Sodium zirconium cyclosilicate

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.

For patients on dialysis sodium zirconium cyclosilicate 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).

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 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, 5 saquinavir, raltegravir, ledipasvir and rilpivirine) and tyrosine kinase inhibitors (erlotinib, dasatinib and nilotinib).

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

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. As a precautionary measure, it is preferable to avoid the use of sodium zirconium cyclosilicate during pregnancy.

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. Sodium zirconium cyclosilicate 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.

Sodium zirconium cyclosilicate has no or negligible influence on the ability to drive and use machines.

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 sodium zirconium cyclosilicate 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 sodium zirconium cyclosilicate 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 sodium zirconium cyclosilicate; and was resolved with dose adjustment or treatment discontinuation.

In a pooled analysis of three placebo-controlled clinical studies of sodium zirconium cyclosilicate 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 sodium zirconium cyclosilicate and 5.7% (12/209) on placebo. Most cases resolved with appropriate clinical management without withdrawing sodium zirconium cyclosilicate.

Tabulated list of adverse reactions

The safety profile of sodium zirconium cyclosilicate was evaluated in clinical trials involving 1 760 patients with 507 patients exposed for one year.

The adverse reactions identified from controlled trials and post-marketing reports are shown in the following table. 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).

List of adverse reactions in clinical trials and post-marketing reports:

Description of selected adverse reactions

Hypokalaemia

In clinical trials, 4.1% of sodium zirconium cyclosilicate patients developed hypokalaemia with a serum potassium value less than 3.5 mmol/L, which was resolved with dose adjustment or discontinuation of sodium zirconium cyclosilicate.

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 sodium zirconium cyclosilicate 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.