Adverse reactions : תופעות לוואי

4.8    Undesirable effects

Summary of the safety profile
In placebo-controlled and uncontrolled phase 3 clinical studies, approximately 6.6% of the patients experienced at least one adverse reaction during difelikefalin treatment. The most common adverse reactions were somnolence (1.1%), dizziness (0.9%), paraesthesia (including hypoesthesia, paraesthesia oral and hypoesthesia oral) (1.1%), headache (0.6%), nausea (0.7%), vomiting (0.7%), diarrhoea (0.2%) and mental status changes (including confusional state) (0.3%). Most of these events were mild or moderate in severity, did not lead to deleterious consequences, and resolved with ongoing therapy. No event was serious and the incidence of events leading to treatment discontinuation was ≤ 0.5% for any of the adverse reactions listed above.



Tabulated list of adverse reactions

The adverse reactions observed in the placebo-controlled and uncontrolled phase 3 clinical studies in patients treated with difelikefalin (N = 1306) are listed in Table 1 by MedDRA system organ class, preferred term and frequency.

The frequency is classified as common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1,000 to < 1/100).

Table 1: Adverse reactions attributed to the treatment with difelikefalin in haemodialysis patients
MedDRA System Organ                    Common                             Uncommon Class
Psychiatric disorders                                                     Mental status changes1 2
Nervous system disorders               Somnolence, Paraesthesia           Dizziness; Headache Gastrointestinal disorders                                                Vomiting; Nausea; Diarrhoea 1 Mental   status changes included MedDRA preferred terms of confusional state and mental status changes.
2 Paraesthesia  included MedDRA preferred terms of paraesthesia, hypoesthesia, paraesthesia oral and hypoesthesia oral.

Description of selected adverse reactions

Somnolence
Somnolence was reported as treatment emergent adverse event in 2.2% of subjects randomised to difelikefalin. The vast majority of these events was mild or moderate in severity. In 0.3% of patients, somnolence led to discontinuation of treatment with difelikefalin. Somnolence was reported as serious adverse event in <0.1% of difelikefalin treated subjects. In 1.1% of patients, somnolence was reported to have a causal relationship to difelikefalin treatment. Somnolence occurred within the first 3 weeks of treatment and tended to subside with continued dosing.
The likelihood of somnolence may increase when difelikefalin is concomitantly used with other medicinal products (see sections 4.4 and 4.5).

Dizziness
Dizziness was reported as treatment emergent adverse event in 7.9% of subjects randomised to difelikefalin. The vast majority of these events was mild or moderate in severity. In 0.5% of patients, dizziness led to discontinuation of treatment with difelikefalin. Dizziness was reported as serious adverse event in 0.5% of difelikefalin treated subjects. In 0.9% of patients, dizziness was reported to have a causal relationship to difelikefalin treatment. Dizziness occurred within the first 9 weeks of treatment and was generally transient.
The likelihood of dizziness may increase when difelikefalin is concomitantly used with other medicinal products (see sections 4.4 and 4.5).

Mental status changes
Mental status change (including confusional state) was reported as treatment emergent adverse event in 4.4% of subjects randomised to difelikefalin.
The majority of these events was mild or moderate in severity. In 0.2% of patients, mental status changes led to discontinuation of treatment with difelikefalin.
Mental status changes were reported as serious adverse event in 2.2% of difelikefalin treated subjects.
In 0.3% of patients, mental status changes were reported to have a causal relationship to difelikefalin 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