Adverse reactions : תופעות לוואי

6          ADVERSE REACTIONS
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.
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)
Adverse Reactions                                   EXONDYS 51 (N=8)                 Placebo (N=4) 
%                             %
Balance disorder                                             38                            0 Vomiting                                                     38                            0 Contact dermatitis                                           25                            0 1 50 mg/kg/week = 1.7 times the recommended dosage


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 [see Warnings and Precautions (5.1)].

6.2        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.


Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il


8          USE IN SPECIFIC POPULATIONS
8.1        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.

8.2        Lactation
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.

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.