure at the maximum recommended human dose (MRHD) (see Data ). Achondroplasia is an autosomal dominant genetic disorder with 100% penetrance.

Therefore, there is a 50% risk for a parent with achondroplasia to have a child with achondroplasia. The estimated background risk of birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.

In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. There was no effect on embryo-fetal survival, fetal toxicity, or embryo-fetal development up to the highest dose tested, corresponding to 10-fold the exposure at the MRHD.

Pediatric Use The safety and effectiveness of YUVIWEL to increase linear growth have been established in pediatric patients aged 2 years and older with achondroplasia with open epiphyses. Use of YUVIWEL for this indication is supported by evidence from a 52-week, randomized, placebo-controlled trial in 84 pediatric patients with achondroplasia. The safety and effectiveness of YUVIWEL in pediatric patients less than 2 years of age have not been established.