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

Posology

Adults, including the elderly

Correction phase

The recommended starting dose of Lokelma is 10 g, administered three times a day orally as a suspension 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 after 48 hours of treatment, the same regimen can be continued for an additional 24 hours. If normokalaemia is not achieved after 72 hours of treatment, other treatment approaches should be considered.

Maintenance phase

When normokalaemia has been achieved, the minimal effective dose of Lokelma to prevent recurrence of hyperkalaemia should be established. A starting dose of 5 g once daily is recommended, with possible titration up to 10 g once daily, or down to 5 g once every other day, as needed, to maintain a normal 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 will depend upon a variety of factors including other medications, progression of chronic kidney disease and 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 recommended starting dose is 5 g once daily. To establish normokalaemia (4.0‑5.0 mmol/L), the dose may be titrated up or down weekly based on the pre‑dialysis serum potassium value after the long inter‑dialytic interval (LIDI). The dose could be adjusted at intervals of one week in increments of 5 g up to 15 g once daily on non‑dialysis days. It is recommended to monitor serum potassium weekly while the dose is 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 or medication affecting serum potassium).

Missed dose

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

Special populations

Patients with renal/hepatic impairment

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

Paediatric population

The safety and efficacy of Lokelma in children and adolescents (< 18 years) have not been established. No data are available.

Method of administration

For oral use.

The suspension can be taken with or without food.

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

Serum potassium levels

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

Hypokalaemia

Hypokalaemia may be observed (see section 4.8). Dose titration as described under maintenance posology may be required in such cases to prevent moderate to severe hypokalaemia. In patients with severe 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 the physiologic 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 of intestinal perforation have been reported with Lokelma. Since intestinal perforation has been reported with polymers that act in the gastrointestinal tract, specific attention should be paid to signs and symptoms related to intestinal perforation.

Sodium content

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 a low 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 expected effects 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 not meaningfully bind other medicinal products, there are limited effects on other medicinal products. Sodium zirconium cyclosilicate can transiently increase gastric pH by absorbing hydrogen ions and can lead to changes in solubility and absorption kinetics for co‑administered medicinal products with pH‑dependent bioavailability. In a clinical drug‑drug interaction study conducted in healthy subjects co-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 C_max and AUC values were approximately 40% lower when co‑administered with sodium zirconium cyclosilicate. No dose adjustments or separation of time of dosing are required for any of these medicinal products. However, sodium zirconium cyclosilicate should be administered at least 2 hours before or 2 hours after oral medications with clinically meaningful gastric pH dependent bioavailability.

Examples of medicinal products that should be administered 2 hours before or after sodium zirconium cyclosilicate 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 oral medications that do not exhibit pH-dependent bioavailability.

In another drug-drug interaction study in healthy volunteers, co-administration of Lokelma 15 g with tacrolimus 5 mg resulted in a decreased tacrolimus AUC and  C_max by 37% and 29% respectively. Therefore, tacrolimus should be taken at least 2 hours before or after Lokelma. In the same study, co-administration of Lokelma and cyclosporin did not show a clinically meaningful interaction.

Pregnancy

There are no data from the use of sodium zirconium cyclosilicate 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 Lokelma during pregnancy.

Breast-feeding

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

Fertility

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.

S

Summary of the safety profile

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

Tabulated list of adverse reactions

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

The adverse reactions identified from controlled trials are shown in Table 1. The following convention was 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

Description of selected adverse reactions

Hypokalaemia

In clinical trials, 4.1% of Lokelma patients developed hypokalaemia with a serum potassium value less than 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 commonly seen in patients treated with 15 g. Up to 53% were managed by initiating a diuretic or adjusting a diuretic 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 following events 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%)]; and hypersensitivity reactions [rash (0.3%) and pruritus (0.1%)]. These events were mild to moderate in nature, none were reported as serious and were generally resolved while the patient continued treatment. Due to the open label study design, a causal relationship between these events and Lokelma cannot be definitively established.

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

Pharmacotherapeutic group: Drugs for treatment of hyperkalaemia and hyperphosphatemia,

ATC code: V03AE10

Mechanism of action

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

Pharmacodynamic effects

Sodium zirconium cyclosilicate starts reducing serum potassium concentrations as soon as 1 hour after ingestion and normokalaemia can be achieved typically within 24 to 48 hours. Sodium zirconium cyclosilicate 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 with higher starting serum potassium levels have greater reductions in serum potassium. There is a reduction in urinary potassium excretion which is a consequence of a reduction in serum potassium concentration. 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 were accompanied by mean increases in faecal potassium excretion. No statistically significant changes in urinary sodium excretion were observed.

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

Sodium zirconium cyclosilicate has also been shown to bind ammonium in vitro and in vivo, thereby removing ammonium and increasing serum bicarbonate levels. Lokelma‑treated patients experienced an 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 g once 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, Lokelma demonstrated 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 pressure has been observed.

In addition, mean reductions in blood urea nitrogen (BUN) were observed in the 5 g (1.1 mg/dL) and 10 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.

Clinical efficacy and safety

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 the initial effect of Lokelma to correct hyperkalaemia during a 48‑hour period and two studies also tested maintenance of normokalaemia effect obtained. The maintenance studies included patients with chronic kidney disease (58%), heart failure (10%), diabetes mellitus (62%) and RAAS inhibitor therapy (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 trial of 196 chronic haemodialysis patients with hyperkalaemia, who received doses of Lokelma for 8 weeks. In the studies, Lokelma reduced serum potassium and maintained normal serum potassium levels regardless of the underlying cause of hyperkalaemia, age, sex, race, comorbid disease or concomitant use of RAAS inhibitors. No dietary restrictions were imposed; patients were instructed to continue 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 of 66 years, range 22 to 93 years) with hyperkalaemia (5 to ≤ 6.5 mmol/L, baseline potassium average 5.3 mmol/L), and included patients with chronic kidney disease, heart failure, diabetes mellitus and those 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

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 after the 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 or below 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 were re‑randomised to receive once daily placebo or once daily Lokelma at the same dose level as they had received three times daily during the correction phase (Table 3).

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

NS: not significant

At the end of the maintenance period, when Lokelma was no longer administered, average potassium levels 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, range 4.1 ‑ 7.2 mmol/L) received 10 g of Lokelma administered three times daily for 48 hours. Reductions in potassium were observed 1 hour after the first 10 g dose of Lokelma. Median time to normokalaemia was 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 and 1.5 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 randomised in a double‑blind fashion to one of three doses of Lokelma [5 g (n=45), 10 g (n=51), or 15 g (n=56)] or placebo (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% and 94%, respectively), compared with placebo (46%). There was a mean decrease in serum potassium of 0.77 mmol/L, 1.10 mmol/L, 1.19 mmol/L and 0.44 mmol/L, respectively, and the proportion of subjects who remained normokalaemic was 71%, 76%, 85% and 48% in the 5 g, 10 g, 15 g once daily doses of Lokelma and placebo groups, respectively.

Maintenance phase with Lokelma titration (open‑label) results: 123 patients entered the 11‑month open‑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 potassium measurements below 3.5 mmol/L was less than 1%; between 3.5 and 5.1 mmol/L was 77%; or between 3.5 and 5.5 mmol/L was 93%, irrespective of other factors that might influence the serum potassium. Treatment was discontinued on study exit (Day 365).

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

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 Lokelma patients; 30 controls) with baseline eGFR between 30-60 ml/min/1.73m² and hyperkalaemia (baseline serum potassium 5.2 mmol/L, range 4.6-6 mmol/L). Patients were randomised to receive escalating doses of Lokelma (0.3 g, 3 g and 10 g) or placebo, administered three times a day with meals for two to four days. The primary endpoint was the rate of change in serum potassium from baseline throughout the initial 2 days of treatment. The trial met the primary efficacy endpoint at the 3 g and 10 g doses of Lokelma compared to placebo. Lokelma at the 10 g dose and the 3 g dose resulted in mean maximal reductions of 0.92 mmol/L and 0.43 mmol/L, respectively. Twenty‑four hour urine collections showed that Lokelma decreased urinary potassium excretion from baseline by 15.8 mmol/24 h compared to placebo increase by 8.9 mmol/24 h (p < 0.001). Sodium excretion was unchanged relative to placebo (10 g, increase by 25.4 mmol/24 h compared to placebo increase by 36.9 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 with hyperkalaemia (baseline average 5.59 mmol/L; range 4.3-7.6 mmol/L). Comorbid conditions included chronic 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. During the correction phase, 10 g of Lokelma was administered three times daily for at least 24 hours and up to 72 hours. Subjects who achieved normokalaemia (3.5‑5.0 mmol/L, inclusive) within 72 hours entered the maintenance phase of the study. All subjects in the maintenance phase received Lokelma at a starting dose of 5 g once daily which could be increased in increments of 5 g once daily (to a maximum of 15 g once daily) or decreased (to a minimum of 5 g once every other day) based upon the titration regimen.

Normokalaemia was achieved in 494/748 (66%), 563/748 (75%) and 583/748 (78%) of subjects after 24, 48 and 72 hours of correction phase dosing with an average reduction in serum potassium of 0.81 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 with the highest baseline serum potassium concentrations having the most prominent decrease after starting the study drug but with the lowest proportion of subjects achieving normokalaemia. One hundred and twenty-six patients had a baseline serum potassium ≥ 6.0 mmol/L (mean baseline potassium 6.28 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 between 3.5 and 5.0 mmol/L, inclusive, or between 3.5 and 5.5 mmol/L, inclusive, by correction phase study day - ITT population

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

Normokalaemia was maintained while patients remained on drug and the mean serum potassium increased 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 the maintenance phase and among those not on RAAS inhibitors at baseline, 14% were able to initiate this therapy. During maintenance phase, 75.6% of subjects maintained normokalaemia, despite use of RAAS inhibitors.

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 on stable dialysis for at least 3 months and persistent pre‑dialysis hyperkalaemia were randomised to receive Lokelma 5 g or placebo once daily on non‑dialysis days. At randomization, mean serum potassium 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 between 4.0‑5.0 mmol/L during the dose adjustment period (initial 4 weeks), the dose could be adjusted weekly in 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 the subsequent 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 those subjects who maintained a pre‑dialysis serum potassium between 4.0 and 5.0 mmol/L on at least 3 out of 4 dialysis treatments after LIDI and who did not receive rescue therapy during the evaluation period, 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/L after the LIDI during the evaluation period was higher in the Lokelma group. 24% of patients were within this range at all 4 visits in the Lokelma group and none in the placebo group. The post-hoc analysis showed the proportion of patients who maintained serum potassium level between 3.5 and 5.5 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 (range 2.6‑5.7 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 session and was measured after the LIDI.

Paediatric population

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 to less than 18 years of age, with hyperkalaemia (see section 4.2 for information on paediatric use).

Absorption

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

Elimination

Sodium zirconium cyclosilicate is eliminated via the faeces.

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

None

Not applicable

Store Below 30 C.

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 ml of water and stirred well. The tasteless liquid should be drunk while still cloudy. The powder will not dissolve. If the powder settles, the liquid should be stirred again and taken. If needed, rinse the glass with more water to ensure that all of the content is taken.

No special requirement for disposal.