Vyondys 53

VYONDYS 53- golodirsen injection
Sarepta Therapeutics, Inc.

1 INDICATIONS AND USAGE

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. This indication is approved under accelerated approval based on an increase in dystrophin production in skeletal muscle observed in patients treated with VYONDYS 53 [see Clinical Studies (14)]. Continued approval for this indication may be contingent upon verification of a clinical benefit in confirmatory trials.

2 DOSAGE AND ADMINISTRATION

2.1 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 [see Warnings and Precautions (5.2)].

2.2 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.

2.3 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.

  1. 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.
  2. Allow the vials to warm to room temperature. Mix the contents of each vial by gently inverting 2 or 3 times. Do not shake.
  3. 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.
  4. 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.
  5. 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.
  6. Administer the diluted solution via an in-line 0.2 micron filter.
  7. 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.

2.4 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 or interrupting the VYONDYS 53 therapy [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

3 DOSAGE FORMS AND STRENGTHS

VYONDYS 53 is a clear to slightly opalescent, colorless liquid, and may contain trace amounts of small, white to off-white amorphous particles, and available as:

  • Injection: 100 mg/2 mL (50 mg/mL) solution in a single-dose vial

4 CONTRAINDICATIONS

None.

5 WARNINGS AND PRECAUTIONS

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including rash, pyrexia, pruritus, urticaria, dermatitis, and skin exfoliation have occurred in VYONDYS 53-treated patients, some requiring treatment. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the VYONDYS 53 therapy [see Dosage and Administration (2.4)].

5.2 Kidney Toxicity

Kidney toxicity was observed in animals who received golodirsen [see Use in Specific Populations (8.4)]. Although kidney toxicity was not observed in the clinical studies with VYONDYS 53, the clinical experience with VYONDYS 53 is limited, and kidney toxicity, including potentially fatal glomerulonephritis, has been observed after administration of some antisense oligonucleotides. Kidney function should be monitored in patients taking VYONDYS 53. Because of the effect of reduced skeletal muscle mass on creatinine measurements, creatinine may not be a reliable measure of kidney function in DMD patients. Serum cystatin C, urine dipstick, and urine protein-to-creatinine ratio should be measured before starting VYONDYS 53. Consider also measuring glomerular filtration rate using an exogenous filtration marker before starting VYONDYS 53. During treatment, monitor urine dipstick every month, and serum cystatin C and urine protein-to-creatinine ratio every three months. Only urine expected to be free of excreted VYONDYS 53 should be used for monitoring of urine protein. Urine obtained on the day of VYONDYS 53 infusion prior to the infusion, or urine obtained at least 48 hours after the most recent infusion, may be used. Alternatively, use a laboratory test that does not use the reagent pyrogallol red, as this reagent has the potential to cross react with any VYONDYS 53 that is excreted in the urine and thus lead to a false positive result for urine protein.

If a persistent increase in serum cystatin C or proteinuria is detected, refer to a pediatric nephrologist for further evaluation.

6 ADVERSE REACTIONS

The following serious adverse reactions are described below and elsewhere in the labeling:

  • Hypersensitivity Reactions [see Warnings and Precautions (5.1)]

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.

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 [see Clinical Studies (14)].

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 [see Warnings and Precautions (5.1)].

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