Leaflet KAPRUVIA 50mcg / ml solution for injection

Kapruvia 50 micrograms/mL solution for injection

Each vial of 1 mL contains 50 micrograms difelikefalin (as acetate).

For the full list of excipients, see section 6.1.

Solution for injection.

Clear, colourless solution, free from particles (pH 4.5).

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

Kapruvia should be restricted for in-centre haemodialysis use only.

Kapruvia is intended for use by healthcare professionals experienced in the diagnosis and treatment ofconditions for which difelikefalin is indicated. Causes of pruritus other than chronic kidney diseaseshould be excluded before initiating treatment with difelikefalin.

Difelikefalin is administered 3 times per week by intravenous bolus injection into the venous line ofthe 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 targetpostdialysis weight). The total dose volume (mL) required from the vial should be calculated asfollows: 0.01 × dry body weight (kg), rounded to the nearest tenth (0.1 mL). For patients with a drybody weight equal to or above 195 kg the recommended dose is 100 micrograms (2 mL). Injectionvolumes are detailed in the table below:

Weight range Injection volume1(Dry body weight in kg) (mL)40 - 44 0.445 - 54 0.555 - 64 0.665 - 74 0.775 - 84 0.885 - 94 0.9

Weight range Injection volume1(Dry body weight in kg) (mL)95 - 104 1.0105 - 114 1.1115 - 124 1.2125 - 134 1.3135 - 144 1.4145 - 154 1.5155 - 164 1.6165 - 174 1.7175 - 184 1.8185 - 194 1.9≥ 195 2.01 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.

If a regularly scheduled haemodialysis treatment is missed, Kapruvia should be administered at thenext haemodialysis treatment at the same dose.

Extra treatment

If a 4th haemodialysis treatment is performed in a week, Kapruvia should be administered atthe end of the haemodialysis per the recommended dose. No more than 4 doses per weekshould be administered even if the number of haemodialysis treatments in a week exceeds 4. A4th dose of Kapruvia is unlikely to lead to accumulation of difelikefalin that would be ofconcern for safety, as the majority of remaining difelikefalin from the previous treatment willbe cleared by haemodialysis (see sections 4.9 and 5.2). However, safety and efficacy of a 4thdose 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 untilthe next haemodialysis session.

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

No dose adjustment is required for patients with mild or moderate hepatic impairment (see section5.2). 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 foruse in this patient population.

Elderly population (≥ 65 years of age)

Dosing recommendations for elderly patients are the same as for adult patients.

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.

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 longercirculating through the dialyzer. Difelikefalin is administered 3 times per week by intravenous bolusinjection into the venous line of the dialysis circuit at the end of the haemodialysis treatment duringrinse-back or after rinse-back.

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

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 placebo-controlled clinical studies a numerically higher rate of adverse events of hyperkalaemia was reportedfor the difelikefalin treated patients (4.7%; 20/424 patients) compared to placebo (3.5%; 15/424patients). No causal relationship was established. Frequent monitoring of potassium levels isrecommended.

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 fibrillationevents was observed in the difelikefalin treated patients compared to placebo, in particular amongpatients with a medical history of atrial fibrillation who discontinued or missed their atrial fibrillationtreatment. 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 centralnervous system (CNS). The blood-brain barrier (BBB) integrity is important for minimizingdifelikefalin 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, activemultiple 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 individualbenefit-risk balance with observation for potential CNS effects.

Dizziness and somnolence

Dizziness and somnolence have occurred in patients taking difelikefalin and may subside over timewith continued treatment (see section 4.8). Concomitant use of sedating antihistamines, opioidanalgesics or other CNS depressants may increase the likelihood of these adverse reactions and shouldbe used with caution during treatment with difelikefalin (see section 4.5).

Compared to placebo, the incidence of somnolence was higher in difelikefalin treated subjects65 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 sodium-free.

No clinical interaction studies have been performed. Difelikefalin does not inhibit or induce CYP450enzymes, and is not a substrate of CYP450 enzymes. It is not an inhibitor of glucuronidating enzymeseither. 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 orother 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 oftherapy 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 ofdifelikefalin on the patient’s ability to drive or operate machinery is known. Somnolence occurredwithin the first 3 weeks of treatment and tended to subside with continued dosing. Dizziness occurredwithin the first 9 weeks of treatment and was generally transient.

In placebo-controlled and uncontrolled phase 3 clinical studies, approximately 6.6% of the patientsexperienced at least one adverse reaction during difelikefalin treatment. The most common adversereactions 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 theseevents were mild or moderate in severity, did not lead to deleterious consequences, and resolvedwith ongoing therapy. No event was serious and the incidence of events leading to treatmentdiscontinuation 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 inpatients 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 haemodialysispatients

MedDRA System Organ Common Uncommon

Class

Psychiatric disorders Mental status changes1

Nervous system disorders Somnolence, Paraesthesia2 Dizziness; Headache

Gastrointestinal disorders Vomiting; Nausea; Diarrhoea1 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

Somnolence was reported as treatment emergent adverse event in 2.2% of subjects randomised todifelikefalin. 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 seriousadverse event in <0.1% of difelikefalin treated subjects. In 1.1% of patients, somnolence was reportedto have a causal relationship to difelikefalin treatment. Somnolence occurred within the first 3 weeksof treatment and tended to subside with continued dosing.

The likelihood of somnolence may increase when difelikefalin is concomitantly used with othermedicinal products (see sections 4.4 and 4.5).

Dizziness

Dizziness was reported as treatment emergent adverse event in 7.9% of subjects randomised todifelikefalin. 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 seriousadverse event in 0.5% of difelikefalin treated subjects. In 0.9% of patients, dizziness was reported tohave a causal relationship to difelikefalin treatment. Dizziness occurred within the first 9 weeks oftreatment and was generally transient.

The likelihood of dizziness may increase when difelikefalin is concomitantly used with othermedicinal products (see sections 4.4 and 4.5).

Mental status changes

Mental status change (including confusional state) was reported as treatment emergent adverse eventin 4.4% of subjects randomised to difelikefalin.

The majority of these events was mild or moderate in severity. In 0.2% of patients, mental statuschanges 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 difelikefalintreatment.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Single dose of difelikefalin up to 12 times and multiple doses of difelikefalin up to 5 times the clinicaldose 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 beprovided. Haemodialysis for 4 hours using a high-flux dialyzer effectively cleared approximately70-80% of difelikefalin from plasma, and difelikefalin was not detectable in plasma at the end of thesecond of two dialysis cycles (see section 5.2).

Pharmacotherapeutic group: all other therapeutic products, other therapeutic products, ATC code:

V03AX04

Difelikefalin is a selective kappa opioid receptor agonist with low central nervous system penetration.

The physicochemical properties of difelikefalin (hydrophilic, synthetic D-amino acid peptide withhigh polar surface area and charge at physiological pH) minimize its passive diffusion (permeability)and active transport across membranes, thus limiting penetration into the central nervous system.

The pathophysiology of chronic kidney disease-associated pruritus is thought to be multifactorial,including systemic inflammation and an imbalance in the endogenous opioid system (e.g.,overexpression of mu opioid receptors and concomitant downregulation of kappa opioid receptors).

Opioid receptors are known to modulate itch signals and inflammation, with kappa opioid receptoractivation reducing itch and producing immunomodulatory effects.

The activation of kappa opioid receptors on peripheral sensory neurons and immune cells bydifelikefalin are considered mechanistically responsible for the antipruritic and anti-inflammatoryeffects.

Placebo-controlled studies

In two pivotal clinical phase-3 studies of similar double-blind, randomised, placebo-controlled design(KALM-1 and KALM-2), chronic kidney disease patients on haemodialysis with moderate-to-severepruritus received either placebo or 0.5 micrograms/kg difelikefalin intravenously 3 times a weekfollowing haemodialysis for 12 weeks. A maximum of 4 doses per week was allowed in patientsreceiving an additional dialysis during a given week. The primary endpoint in both studies was thepercentage of patients who achieved at least a 3-point reduction from baseline in the Worst

Itching-Numerical Rating Scale (WI-NRS) at 12 weeks. The main secondary endpoints in both studieswere the percentages of patients with an improvement in the WI-NRS of at least 4 points after12 weeks and the changes in itch severity and itch-related quality of life (QoL) as measured by thetotal Skindex-10 and the 5-D Itch scale. A responder analysis based on Patient Global Impression of

Change was also included.

A total of 851 patients with moderate-to-severe pruritus (baseline WI-NRS >4) were enrolled in thepivotal studies. Mean age was 59 years, 33.1% were aged 65 and over and 11.1% were aged 75 andover; 60% of patients were male. The baseline mean WI-NRS scores were 7.18 in both, difelikefalinand placebo arms; baseline median WI-NRS scores were 7.13 (range 4.2 to 10) in difelikefalin and7.13 (range 4.1 to 10) in placebo arm. Other disease characteristics at baseline were comparable indifelikefalin and placebo arms: time from diagnosis of chronic kidney disease (8.22 years vs.8.54 years), duration of pruritus (3.20 years vs. 3.31 years) and use of medicinal products intended torelieve pruritus such as antihistamines, corticosteroids, gabapentin or pregabalin (37.5% vs. 38%).

Across studies, difelikefalin significantly reduced itch intensity and improved itch-related QoL over12 weeks as shown in Table 2.

Table 2: Summary of primary and key secondary outcomes in KALM-1 and KALM-2 at week

KALM-1 (n = 378) KALM-2 (n = 473)

Endpoint by difelikefalin Placebo difelikefalin Placeboend of week 12 (n = 189) (n = 189) (n = 237) (n = 236)

Primary endpoint

WI-NRS

Patients with ≥ 3-point 51.0% 27.6% 54.0% 42.2%improvement (%) (p < 0.001) (p = 0.02)

Secondary endpoints

WI-NRS

Patients with ≥ 4-point 38.9% 18.0% 41.2% 28.4%improvement (%) (p < 0.001) (p = 0.01)

Skindex-10

Change from baseline -17.2 -12.0 -16.6 -14.8[total score] (p < 0.001) (p = 0.171)5-D Itch

Change from baseline -5.0 -3.7 -4.9 -3.8[total score] (p < 0.001) Not applicable11 Was not tested based on the hierarchical testing order.

Figure 1 shows the mean percentage from KALM-1 and KALM-2 with a ≥ 3-point improvementfrom baseline in WI-NRS score by study week. Based on odds ratios, statistically significantimprovements favouring the difelikefalin group were seen by week 3 in KALM-1 and by week 2 in

KALM-2 and continued at each subsequent week through week 12 in both studies.

Figure 1: Percentage of patients with ≥ 3-point improvement with respect to WI-NRS score byweek in KALM-1 and KALM-2 (ITT population)

KALM-1

KALM-2

CI = confidence interval; ITT = intent to treat; LS = least squares; WI-NRS = Worst Itching-Numerical Rating Scale

Open label extension studies

The effect of treatment with difelikefalin for up to 52 weeks was evaluated using the 5-D Itch Scale insingle arm, open label extensions of studies KALM-1 and KALM-2 including 712 patients.

In patients switching from placebo to difelikefalin at the end of the double-blind phase, animprovement in 5-D Itch score was observed after 4 weeks of treatment, with an LS mean (SE) of thechange from baseline comparable to the patients receiving difelikefalin from study start: -6.0 (0.22) vs.

- 5.7 (0.23). The improvement in 5-D Itch score was maintained in both treatment groups throughoutthe 52-week treatment.

A total of 8 adolescents (12 to 17 years) on haemodialysis were enrolled in an open-label, single armstudy to evaluate the pharmacokinetics of a single dose of intravenous difelikefalin. It has beendemonstrated that the administration of a single dose of difelikefalin of 0.5 μg/kg, based on dry bodyweight provides comparable exposure between adolescents and adults on HD. The safety profile ofdifelikefalin 0.5 μg/kg of dry body weight, administered in adolescents as a single intravenous dose,was consistent with the known safety profile of difelikefalin in adults.

The European Medicines Agency has deferred the obligation to submit the results of studies withdifelikefalin in one or more subsets of the paediatric population in the treatment of chronic kidneydisease associated pruritus (see section 4.2 for information on paediatric use).

In patients with severe renal impairment undergoing haemodialysis, total body clearance ofdifelikefalin is reduced compared to healthy subjects and plasma concentrations decrease slowly untilcleared during dialysis. Due to the 70-80% of difelikefalin removed during dialysis, difelikefalin isadministered after each haemodialysis session in these patients. The available data on interindividualvariability in haemodialysis subjects receiving 0.5 microgram/kg difelikefalin suggest that variabilityof AUC can exceed 30%.

Plasma protein binding of difelikefalin is low to moderate(24-32%) and remains unaffected by renalimpairment. Mean volume of distribution at steady state ranged from 145 to 189 mL/kg in healthysubjects and from 214 to 301 mL/kg in haemodialysis patients with moderate-to-severe pruritus.

Difelikefalin penetration into the central nervous system is limited (below limit of quantification) asshown by physico-chemical, in-vitro and animal data.

In healthy subjects, the primary route of elimination for difelikefalin is renal, accounting for about81% of the dose being excreted in urine as compared to 11% via faecal excretion. In both healthyvolunteers and subjects on haemodialysis, most of the dose excreted into urine and faeces wasunchanged difelikefalin with minor quantities of putative metabolites, none exceeding 2.5%. Meantotal clearance ranged from 54 to 71 mL/h/kg and mean half-lives from 2 to 3 hours. By contrast, inhaemodialysis patients, elimination was predominantly via faeces, accounting on average for about59% of the dose; about 19% were recovered in dialysate and about 11% were found in urine. Ascompared to subjects with normal renal function, mean total clearance decreased and half-livesincreased about 10-fold with ranges of 5.3 to 7.5 mL/h/kg and 23 to 31 hours, respectively.

Interaction with other medicinal products

Difelikefalin is neither a substrate for CYP1A2, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or

CYP3A4, nor an inhibitor of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or

CYP3A4/5 and has minimal to no potential for induction of human CYP1A2, CYP2B6, or CYP3A. Itis not an inhibitor of glucuronidation enzymes either (UGT1A3, UGT1A9, or UGT2B7).

In addition, difelikefalin is not an inhibitor of BCRP, BSEP, LAT1, MATE1, MATE2-K, MRP2,

OAT1, OAT3, OATP1A2, OATP1B1, OATP1B3, OCT1, OCT2, OCT3, P-glycoprotein, PEPT1 or

PEPT2, and is not a substrate for ASBT, BCRP, BSEP, LAT1, MATE1, MATE2-K, MRP2, OAT1,

OAT2, OAT3, OATP1A2, OATP1B1, OATP1B3, OATP2B1, OCT1, OCT2, OCT3, OCTN1,

OCTN2, OSTαβ, P-glycoprotein, PEPT1 or PEPT2.

Pharmacokinetics of difelikefalin were demonstrated to be linear and dose-proportional in healthysubjects (tested over dose ranges of 1 to 40 and 1 to 20 micrograms/kg in single and repeated dosestudies, respectively). Steady state dose proportionality was also established in chronic kidney diseasepatients on haemodialysis receiving repeated doses from 0.5 to 2.5 micrograms/kg, 3 times per weekfor 1 week. However, in another study dose proportionality was observed at doses of 0.5 and1 micrograms/kg, but not at the dose of 1.5 micrograms/kg. Trough plasma concentration valuesreached steady state by the second dose and for the dose of 0.5 micrograms/kg, mean accumulationratio was 1.144 in one study based on AUC0-48h and 1.33 in another study, based on AUC0-44h; showingthat variability for accumulation parameters can exceed 30%.

Characteristics in specific groups of subjects or patients

Based on available evidence, there is no indication that factors such as age, sex, ethnicity, or mild tomoderate hepatic impairment have any impact on the pharmacokinetics of difelikefalin.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeat-dose toxicity, genotoxicity and carcinogenic potential.

In rats, male and female fertility, early embryonic, and prenatal and postnatal development were notaffected up to 2000-fold the human AUC. In the rabbit, prenatal development was neither impaireddespite marked maternal toxicity at 30-fold the human AUC.

Difelikefalin crosses the placenta in rats.

Abuse and dependence potential

The abuse and dependence potential studies in the rat suggest that difelikefalin is not likely to presenta risk of physical dependence or abuse potential.

Acetic acid (for pH adjustment)

Sodium acetate trihydrate (for pH adjustment)

Sodium chloride

Water for injections

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinalproducts.

3 years.

This medicinal product does not require any special storage conditions.

Kapruvia is supplied in a single use 2 mL glass vial (type I), with a bromobutyl rubber stopper, analuminium seal and a blue flip-off plastic cap.

Pack sizes of 3 and 12 vials containing 1 mL of solution for injection.

Not all pack sizes may be marketed.

For single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Vifor Fresenius Medical Care Renal Pharma France100-101 Terrasse Boieldieu

Tour Franklin La Défense 892042 Paris la Défense Cedex

France

EU/1/22/1643/001

EU/1/22/1643/002

Date of first authorisation: 25 April 2022

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.