Korsuva Adverse Reactions

Thyroid Stimulating Hormone (TSH) and Free Thyroxine Levels: In a Phase 2 placebo-controlled, randomized, double-blind study (14 day study drug administration period) conducted in Japanese patients with CKD and pruritus undergoing haemodialysis, dose-dependent decreases in serum TSH and free thyroxine levels were observed on the fourth dialysis day in patients administered IV difelikefalin three times per week at doses ranging from 0.25 micrograms per kg to 1.5 micrograms per kg, with a return to baseline levels following treatment discontinuation. There was also an increase in treatment-emergent adverse events of decreased TSH in patients administered IV difelikefalin (0.25 micrograms per kg [9.5% of patients], 0.50 micrograms per kg [0% of patients], 1.0 microgram per kg [31.6% of patients], 1.5 micrograms per kg [30.4% of patients]), compared to no events in patients administered placebo. Treatment-emergent adverse events of decreased free thyroxine were also reported in all IV difelikefalin dose groups (0.25 micrograms per kg [4.8% of patients], 0.50 micrograms per kg [4.8% of patients], 1.0 micrograms per kg [5.3% of patients], 1.5 micrograms per kg [8.7% of patients]) compared to no events in patients administered placebo.
TSH and free thyroxine were not assessed in the placebo-controlled Phase 3 trials. In pooled safety analyses from Phase 2/3 placebo-controlled studies in patients with CKD undergoing haemodialysis, there was one treatment-emergent adverse event of free thyroxine decreased in a patient treated with difelikefalin that was considered by the investigator to be related to study treatment; however, there was no overall imbalance in thyroid-related adverse events in in haemodialysis patients treated with difelikefalin compared to placebo in the Phase 3 trials. The clinical relevance of this is unknown.
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%), headache (0.6%), nausea (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 as previously mentioned.
Tabulated list of adverse reactions: The adverse reactions observed in the placebo-controlled and uncontrolled phase 3 clinical studies in patients (N = 1306) treated with difelikefalin are listed in Table 3 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).
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. (See Table 3.)

Click on icon to see table/diagram/image

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 Precautions and Interactions).
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 Precautions and Interactions).
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 less than 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.