KAPRUVIA

Kapruvia should be restricted for in-centre haemodialysis use only. Kapruvia is intended for use by healthcare professionals experienced in the diagnosis and treatment of conditions for which difelikefalin is indicated. Causes of pruritus other than chronic kidney disease should be excluded before initiating treatment with difelikefalin.

Posology Difelikefalin is administered 3 times per week by intravenous bolus injection into the venous line of the dialysis circuit at the end of the haemodialysis treatment during rinse-back or after rinse-back. , the target postdialysis weight).

1 mL). For patients with a dry body weight equal to or above 195 kg the recommended dose is 100 micrograms (2 mL). 0 1 More than 1 vial may be necessary if an injection volume of more than 1 mL is required An effect of difelikefalin in reducing pruritus is expected after 2-3 weeks of treatment.

Missed doses If a regularly scheduled haemodialysis treatment is missed, Kapruvia should be administered at the next haemodialysis treatment at the same dose. Extra treatment If a 4th haemodialysis treatment is performed in a week, Kapruvia should be administered at the end of the haemodialysis per the recommended dose.

No more than 4 doses per week should be administered even if the number of haemodialysis treatments in a week exceeds 4. 2). However, safety and efficacy of a 4th dose has not been fully established due to insufficient data. Patients with incomplete haemodialysis treatment For haemodialysis treatments less than 1 hour, administration of difelikefalin should be withheld until the next haemodialysis session.

2). Difelikefalin plasma level remaining at the time of the next haemodialysis is reduced by about 40-50% within one hour of haemodialysis. 2). Difelikefalin has not been studied in subjects with severe hepatic impairment (National Cancer Institute (NCI) Organ Dysfunction Working Group (ODWG)) and is therefore not recommended for use in this patient population.

Elderly population (≥ 65 years of age) Dosing recommendations for elderly patients are the same as for adult patients. Paediatric population The safety and efficacy of difelikefalin in children aged 12-17 years has not yet been established.

1. The safety and efficacy of difelikefalin in children below 12 years has not yet been established. No data are available in patients below 12 years. Method of administration Kapruvia should not be diluted and should not be mixed with other medicinal products.

6% of the patients experienced at least one adverse reaction during difelikefalin treatment. 3%). Most of these events were mild or moderate in severity, did not lead to deleterious consequences, and resolved with ongoing therapy. 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 Class Common Uncommon Psychiatric disorders Mental status changes1 Nervous system disorders Somnolence, Paraesthesia2 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. 2% of subjects randomised to difelikefalin. The vast majority of these events was mild or moderate in severity. 3% of patients, somnolence led to discontinuation of treatment with difelikefalin.

1% of difelikefalin treated subjects. 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.

5). 9% of subjects randomised to difelikefalin. The vast majority of these events was mild or moderate in severity. 5% of patients, dizziness led to discontinuation of treatment with difelikefalin. 5% of difelikefalin treated subjects.

Hyperkalaemia Hyperkalaemia frequently occurs in chronic kidney disease patients on haemodialysis. 5%; 15 / 424 patients). No causal relationship was established. Frequent monitoring of potassium levels is recommended. Cardiac failure and atrial fibrillation 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. Patients with impaired blood-brain barrier Difelikefalin is a peripherally acting kappa opioid receptor agonist with restricted access to the central nervous system (CNS). 1). , 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. 8). 5). 8%). Excipients with known effect This medicinal product contains less than 1 mmol sodium per vial, that is to say essentially sodium-free.

1.