Adverse reactions : תופעות לוואי

4.8     Undesirable effects

Summary of the safety profile
The safety profile of ataluren is based on pooled data from two randomised, double-blind, 48-week placebo-controlled studies conducted in a total of 232 male patients with Duchenne muscular dystrophy (nmDMD) caused by a nonsense mutation treated at the recommended dose of 40 mg/kg/day (10, 10, 20 mg/kg; n=172) or at a dose of 80 mg/kg/day (20, 20, 40 mg/kg; n=60), as compared to placebo-treated patients (n=172).

The most common adverse reactions in the 2 placebo-controlled studies were vomiting, diarrhoea, nausea, headache, upper abdominal pain, and flatulence, all occurring in ≥5% of all ataluren-treated patients. In both studies, 1/232 (0.43%) patients treated with ataluren discontinued due to an adverse reaction of constipation and 1/172 (0.58%) placebo patients discontinued treatment due to an adverse reaction of disease progression (loss of ambulation).

An open-label study was performed including patients aged 2-5 years (n=14) to evaluate the PK and safety of ataluren. A higher frequency of malaise (7.1%), pyrexia (42.9%), ear infection (28.6%), and rash (21.4%) were reported in patients aged 2-5 years compared with patients 5 years of age and older. However, these conditions are reported more frequently in the younger children in general.
Safety data from 28 weeks of therapy showed a similar safety profile of ataluren in patients 2-5 years as compared with patients aged 5 years and older.

Adverse reactions were generally mild or moderate in severity, and no treatment-related serious adverse events were reported among ataluren-treated patients in these 2 studies.

Tabulated list of adverse reactions

The adverse reactions reported in patients with nmDMD treated with the recommended daily dose of 40 mg/kg/ day ataluren in the 2 placebo-controlled studies are presented in Table 1. Adverse reactions reported in >1 patient in the 40 mg/kg/day group at a frequency greater than that of the placebo group are presented by MedDRA System Organ Class, Preferred Term, and frequency. Frequency groupings are defined to the following convention: very common (≥ 1/10) and common (≥ 1/100 to < 1/10).

Table 1. Adverse reactions reported in >1 ataluren-treated patients with nmDMD at a frequency greater than placebo in the 2 placebo-controlled studies (pooled analysis) 
Very                               Frequency not known
System Organ Class                              Common common
Change in lipid profile
Metabolism and                                Decreased appetite
(increased triglycerides nutrition disorders                           hypertriglyceridaemia and cholesterol)
Nervous system
Headache disorders
Vascular disorders                            Hypertension
Respiratory, thoracic,
and mediastinal                               Cough, epistaxis disorders



Very                               Frequency not known
System Organ Class                              Common common
Nausea, upper abdominal pain,
Gastrointestinal
Vomiting       flatulence, abdominal disorders discomfort,
constipation
Skin and subcutaneous
Rash erythematous tissue disorders
Musculoskeletal and                       Pain in extremity,
connective tissue                         musculoskeletal chest disorders                                 pain
Change in renal function tests
Renal and urinary                         Haematuria,
(increased creatinine,
disorders                                 enuresis blood urea nitrogen,
cystatin C)
General disorders and
Pyrexia, weight administration site decreased conditions
In a 48-week open-label extension study in patients with nmDMD patients who were ambulant or non-ambulant demonstrated a similar safety profile. Long term safety data is not available.

Description of selected adverse reactions (laboratory abnormalities)

Serum lipids
An increase in serum lipids, i.e. cholesterol and triglycerides, was observed. There have been cases reported where this increase to abnormal high values was already observed after 4 weeks.

Renal function tests
During the randomised, placebo-controlled studies, small increases in mean serum creatinine, BUN, and cystatin C were observed. The values tended to stabilize early in the study and did not increase further with continued treatment.

Reporting of suspected adverse reactions
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/.