LOKELMA 5g powder for oral suspension medication leaflet

Lokelma 5 g powder for oral suspension

Lokelma 10 g powder for oral suspension

Lokelma 5 g powder for oral suspension

Each sachet contains 5 g sodium zirconium cyclosilicate

Each 5 g sachet contains approximately 400 mg sodium.

Lokelma 10 g powder for oral suspension

Each sachet contains 10 g sodium zirconium cyclosilicate

Each 10 g sachet contains approximately 800 mg sodium.

Powder for oral suspension.

White to grey powder.

Lokelma is indicated for the treatment of hyperkalaemia in adult patients (see section 4.4 and 5.1).

Adults, including the elderly

Correction phase

The recommended starting dose of Lokelma is 10 g, administered three times a day orally as asuspension in water. When normokalaemia is achieved, the maintenance regimen should be followed(see below).

Typically, normokalaemia is achieved within 24 to 48 hours. If patients are still hyperkalaemic after48 hours of treatment, the same regimen can be continued for an additional 24 hours. Ifnormokalaemia is not achieved after 72 hours of treatment, other treatment approaches should beconsidered.

Maintenance phase

When normokalaemia has been achieved, the minimal effective dose of Lokelma to prevent recurrenceof hyperkalaemia should be established. A starting dose of 5 g once daily is recommended, withpossible titration up to 10 g once daily, or down to 5 g once every other day, as needed, to maintain anormal potassium level. No more than 10 g once daily should be used for maintenance therapy.

Serum potassium levels should be monitored regularly during treatment. Monitoring frequency willdepend upon a variety of factors including other medications, progression of chronic kidney diseaseand dietary potassium intake.

If severe hypokalaemia should occur, Lokelma should be discontinued and the patient re-evaluated.

Patients on chronic haemodialysis

For patients on dialysis Lokelma should only be dosed on non-dialysis days. The recommendedstarting dose is 5 g once daily. To establish normokalaemia (4.0-5.0 mmol/L), the dose may be titratedup or down weekly based on the pre-dialysis serum potassium value after the long inter-dialyticinterval (LIDI). The dose could be adjusted at intervals of one week in increments of 5 g up to 15 gonce daily on non-dialysis days. It is recommended to monitor serum potassium weekly while the doseis adjusted; once normokalaemia is established, potassium should be monitored regularly (e.g.

monthly, or more frequently based on clinical judgement including changes in dietary potassium ormedication affecting serum potassium).

If a patient misses a dose they should be instructed to take the next usual dose at their normal time.

Patients with renal/hepatic impairment

No changes from the normal doses are required for patients with renal or hepatic impairment.

The safety and efficacy of Lokelma in children and adolescents (< 18 years) have not been established.

No data are available.

For oral use.

The suspension can be taken with or without food.

For instructions on preparation of the suspension, see section 6.6.

Hypersensitivity to the active substance.

Serum potassium levels

Serum potassium should be monitored when clinically indicated, including after changes are made tomedicinal products that affect the serum potassium concentration (e.g. renin-angiotensin-aldosteronesystem (RAAS) inhibitors or diuretics) and after the Lokelma dose is titrated.

Hypokalaemia may be observed (see section 4.8). Dose titration as described under maintenanceposology may be required in such cases to prevent moderate to severe hypokalaemia. In patients withsevere hypokalaemia, Lokelma should be discontinued and the patient re-evaluated.

QT Prolongation

During correction of hyperkalaemia, a lengthening of the QT interval can be observed as thephysiologic result of a decline in serum potassium concentration.

The risk of interaction with X-rays

Sodium zirconium cyclosilicate may be opaque to X-rays. If the patient is having abdominal X-rays,radiographers should keep this in mind.

Intestinal perforation

The risk for intestinal perforation with the use of Lokelma is currently unknown. No events ofintestinal perforation have been reported with Lokelma. Since intestinal perforation has been reportedwith polymers that act in the gastrointestinal tract, specific attention should be paid to signs andsymptoms related to intestinal perforation.

This medicinal product contains approximately 400 mg sodium per 5 g dose, equivalent to 20% of the

WHO recommended maximum daily intake of 2 g sodium for an adult.

Lokelma is considered high in sodium. This should be particularly taken into account for those on alow salt diet.

Limitations of the clinical data

Severe hyperkalaemia

There is limited experience in patients with serum potassium concentrations greater than 6.5 mmol/L.

Long-term exposure

Clinical trials with Lokelma have not included exposure longer than one year.

Effect of other medicinal products on sodium zirconium cyclosilicate

As sodium zirconium cyclosilicate is not absorbed or metabolised by the body, there are no expectedeffects of other medicinal products on the pharmacologic action of sodium zirconium cyclosilicate.

Effect of sodium zirconium cyclosilicate on other medicinal products

As sodium zirconium cyclosilicate is not absorbed or metabolised by the body, and does notmeaningfully bind other medicinal products, there are limited effects on other medicinal products.

Sodium zirconium cyclosilicate can transiently increase gastric pH by absorbing hydrogen ions andcan lead to changes in solubility and absorption kinetics for co-administered medicinal products withpH-dependent bioavailability. In a clinical drug-drug interaction study conducted in healthy subjectsco-administration of sodium zirconium cyclosilicate with amlodipine, clopidogrel, atorvastatin,furosemide, glipizide, warfarin, losartan or levothyroxine did not result in clinically meaningful drug-drug interactions. Consistent with co-administration of dabigatran with other gastric acid modifiers,dabigatran Cmax and AUC values were approximately 40% lower when co-administered with sodiumzirconium cyclosilicate. No dose adjustments or separation of time of dosing are required for any ofthese medicinal products. However, sodium zirconium cyclosilicate should be administered at least2 hours before or 2 hours after oral medications with clinically meaningful gastric pH dependentbioavailability.

Examples of medicinal products that should be administered 2 hours before or after sodium zirconiumcyclosilicate to avoid possible raised gastric pH drug interaction are azole antifungals (ketoconazole,itraconazole and posaconazole), anti-HIV drugs (atazanavir, nelfinavir, indinavir, ritonavir, saquinavir,raltegravir, ledipasvir and rilpivirine) and tyrosine kinase inhibitors (erlotinib, dasatinib and nilotinib).

Sodium zirconium cyclosilicate can be co-administered without spacing of dosing times with oralmedications that do not exhibit pH-dependent bioavailability.

There are no data from the use of sodium zirconium cyclosilicate in pregnant women. Animal studiesdo 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 Lokelma during pregnancy.

In a postnatal study in rats, maternal exposure to sodium zirconium cyclosilicate had no effect onpostnatal development. Due to its physicochemical properties, sodium zirconium cyclosilicate is notsystemically absorbed and is not expected to be excreted in breast milk. No effects on the breastfednewborn/infant are anticipated since the systemic exposure of the breast-feeding woman to sodiumzirconium cyclosilicate is negligible. Lokelma can be used during breast-feeding.

There were no adverse effects on embryo-foetal development in treated rats or in rabbits.

Lokelma has no or negligible influence on the ability to drive and use machines.

The most commonly reported adverse reactions were hypokalaemia (4.1%) and oedema related events(5.7%).

The safety profile of Lokelma was evaluated in clinical trials involving 1760 patients with 507 patientsexposed for one year.

The adverse reactions identified from controlled trials are shown in Table 1. The following conventionwas used for frequency of adverse reactions: Very common (≥ 1/10); Common (≥ 1/100 to < 1/10);

Uncommon (≥ 1/1,000 to < 1/100); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), not known(cannot be estimated from the available data).

Table 1. List of adverse reactions in clinical studies

System Organ class Common

Metabolism and nutrition disorders Hypokalaemia

General disorders and administration site Oedema related eventsconditions

In clinical trials, 4.1% of Lokelma patients developed hypokalaemia with a serum potassium value lessthan 3.5 mmol/L, which was resolved with dose adjustment or discontinuation of Lokelma.

Oedema related events

Oedema related events, including fluid overload, fluid retention, generalised oedema, hypervolaemia,localised oedema, oedema, oedema peripheral and peripheral swelling, were reported by 5.7% of

Lokelma patients. The events were observed in the maintenance phase only and were more commonlyseen in patients treated with 15 g. Up to 53% were managed by initiating a diuretic or adjusting adiuretic dose; the remainder did not require treatment.

Long term exposure

In 2 clinical studies with open label exposure of Lokelma up to 1 year in 874 subjects, the followingevents were reported as related by investigators: gastrointestinal events [constipation (2.9%),diarrhea (0.9%), abdominal pain/distension (0.5%), nausea (1.6%) and vomiting (0.5%)]; andhypersensitivity reactions [rash (0.3%) and pruritus (0.1%)]. These events were mild to moderate innature, none were reported as serious and were generally resolved while the patient continuedtreatment. Due to the open label study design, a causal relationship between these events and Lokelmacannot be definitively established.

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.

Overdose with sodium zirconium cyclosilicate could lead to hypokalaemia. Serum potassium shouldbe checked and potassium supplemented as needed.

Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphatemia,

ATC code: V03AE10

Sodium zirconium cyclosilicate is a non-absorbed, non-polymer inorganic powder with a uniformmicropore structure that preferentially captures potassium in exchange for hydrogen and sodiumcations. Sodium zirconium cyclosilicate is highly selective for potassium ions, even in the presence ofother cations, such as calcium and magnesium, in vitro. Sodium zirconium cyclosilicate capturespotassium throughout the entire gastrointestinal (GI) tract and reduces the concentration of freepotassium in the GI lumen, thereby lowering serum potassium levels and increasing faecal potassiumexcretion to resolve hyperkalaemia.

Sodium zirconium cyclosilicate starts reducing serum potassium concentrations as soon as 1 hour afteringestion and normokalaemia can be achieved typically within 24 to 48 hours. Sodium zirconiumcyclosilicate does not affect serum calcium or magnesium concentrations, or urinary sodium excretion.

There is a close correlation between starting serum potassium levels and effect size; patients withhigher starting serum potassium levels have greater reductions in serum potassium. There is areduction in urinary potassium excretion which is a consequence of a reduction in serum potassiumconcentration. In a study of healthy subjects given Lokelma 5 g or 10 g once daily for four days, dose-dependent reduction in serum potassium concentration and total urinary potassium excretion wereaccompanied by mean increases in faecal potassium excretion. No statistically significant changes inurinary sodium excretion were observed.

There were no studies conducted to investigate the pharmacodynamics when sodium zirconiumcyclosilicate is administered with or without food.

Sodium zirconium cyclosilicate has also been shown to bind ammonium in vitro and in vivo, therebyremoving ammonium and increasing serum bicarbonate levels. Lokelma-treated patients experiencedan increase of 1.1 mmol/L at 5 g once daily, 2.3 mmol/L at 10 g once daily and 2.6 mmol/L at 15 gonce daily in bicarbonate compared with a mean increase of 0.6 mmol/L for those receiving placebo.

In an environment where other factors affecting renin and aldosterone were not controlled, Lokelmademonstrated a dose-independent change in mean serum aldosterone levels (range: -30% to -31%)compared with the placebo group (+14%). No consistent effect on systolic and diastolic blood pressurehas been observed.

In addition, mean reductions in blood urea nitrogen (BUN) were observed in the 5 g (1.1 mg/dL) and10 g (2.0 mg/dL) three times daily groups compared with small mean increases in the placebo(0.8 mg/dL) and low dose sodium zirconium cyclosilicate (0.3 mg/dL) groups.

The potassium-lowering effects of Lokelma have been demonstrated in three randomised,double-blind, placebo-controlled trials in patients with hyperkalaemia. All three studies tested theinitial effect of Lokelma to correct hyperkalaemia during a 48-hour period and two studies also testedmaintenance of normokalaemia effect obtained. The maintenance studies included patients withchronic kidney disease (58%), heart failure (10%), diabetes mellitus (62%) and RAAS inhibitortherapy (68%). In addition, two open-label maintenance studies tested long-term safety of Lokelma.

These five studies included 1760 patients given doses of Lokelma; 507 exposed for at least 360 days.

In addition, the efficacy and safety of Lokelma was studied in a double-blind, placebo-controlled trialof 196 chronic haemodialysis patients with hyperkalaemia, who received doses of Lokelma for8 weeks. In the studies, Lokelma reduced serum potassium and maintained normal serum potassiumlevels regardless of the underlying cause of hyperkalaemia, age, sex, race, comorbid disease orconcomitant use of RAAS inhibitors. No dietary restrictions were imposed; patients were instructed tocontinue their usual diet without any specified alterations.

Study 1

A two-phase, placebo-controlled correction and maintenance use study

A two-part, double-blind, randomised, placebo-controlled clinical trial of 753 patients (mean age of66 years, range 22 to 93 years) with hyperkalaemia (5 to ≤ 6.5 mmol/L, baseline potassium average5.3 mmol/L), and included patients with chronic kidney disease, heart failure, diabetes mellitus andthose on RAAS inhibitor therapy.

During the correction phase, patients were randomised to receive Lokelma (1.25 g, 2.5 g, 5 g or 10 g)or placebo, administered three times daily for the initial 48 hours (Table 2).

Table 2. Correction phase (Study 1): Percentage of normokalaemic subjects after 48 hours of

Lokelma

Lokelma dose (three times daily)

Placebo 1.25 g 2.5 g 5 g 10 g

N 158 154 141 157 143

Baseline serum potassium, mmol/L 5.3 5.4 5.4 5.3 5.3

Normokalaemic at 48 hours, % 48 51 68 78 86p-value vs. placebo NS < 0.001 < 0.001 < 0.001

NS: not significant

Lokelma 10 g administered three times daily lowered serum potassium by 0.7 mmol/L at 48 hours(p < 0.001 vs. placebo); statistically significant 14% potassium reduction was observed 1 hour afterthe first dose. Patients with higher starting potassium levels had a greater response to Lokelma.

Patients with pre-treatment potassium levels in excess of 5.5 mmol/L (average baseline 5.8 mmol/L)saw an average decrease of 1.1 mmol/L at 48 hours while those with starting potassium levels at orbelow 5.3 mmol/L had an average decrease of 0.6 mmol/L at the highest dose.

Patients who became normokalaemic after receiving Lokelma during the correction phase werere-randomised to receive once daily placebo or once daily Lokelma at the same dose level as they hadreceived three times daily during the correction phase (Table 3).

Table 3. Maintenance phase (12 days, Study 1): Mean number of normokalaemic days

Maintenance phase treatment (once daily)

Placebo Lokelma P-value vs.placebo

Correction phase Lokelma dose N Days n Days1.25 g three times daily 41 7.6 49 7.2 NS2.5 g three times daily 46 6.2 54 8.6 0.0085 g three times daily 68 6.0 64 9.0 0.00110 g three times daily 61 8.2 63 10.2 0.005

NS: not significant

At the end of the maintenance period, when Lokelma was no longer administered, average potassiumlevels increased to near baseline levels.

Study 2

A multi-phase, placebo-controlled maintenance study with an additional open-label phase

In the correction phase of the study, 258 patients with hyperkalaemia (baseline average 5.6, range4.1 - 7.2 mmol/L) received 10 g of Lokelma administered three times daily for 48 hours. Reductions inpotassium were observed 1 hour after the first 10 g dose of Lokelma. Median time to normokalaemiawas 2.2 hours with 66% of patients achieving normokalaemia at 24 hours and 88% at 48 hours.

Responses were larger in patients with more severe hyperkalaemia; serum potassium fell 0.8, 1.2 and1.5 mmol/L in patients with baseline serum potassium < 5.5, 5.5-5.9 and ≥ 6 mmol/L, respectively.

Patients who achieved normokalaemia (potassium levels between 3.5 and 5 mmol/L) were randomisedin a double-blind fashion to one of three doses of Lokelma [5 g (n=45), 10 g (n=51), or 15 g (n=56)] orplacebo (n=85) administered once daily for 28 days (the double-blind randomised withdrawal phase).

The proportion of subjects with average serum potassium < 5.1 mmol/L from Study Day 8 to 29(three-week period) was greater at the 5 g, 10 g and 15 g once daily doses of Lokelma (80%, 90% and94%, respectively), compared with placebo (46%). There was a mean decrease in serum potassium of0.77 mmol/L, 1.10 mmol/L, 1.19 mmol/L and 0.44 mmol/L, respectively, and the proportion ofsubjects who remained normokalaemic was 71%, 76%, 85% and 48% in the 5 g, 10 g, 15 g once dailydoses of Lokelma and placebo groups, respectively.

Maintenance phase with Lokelma titration (open-label) results: 123 patients entered the 11-monthopen-label phase. The proportion of subjects with average serum potassium < 5.1 mmol/L was 88%,the average serum potassium level was 4.66 mmol/L and the proportion of serum potassiummeasurements below 3.5 mmol/L was less than 1%; between 3.5 and 5.1 mmol/L was 77%; orbetween 3.5 and 5.5 mmol/L was 93%, irrespective of other factors that might influence the serumpotassium. Treatment was discontinued on study exit (Day 365).

Kaplan-Meier estimates of time to relapse for maintenance phase showed dose dependence in time torelapse with median time for 5 g dose ranging from 4 to 21 days depending on the baseline serumpotassium values. Serum potassium should be monitored periodically and the Lokelma dose titrated asdescribed in section 4.2 Posology and Method of Administration.

Figure 1 illustrates the mean serum potassium over the correction and maintenance phases of thestudy.

Figure 1. Correction and maintenance phases (Study 2): mean serum potassium over time with95% CI10g* Placebo 5g Titrated dose10g 15g Off treatment

Exit EOS

Correction (hour) Maintenance fixed dose (day) Maintenance titrated-dose (day)

Exit=Last Visit within 1 day of Last Dose, EOS=End of Study (7 days +/- 1 day after Last Dose)

*Given three times daily

Study 3

A study in chronic kidney disease patients with hyperkalaemia

This study was a double-blind placebo-controlled dose-escalating study in 90 patients (60 Lokelmapatients; 30 controls) with baseline eGFR between 30-60 ml/min/1.73m2 and hyperkalaemia (baselineserum potassium 5.2 mmol/L, range 4.6-6 mmol/L). Patients were randomised to receive escalatingdoses of Lokelma (0.3 g, 3 g and 10 g) or placebo, administered three times a day with meals for twoto four days. The primary endpoint was the rate of change in serum potassium from baselinethroughout the initial 2 days of treatment. The trial met the primary efficacy endpoint at the 3 g and10 g doses of Lokelma compared to placebo. Lokelma at the 10 g dose and the 3 g dose resulted inmean maximal reductions of 0.92 mmol/L and 0.43 mmol/L, respectively. Twenty-four hour urinecollections showed that Lokelma decreased urinary potassium excretion from baseline by15.8 mmol/24 h compared to placebo increase by 8.9 mmol/24 h (p < 0.001). Sodium excretion wasunchanged relative to placebo (10 g, increase by 25.4 mmol/24 h compared to placebo increase by36.9 mmol/24 h (NS)).

Study 4

A two-phase, multicenter, multi-dose, open-label safety and efficacy study

The long term (up to 12 months) effects of Lokelma were assessed in this study in 751 subjects withhyperkalaemia (baseline average 5.59 mmol/L; range 4.3-7.6 mmol/L). Comorbid conditions includedchronic kidney disease (65%), diabetes mellitus (64%), heart failure (15%) and hypertension (83%).

Use of diuretics and RAAS inhibitors was reported by 51 and 70% of subjects, respectively. Duringthe correction phase, 10 g of Lokelma was administered three times daily for at least 24 hours and upto 72 hours. Subjects who achieved normokalaemia (3.5-5.0 mmol/L, inclusive) within 72 hoursentered the maintenance phase of the study. All subjects in the maintenance phase received Lokelma ata starting dose of 5 g once daily which could be increased in increments of 5 g once daily (to amaximum of 15 g once daily) or decreased (to a minimum of 5 g once every other day) based upon thetitration regimen.

Mean Serum Potassium with 95% CI (mmol/L)

Normokalaemia was achieved in 494/748 (66%), 563/748 (75%) and 583/748 (78%) of subjects after24, 48 and 72 hours of correction phase dosing with an average reduction in serum potassium of0.81 mmol/L, 1.02 mmol/L and 1.10 mmol/L at 24 (n=748), 48 (n=104) and 72 (n=28) hours,respectively. Normokalaemia was dependent on baseline potassium concentration, with subjects withthe highest baseline serum potassium concentrations having the most prominent decrease after startingthe study drug but with the lowest proportion of subjects achieving normokalaemia. One hundred andtwenty-six patients had a baseline serum potassium ≥ 6.0 mmol/L (mean baseline potassium6.28 mmol/L). These subjects had a mean reduction of 1.37 mmol/L at the end of the correction phase.

Table 4. Correction phase (Study 4): proportion of subjects with serum potassium concentrations between3.5 and 5.0 mmol/L, inclusive, or between 3.5 and 5.5 mmol/L, inclusive, by correction phase study day -

ITT population

Lokelma 10 g three times daily (N=749)

Serum potassium 3.5 to 5.0 mmol/L, Serum potassium 3.5 to 5.5 mmol/L,

Correction Phase (CP)inclusive inclusiven/N Proportion 95% CI n/N Proportion 95% CI

CP at 24 hours 494/748 0.660 0.625, 0.694 692/748 0.925 0.904, 0.943

CP at 48 hours 563/748 0.753 0.720, 0.783 732/748 0.979 0.965, 0.988

CP at 72 hours/CP Last 583/748 0.779 0.748, 0.809 738/748 0.987 0.976, 0.994

Note: One subject had a post-dose value that was more than 1 day after last dose. Therefore, thesubject was eligible for the Correction Phase ITT Population; however, the time point was excludedfrom the analysis.

Normokalaemia was maintained while patients remained on drug and the mean serum potassiumincreased following discontinuation. Among those patients using RAAS inhibitors at baseline, 89%did not discontinue RAAS inhibitor therapy, 74% were able to maintain the same dose during themaintenance phase and among those not on RAAS inhibitors at baseline, 14% were able to initiate thistherapy. During maintenance phase, 75.6% of subjects maintained normokalaemia, despite use of

RAAS inhibitors.

Figure 2 illustrates the mean serum potassium over the correction and maintenance phases of thestudy.

Figure 2: Correction and maintenance phases in 12-month open-label study (Study 4) - meanserum potassium over time with 95% CI10g Titrated dose Off treatment

CPBL MPBL Exit EOS

Correction (hour) Maintenance (day)

CPBL=Correction Phase Baseline, MPBL=Maintenance Phase Baseline

Exit=Last Visit within 1 day of Last Dose, EOS=End of Study (7 days +/- 1 day after Last Dose)

Study 5

A randomised, double-blind, placebo-controlled study in patients on chronic haemodialysis

In this study, 196 patients (mean age 58 years, range 20 to 86 years) with end stage renal disease onstable dialysis for at least 3 months and persistent pre-dialysis hyperkalaemia were randomised toreceive Lokelma 5 g or placebo once daily on non-dialysis days. At randomization, mean serumpotassium levels were 5.8 mmol/L (range 4.2-7.3 mmol/L) in the Lokelma group and 5.9 mmol/L(range 4.2-7.3 mmol/L) in the placebo group. To achieve pre-dialysis serum potassium level between4.0-5.0 mmol/L during the dose adjustment period (initial 4 weeks), the dose could be adjusted weeklyin 5 g increments up to 15 g once daily based on pre-dialysis serum potassium measurement after the

LIDI. The dose reached at the end of the dose-adjustment period was maintained throughout thesubsequent 4-week evaluation period. At the end of the dose adjustment period, 37%, 43%, and 19%of patients were on Lokelma 5 g, 10 g and 15 g. The proportion of responders, defined as thosesubjects who maintained a pre-dialysis serum potassium between 4.0 and 5.0 mmol/L on at least 3 outof 4 dialysis treatments after LIDI and who did not receive rescue therapy during the evaluationperiod, was 41% in the Lokelma group, and 1% in the placebo group (p < 0.001) (see Figure 3).

In post-hoc analyses the number of times patients had serum potassium between 4.0 and 5.0 mmol/Lafter the LIDI during the evaluation period was higher in the Lokelma group. 24% of patients werewithin this range at all 4 visits in the Lokelma group and none in the placebo group. The post-hocanalysis showed the proportion of patients who maintained serum potassium level between 3.5 and5.5 mmol/L on at least 3 out of 4 dialysis treatments after LIDI during the evaluation period was 70%in the Lokelma group and 21% in the placebo group.

At the end of treatment, the mean post-dialysis serum potassium level was 3.6 mmol/L (range2.6-5.7 mmol/L) in Lokelma group and 3.9 mmol/L (range 2.2-7.3 mmol/L) in the placebo group.

There were no differences between Lokelma and placebo groups in interdialytic weight gain (IDWG).

IDWG was defined as pre-dialysis weight minus post-dialysis weight on the previous dialysis sessionand was measured after the LIDI.

Serum Potassium with 95% CI (mmol/L)

Figure 3: Mean pre-dialysis serum potassium levels over time in patients on chronicdialysis

Lokelma

Placebo

Screening (Day) Dose adjustment (Day) Evaluation (Day) F/U (Day)

Subjects (n)

Lokelma

Placebo

F/U- follow-up period

The displayed error bars correspond to 95% confidence intervals.n = Number of patients with non-missing potassium measurements at a particular visit.

The European Medicines Agency has deferred the obligation to submit the results of studies with

Lokelma in one or more subsets of the paediatric population in male and female children from birth toless than 18 years of age, with hyperkalaemia (see section 4.2 for information on paediatric use).

Sodium zirconium cyclosilicate is an inorganic, insoluble compound that is not subject to enzymaticmetabolism. In addition, clinical studies have shown it not to be systemically absorbed. An in vivomass balance study in rats showed that sodium zirconium cyclosilicate was recovered in the faeceswith no evidence of systemic absorption. Due to these factors and its insolubility, no in vivo or in vitrostudies have been performed to examine its effect on cytochrome P450 (CYP450) enzymes ortransporter activity.

Sodium zirconium cyclosilicate is eliminated via the faeces.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

None

Serum potassium with 95% CI (mmol/L)

Not applicable

3 years

This medicinal product does not require any special storage conditions.

5 or 10 g of powder in sachets made of a PET/alu/LLDPE or PET/LDPE/alu/EAA/LLDPE laminate

Pack sizes: 3, 28 or 30 sachets

Not all pack sizes may be marketed.

Preparation of oral suspension

The entire contents of the sachet should be emptied in a drinking glass containing approximately 45 mlof water and stirred well. The tasteless liquid should be drunk while still cloudy. The powder will notdissolve. If the powder settles, the liquid should be stirred again and taken. If needed, rinse the glasswith more water to ensure that all of the content is taken.

No special requirement for disposal.

AstraZeneca AB

SE-151 85 Södertälje

Sweden

EU/1/17/1173/001

EU/1/17/1173/002

EU/1/17/1173/003

EU/1/17/1173/004

EU/1/17/1173/005

EU/1/17/1173/006

EU/1/17/1173/007

EU/1/17/1173/008

EU/1/17/1173/009

EU/1/17/1173/010

EU/1/17/1173/011

EU/1/17/1173/012

Date of first authorisation: 22 March 2018

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

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