EXONDYS 51 Solution for injection Ref.[10204] Active ingredients: Eteplirsen

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)].

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.

Table 1. Adverse Reactions in DMD Patients Treated with 30 or 50 mg/kg/week¹ EXONDYS 51 with Incidence at Least 25% More than Placebo (Study 1):

¹ 50 mg/kg/week = 1.7 times the recommended dosage

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)].

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.

Risk Summary

There are no human or animal data to assess the effect of EXONDYS 51 on milk production, the presence of eteplirsen in milk, or the effects of EXONDYS 51 on the breastfed infant.

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for EXONDYS 51 and any potential adverse effects on the breastfed infant from EXONDYS 51 or from the underlying maternal condition.

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).

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

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.