2.1 Dosing Information

The recommended dose of EXONDYS 51 is 30 milligrams per kilogram administered once weekly as a 35 to 60 minute intravenous infusion.

If a dose of EXONDYS 51 is missed, it may be administered as soon as possible after the scheduled time.

2.2 Preparation Instructions

EXONDYS 51 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 EXONDYS 51 to be administered based on the patient's weight and the recommended dose of 30 milligrams per kilogram. Determine the volume of EXONDYS 51 needed and the correct number of vials to supply the full calculated dose.
2. Allow 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 EXONDYS 51. EXONDYS 51 is a clear, colorless solution that may have some opalescence. Do not use if the solution in the vials is discolored or particulate matter is present.
4. With a syringe fitted with a 21-gauge or smaller non-coring needle, withdraw the calculated volume of EXONDYS 51 from the appropriate number of vials.
5. Dilute the withdrawn EXONDYS 51 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100-150 mL. Visually inspect the diluted solution for particulates.
6. EXONDYS 51 contains no preservatives and should be administered immediately after dilution. Complete infusion of diluted EXONDYS 51 solution within 4 hours of dilution. If immediate use is not possible, the diluted solution may be stored for up to 24 hours at 2ºC to 8ºC (36ºF to 46ºF). Do not freeze. Discard unused EXONDYS 51.

2.3 Administration Instructions

Application of a topical anesthetic cream to the infusion site prior to administration of EXONDYS 51 may be considered.

EXONDYS 51 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 EXONDYS 51 solution over 35 to 60 minutes. Do not mix other medications with EXONDYS 51 or infuse other medications concomitantly via the same intravenous access line.

If a hypersensitivity reaction occurs, consider slowing the infusion or interrupting the EXONDYS 51 therapy [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

5.1 Hypersensitivity Reactions

Hypersensitivity reactions, including rash and urticaria, pyrexia, flushing, cough, dyspnea, bronchospasm, and hypotension, have occurred in patients who were treated with EXONDYS 51. If a hypersensitivity reaction occurs, institute appropriate medical treatment and consider slowing the infusion or interrupting the EXONDYS 51 therapy [see Dosage and Administration (2.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in 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 EXONDYS 51 clinical development program, 107 patients received at least one intravenous dose of EXONDYS 51, ranging between 0.5 mg/kg (0.017 times the recommended dosage) and 50 mg/kg (1.7 times the recommended dosage). All patients were male and had genetically confirmed Duchenne muscular dystrophy. Age at study entry was 4 to 19 years. Most (89%) patients were Caucasian.

EXONDYS 51 was studied in a double-blind, placebo-controlled study for 24 weeks (Study 1), followed by an open label extension (Study 2). In Study 1, 12 patients were randomized to receive weekly intravenous infusions of EXONDYS 51 (n=8) or placebo (n=4) for 24 weeks. All 12 patients continued in Study 2 and received open-label EXONDYS 51 weekly for up to 208 weeks.

In Study 1, 4 patients received placebo, 4 patients received EXONDYS 51 30 mg/kg, and 4 patients received EXONDYS 51 50 mg/kg (1.7 times the recommended dosage). In Study 2, 6 patients received EXONDYS 51 30 mg/kg/week and 6 patients received EXONDYS 51 50 mg/kg/week [see Clinical Studies (14)].

Adverse reactions that occurred in 2 or more patients who received EXONDYS 51 and were more frequent than in the placebo group in Study 1 are presented in Table 1 (the 30 and 50 mg/kg groups are pooled). Because of the small numbers of patients, these represent crude frequencies that may not reflect the frequencies observed in practice. The 50 mg/kg once weekly dosing regimen of EXONDYS 51 is not recommended [see Dosage and Administration (2.1)].

The most common adverse reactions were balance disorder and vomiting.

In the 88 patients who received ≥30 mg/kg/week of EXONDYS 51 for up to 208 weeks in clinical studies, the following events were reported in ≥10% of patients and occurred more frequently than on the same dose in Study 1: vomiting, contusion, excoriation, arthralgia, rash, catheter site pain, and upper respiratory tract infection.

Hypersensitivity reactions have occurred in patients treated with EXONDYS 51 [see Warnings and Precautions (5.1)].

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

EXONDYS 51 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 51 skipping, including pediatric patients [see Clinical Studies (14)].

Intravenous administration of eteplirsen (0, 100, 300, or 900 mg/kg) to juvenile male rats once weekly for 10 weeks beginning on postnatal day 14 resulted in renal tubular necrosis at the highest dose tested and decreased bone densitometry parameters (mineral density, mineral content, area) at all doses. The kidney findings were associated with clinical pathology changes (increased serum urea nitrogen and creatinine, decreased urine creatinine clearance). No effects were observed on the male reproductive system, neurobehavioral development, or immune function. An overall no-effect dose was not identified. Plasma eteplirsen exposure (AUC) at the lowest dose tested (100 mg/kg) was similar to that in humans at the recommended human dose (30 mg/kg).

8.5 Geriatric Use

DMD is largely a disease of children and young adults; therefore, there is no geriatric experience with EXONDYS 51.

8.6 Patients with Renal Impairment

Renal clearance of eteplirsen is reduced in non-DMD adults with renal impairment based on estimated creatinine clearance [see Clinical Pharmacology (12.3)]. However, because of the effect of reduced skeletal muscle mass on creatinine measurements in DMD patients, no specific dosage adjustment can be recommended for DMD patients with renal impairment.

12.1 Mechanism of Action

Eteplirsen is designed to bind to exon 51 of dystrophin pre-mRNA, resulting in exclusion of this exon during mRNA processing in patients with genetic mutations that are amenable to exon 51 skipping. Exon skipping is intended to allow for production of an internally truncated dystrophin protein, which was evaluated in Study 2 and Study 3 [see Clinical Studies (14)].

12.2 Pharmacodynamics

All EXONDYS 51-treated patients evaluated (n=36) were found to produce messenger ribonucleic acid (mRNA) for a truncated dystrophin protein by reverse transcription polymerase chain reaction.

In Study 2, the average dystrophin protein level in muscle tissue after 180 weeks of treatment with EXONDYS 51 was 0.93% of normal (i.e., 0.93% of the dystrophin level in healthy subjects). Because of insufficient information on dystrophin protein levels before treatment with EXONDYS 51 in Study 1, it is not possible to estimate dystrophin production in response to EXONDYS 51 in Study 1.

In Study 3, the average dystrophin protein level was 0.16% of normal before treatment, and 0.44% of normal after 48 weeks of treatment with EXONDYS 51 [see Clinical Studies (14)]. The median increase in truncated dystrophin in Study 3 was 0.1% [see Clinical Studies (14)].

12.3 Pharmacokinetics

Following single or multiple intravenous infusions of EXONDYS 51 in male pediatric DMD patients, plasma concentration-time profiles of eteplirsen were generally similar and showed multi-phasic decline. The majority of drug elimination occurred within 24 hours. Approximate dose-proportionality and linearity in PK properties were observed following multiple-dose studies (0.5 mg/kg/week [0.017 times the recommended dosage] to 50 mg/kg/week [1.7 times the recommended dosage]). There was no significant drug accumulation following weekly dosing across this dose range. The inter-subject variability for eteplirsen Cmax and AUC range from 20 to 55%.

Following single or multiple intravenous infusions of EXONDYS 51, the peak plasma concentrations (Cmax) of eteplirsen occurred near the end of infusion (i.e., 1.1 to 1.2 hours across a dose range of 0.5 mg/kg/week to 50 mg/kg/week).

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16.1 How Supplied

EXONDYS 51 injection is supplied in single-dose vials. The solution is clear and colorless, and may have some opalescence.

16.2 Storage and Handling

Store EXONDYS 51 at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect from light and store EXONDYS 51 in the original carton until ready for use.

Hypersensitivity Reactions

Advise patients and/or caregivers that symptoms of hypersensitivity, including bronchospasm and hypotension, can occur with EXONDYS 51. Instruct them to seek immediate medical care should they experience signs and symptoms of hypersensitivity [see Warnings and Precautions (5.1)].

Manufactured for:
Sarepta Therapeutics, Inc.
Cambridge, MA 02142 USA