Exondys 51 Drug Information

Dosing Information

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

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.

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. Allow 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 EXONDYS 51. EXONDYS 51 is a clear, colorless solution that may have some opalescence, and may contain 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 white to off-white amorphous particles. 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. Dilute the withdrawn EXONDYS 51 in 0.9% Sodium Chloride Injection, USP, to make a total volume of 100-150 mL.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.

Do not use if the solution is cloudy, discolored or contains extraneous particulate matter other than white to off-white amorphous particles. Administer the diluted solution via an in-line 0.2 micron filter. EXONDYS 51 contains no preservatives and should be administered immediately after dilution.

Complete infusion of diluted EXONDYS 51 solution within 8 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.

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 via an in-line 0.2 micron filter. 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.

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. 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 . 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. The most common adverse reactions were balance disorder and vomiting.

Table 1. Adverse Reactions in DMD Patients Treated with 30 or 50 mg/kg/week 1 EXONDYS 51 with Incidence at Least 25% More than Placebo (Study 1) 1 50 mg/kg/week = 1.7 times the recommended dosage Adverse Reactions EXONDYS 51 (N=8) Placebo (N=4) % % Balance disorder 38 0 Vomiting 38 0 Contact dermatitis 25 0 Adverse Reactions from Observational Clinical Studies The following adverse reactions have been identified during observational studies that were conducted as part of the clinical development program and continued postapproval. In open-label observational studies, 163 patients received at least one intravenous dose of EXONDYS 51, with doses 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 6 months to 19 years.

Most (85%) patients were Caucasian. The most common adverse reactions seen in greater than 10% of the study population were headache, cough, rash, and vomiting. Hypersensitivity reactions have occurred in patients treated with EXONDYS 51 .

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of EXONDYS 51. 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. Postmarketing adverse reactions that occurred during infusion include bronchospasm, cyanosis of the lips, and malaise. The following adverse reactions have also been reported in patients receiving EXONDYS 51: pyrexia, flushing, protein urine present, and dehydration.

Pregnancy Risk Summary There are no human or animal data available to assess the use of EXONDYS 51 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 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 . 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).