Vyondys 53 Drug Information

Monitoring to Assess Safety Serum cystatin C, urine dipstick, and urine protein-to-creatinine

ratio should be measured before starting VYONDYS 53. Consider measurement of glomerular filtration rate prior to initiation of VYONDYS 53. Monitoring for kidney toxicity during treatment is recommended. Obtain the urine samples prior to infusion of VYONDYS 53 or at least 48 hours after the most recent infusion .

Dosing Information

The recommended dosage of VYONDYS 53 is 30 milligrams per kilogram administered once weekly as a 35 to 60-minute intravenous infusion via an in-line 0.2 micron filter. If a dose of VYONDYS 53 is missed, it may be administered as soon as possible after the scheduled dose.

Preparation Instructions

VYONDYS 53 is supplied in single-dose vials as a preservative-free concentrated solution that requires dilution prior to administration. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use aseptic technique.

Calculate the total dose of VYONDYS 53 to be administered based on the patient's weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of VYONDYS 53 needed and the correct number of vials to supply the full calculated dose. Allow the vials to warm to room temperature.

Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake. Visually inspect each vial of VYONDYS 53. The solution is a clear to slightly opalescent, colorless liquid, and may contain trace amounts of small, white to off-white amorphous particles.

Do not use if the solution in the vials is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles. With a syringe fitted with a 21-gauge or smaller bore non-coring needle, withdraw the calculated volume of VYONDYS 53 from the appropriate number of vials. Dilute the withdrawn VYONDYS 53 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100 to150 mL. Gently invert 2 to 3 times to mix.

Do not shake. Visually inspect the diluted solution. Do not use if the solution is cloudy, discolored or contains extraneous particulate matter other than trace amounts of small, white to off-white amorphous particles.

Administer the diluted solution via an in-line 0.2 micron filter. VYONDYS 53 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted VYONDYS 53 within 4 hours of dilution.

If immediate use is not possible, the diluted product may be stored for up to 24 hours at 2°C to 8°C (36°F to 46°F). Do not freeze. Discard unused VYONDYS 53.

Administration Instructions Application of a topical anesthetic cream to the infusion site

prior to administration of VYONDYS 53 may be considered. VYONDYS 53 is administered via intravenous infusion. Flush the intravenous access line with 0.9% Sodium Chloride Injection, USP, prior to and after infusion.

Infuse the diluted VYONDYS 53 over 35 to 60 minutes via an in-line 0.2 micron filter. Do not mix other medications with VYONDYS 53 or infuse other medications concomitantly via the same intravenous access line with VYONDYS 53. If a hypersensitivity reaction occurs, consider slowing the infusion, interrupting, or discontinuing the VYONDYS 53 therapy .

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. In the VYONDYS 53 clinical development program, 58 patients received at least one intravenous dose of VYONDYS 53, ranging between 4 mg/kg (0.13 times the recommended dosage) and 30 mg/kg (the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 6 to 13 years.

Most (86%) patients were Caucasian. VYONDYS 53 was studied in 2 double-blind, placebo-controlled studies. In Study 1 Part 1, patients were randomized to receive once-weekly intravenous infusions of VYONDYS 53 (n=8) in four increasing dose levels from 4 mg/kg to 30 mg/kg or placebo (n=4), for at least 2 weeks at each level.

All patients who participated in Study 1 Part 1 (n=12) were continued into Study 1 Part 2, an open-label extension, during which they received VYONDYS 53 at a dose of 30 mg/kg IV once weekly . In Study 2, patients received VYONDYS 53 (n=33) 30 mg/kg or placebo (n=17) IV once weekly for up to 96 weeks, after which all patients received VYONDYS 53 at a dose of 30 mg/kg. Adverse reactions observed in at least 20% of treated patients in the placebo-controlled sections of Studies 1 and 2 are shown in Table 1. Table 1: Adverse Reactions That Occurred in At Least 20% of VYONDYS 53-Treated Patients and at a Rate Greater than Placebo in Studies 1 and 2 Adverse Reaction VYONDYS 53 (N = 41) % Placebo (N = 21) % Headache 41 10 Pyrexia 41 14 Fall 29 19 Abdominal pain 27 10 Nasopharyngitis 27 14 Cough 27 19 Vomiting 27 19 Nausea 20 10 Other adverse reactions that occurred at a frequency greater than 5% of VYONDYS 53-treated patients and at a greater frequency than placebo were: administration site pain, back pain, pain, diarrhea, dizziness, ligament sprain, contusion, influenza, oropharyngeal pain, rhinitis, skin abrasion, ear infection, seasonal allergy, tachycardia, catheter site related reaction, constipation, and fracture. Hypersensitivity reactions have occurred in patients treated with VYONDYS 53.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of VYONDYS 53. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Immune System Disorders: anaphylaxis

Pregnancy Risk Summary There are no human or animal data available to assess the use of VYONDYS 53 during pregnancy. In the U.S. general population, major birth defects occur in 2 to 4% and miscarriage occurs in 15 to 20% of clinically recognized pregnancies.

Pediatric Use VYONDYS 53 is indicated for the treatment of Duchenne muscular dystrophy (DMD) in patients who have a confirmed mutation of the DMD gene that is amenable to exon 53 skipping, including pediatric patients. Intravenous administration of golodirsen (0, 100, 300, or 900 mg/kg) to juvenile male rats once weekly for 10 weeks (postnatal days 14 to 77) did not result in postnatal developmental (e.g., neurobehavioral, immune function, or male reproductive) toxicity. However, at the highest dose tested (900 mg/kg/week), golodirsen resulted in the death of animals because of renal impairment or failure.

In surviving animals (including one animal at the lowest dose tested), there was a dose-dependent increase in the incidence and severity of renal tubular effects (including degeneration/regeneration, fibrosis, vacuolation, and dilatation), which correlated with changes in clinical pathology parameters, reflecting a dose-dependent impairment of renal function. In addition, decreases in bone area, mineral content, and mineral density were observed at the highest dose tested (900 mg/kg week) but with no effect on bone growth. A no-effect dose for renal toxicity was not identified; the lowest dose tested (100 mg/kg/week) was associated with plasma exposures (AUC) approximately 2.5 times that in humans at the recommended human dose of 30 mg/kg/week.

53 is contraindicated in patients with a serious hypersensitivity reaction to golodirsen or to any of the inactive ingredients in VYONDYS 53. Anaphylaxis has occurred in patients receiving VYONDYS 53 . VYONDYS 53 is contraindicated in patients with serious hypersensitivity to golodirsen or to any of the inactive ingredients in VYONDYS 53.