4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

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 (see section 4.4).

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 impairment

No changes from the normal doses are required for patients with renal impairment who are not 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).

Patients with hepatic impairment

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

Elderly population

No special dose and administration guidelines are recommended for this population.

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 entire contents of the sachet(s) 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.

The suspension can be taken with or without food.

4.3. Contraindications

Hypersensitivity to the active substance.

4.4. Special warnings and precautions for use

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.

Monitoring frequency will depend upon a variety of factors including other medicinal products, progression of chronic kidney disease and dietary potassium intake.

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.

Worsening of pre-existing heart failure

Patients with pre-existing heart failure, particularly those in whom an increased sodium intake may lead to fluid overload and decompensation, should be monitored for manifestations of worsening heart failure. These may include increased dyspnoea, oedema and rapid weight gain, and should be managed as per standard clinical practice (see section 4.8).

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. Since intestinal perforation has been reported with potassium binders including Loklema, 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.

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

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 Cmax 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 medicinal products 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 agents (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 medicinal products 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 Cmax 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.

4.6. Fertility, pregnancy and lactation

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

No human data on the effect of sodium zirconium cyclosilicate on fertility are available. In rats, there was no effect on fertility with sodium zirconium cyclosilicate treatment.

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Summary of the safety profile

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

In 2 clinical trials 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%), nausea (1.6%), diarrhoea (0.9%), abdominal pain/distension (0.5%) 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 established.

In clinical studies conducted in countries with a predominantly Asian population, constipation with an estimated frequency of 8.9% occurred in non-dialysis patients receiving Lokelma; and was resolved with dose adjustment or treatment discontinuation.

In a pooled analysis of three placebo-controlled clinical studies of Lokelma in non-dialysis patients, some patients with pre-existing heart failure experienced worsening of heart failure, which occurred at a frequency of 13.6% (30/220) on Lokelma and 5.7% (12/209) on placebo. Most cases resolved with appropriate clinical management without withdrawing Lokelma (see section 4.4).

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 and post-marketing reports are shown in Table 1. Adverse reactions listed below are classified according to frequency and system organ class (SOC). 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 trials and post-marketing reports

System Organ class

Very Common

Common

Metabolism and nutrition disorders

Hypokalaemia

Gastrointestinal disorders

Constipation

General disorders and administration site conditions

Oedema related events

Cardiac disorders

Worsening of pre-existing heart failure

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 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.

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 Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

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