Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Vifor Fresenius Medical Care Renal Pharma France, 100–101 Terrasse Boieldieu, Tour Franklin La Défense 8, 92042 Paris la Défense Cedex, France
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Hyperkalaemia frequently occurs in chronic kidney disease patients on haemodialysis. In the placebocontrolled clinical studies a numerically higher rate of adverse events of hyperkalaemia was reported for the difelikefalin treated patients (4.7%; 20/424 patients) compared to placebo (3.5%; 15/424 patients). No causal relationship was established. Frequent monitoring of potassium levels is recommended.
Difelikefalin has not been studied in patients with New York Heart Association class IV heart failure. In the pivotal clinical studies a small numerical imbalance of cardiac failure and atrial fibrillation events was observed in the difelikefalin treated patients compared to placebo, in particular among patients with a medical history of atrial fibrillation who discontinued or missed their atrial fibrillation treatment. No causal relationship was established.
Difelikefalin is a peripherally acting kappa opioid receptor agonist with restricted access to the central nervous system (CNS). The blood-brain barrier (BBB) integrity is important for minimizing difelikefalin uptake into the CNS (see section 5.1). Patients with clinically important disruptions to the BBB (e.g., primary brain malignancies, CNS metastases or other inflammatory conditions, active multiple sclerosis, advanced Alzheimer’s disease) may be at risk for difelikefalin entry into the CNS. Kapruvia should be prescribed with caution in such patients taking into account their individual benefit-risk balance with observation for potential CNS effects.
Dizziness and somnolence have occurred in patients taking difelikefalin and may subside over time with continued treatment (see section 4.8). Concomitant use of sedating antihistamines, opioid analgesics or other CNS depressants may increase the likelihood of these adverse reactions and should be used with caution during treatment with difelikefalin (see section 4.5).
Compared to placebo, the incidence of somnolence was higher in difelikefalin treated subjects 65 years of age and older (7.0%) than in difelikefalin treated subjects less than 65 years of age (2.8%).
This medicinal product contains less than 1 mmol sodium per vial, that is to say essentially sodiumfree.
No clinical interaction studies have been performed. Difelikefalin does not inhibit or induce CYP450 enzymes, and is not a substrate of CYP450 enzymes. It is not an inhibitor of glucuronidating enzymes either. Difelikefalin is not a substrate or an inhibitor of human transporters (see section 5.2). Therefore, interactions of difelikefalin with other medicinal products are unlikely.
Concurrent administration of medicinal products such as sedating antihistamines, opioid analgesics or other CNS depressants (e.g., clonidine, ondansetron, gabapentin, pregabalin, zolpidem, alprazolam, sertraline, trazodone) may increase the likelihood of dizziness and somnolence (see section 4.4).
There are no or limited amount of data from the use of difelikefalin in pregnant women.
Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).
As a precautionary measure, it is preferable to avoid the use of Kapruvia during pregnancy.
It is unknown whether difelikefalin is excreted in human breast milk.
A risk to the newborns/infants cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Kapruvia therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Animal studies have shown excretion of difelikefalin in breast milk.
There are no data on the effect of difelikefalin on fertility in humans. In rat studies with difelikefalin, there was no effect on fertility (see section 5.3).
Kapruvia has minor influence on the ability to drive and use machines. Somnolence and/or dizziness have been reported in patients receiving difelikefalin (see section 4.8). Patients should be cautioned about driving or operating hazardous machinery until the effect of difelikefalin on the patient’s ability to drive or operate machinery is known. Somnolence occurred within the first 3 weeks of treatment and tended to subside with continued dosing. Dizziness occurred within the first 9 weeks of treatment and was generally transient.
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.
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 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). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1. Adverse reactions attributed to the treatment with difelikefalin in haemodialysis patients:
| MedDRA System Organ Class | Common | Uncommon |
|---|---|---|
| Psychiatric disorders | Mental status changes1 | |
| Nervous system disorders | Somnolence, Paraesthesia2 | Dizziness; Headache |
| Gastrointestinal disorders | 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.
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 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 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.
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. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.
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