Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
The most frequent adverse reactions reported in the pivotal phase III study with osilodrostat were adrenal insufficiency (51%), fatigue (44%), oedema (21%), vomiting (22%), nausea (42%) and headache (34%).

The most serious adverse reaction associated with the use of osilodrostat is adrenal insufficiency (see also sections 4.2 and 4.4).

Tabulated list of adverse reactions

Adverse drug reactions (Table 1) are listed by MedDRA system organ class. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first.
Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000).

Table 1      Adverse drug reactions

System organ class                        Frequency           Preferred term* category
Endocrine disorders                       Very common         Adrenal insufficiency Metabolism and nutrition disorders        Very common         Hypokalaemia, decreased appetite Nervous system disorders                  Very common         Dizziness, headache Common              Syncope
Cardiac disorders                         Common              Tachycardia Vascular disorders                        Very common         Hypotension Gastrointestinal disorders                Very common         Vomiting, nausea, diarrhoea, abdominal pain
Skin and subcutaneous tissue disorders    Very common         Rash
Common              Hirsutism**, acne**
Musculoskeletal and connective tissue     Very common         Myalgia disorders                                                     Arthralgia General disorders and administration      Very common         Fatigue, oedema site conditions                           Common              Malaise Investigations                            Very common         Blood testosterone increased**, blood corticotrophin increased
Common              Electrocardiogram QT prolonged,
transaminases increased



*      Some terms denote grouped term of two or more MedDRA preferred terms that were considered clinically similar. The term “adrenal insufficiency” includes the terms glucocorticoid deficiency, adrenocortical insufficiency acute, steroid withdrawal syndrome, urine free cortisol decreased, cortisol decreased.
**     Frequency “very common” in female patients.

Description of selected adverse reactions

CYP11B1 inhibition by osilodrostat is associated with adrenal steroid precursor accumulation and testosterone increases. In a clinical study with osilodrostat, mean testosterone levels in female patients increased from high normal at baseline to above the upper limit of the normal range. The increases reversed when treatment was interrupted. The testosterone increase was associated with mild to moderate cases of hirsutism or acne in a subset of patients.

ACTH values above 10-fold upper limit of normal were observed in some Cushing’s disease patients treated with osilodrostat in the clinical studies (see section 5.1) and may be associated with cortisol values below the lower limit of normal.

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