4.1. Therapeutic indications

Kapruvia is indicated for the treatment of moderate-to-severe pruritus associated with chronic kidney disease in adult patients on haemodialysis (see section 5.1).

4.2. Posology and method of administration

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 recommended dose of difelikefalin is 0.5 micrograms/kg dry body weight (i.e., the target postdialysis weight). The total dose volume (mL) required from the vial should be calculated as follows: 0.01 × dry body weight (kg), rounded to the nearest tenth (0.1 mL). For patients with a dry body weight equal to or above 195 kg the recommended dose is 100 micrograms (2 mL). Injection volumes are detailed in the table below:

Weight range

(Dry body weight in kg)

Injection volume1

(mL)

40 – 44

0.4

45 – 54

0.5

55 – 64

0.6

65 – 74

0.7

75 – 84

0.8

85 – 94

0.9

95 – 104

1.0

105 – 114

1.1

115 – 124

1.2

125 – 134

1.3

135 – 144

1.4

145 – 154

1.5

155 – 164

1.6

165 – 174

1.7

175 – 184

1.8

185 – 194

1.9

≥ 195

2.0

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. A 4th dose of Kapruvia is unlikely to lead to accumulation of difelikefalin that would be of concern for safety, as the majority of remaining difelikefalin from the previous treatment will be cleared by haemodialysis (see sections 4.9 and 5.2). 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.

Following administration of difelikefalin in haemodialysis subjects, up to 70% is eliminated from the body prior to the next haemodialysis session (see sections 4.9 and 5.2). Difelikefalin plasma level remaining at the time of the next haemodialysis is reduced by about 40-50% within one hour of haemodialysis.

Patients with hepatic impairment

No dose adjustment is required for patients with mild or moderate hepatic impairment (see section 5.2). 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.

Currently available data are described in section 5.1.

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.

Difelikefalin is removed by the dialyzer membrane and must be administered after blood is no longer circulating through the dialyzer. 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.

When given after rinse-back, at least 10 mL of sodium chloride 9 mg/mL (0.9%) solution for injection rinse-back volume should be administered after injection of Kapruvia. If the dose is given during rinse‑back, no additional sodium chloride 9 mg/mL (0.9%) solution for injection is needed to flush the line.

4.3. Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Hyperkalaemia

Hyperkalaemia frequently occurs in chronic kidney disease patients on haemodialysis. In the placebo-controlled 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.

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). 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

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%).

Excipients with known effect

This medicinal product contains less than 1 mmol sodium per vial, that is to say essentially sodium-free.

4.5. Interaction with other medicinal products and other forms of interaction

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).

4.6. Fertility, pregnancy and lactation

Pregnancy

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.

Breast-feeding

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.

Fertility

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).

4.7. Effects on ability to drive and use machines

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.

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 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.

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. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at https://yellowcard.mhra.gov.uk or search for 'MHRA Yellow Card' in the Google Play or Apple App Store.

4.9. Overdose

Single dose of difelikefalin up to 12 times and multiple doses of difelikefalin up to 5 times the clinical dose of 0.5 micrograms/kg were administered in clinical studies in patients undergoing haemodialysis. A dose-dependent increase in adverse events including dizziness, somnolence, mental status changes, paraesthesia, fatigue, hypertension and vomiting, was observed.

In the event of overdose, the appropriate medical attention based on patient's clinical status should be provided. Haemodialysis for 4 hours using a high-flux dialyzer effectively cleared approximately 70‑80% of difelikefalin from plasma, and difelikefalin was not detectable in plasma at the end of the second of two dialysis cycles (see section 5.2).