Lokelma · 4.5 Interaction with other medicinal products and other forms of interaction · 1

HOS-097511 · has-adverse-reaction-information · PDF-Seite 5

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 5 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 1 760 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

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HOS-097507 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance.

HOS-097506 · has-indication-information · PDF-Seite 2

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

HOS-097509 · has-interaction-information · PDF-Seite 4

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, 4 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- administrat

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HOS-097510 · has-pregnancy-information · PDF-Seite 5

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.

HOS-097508 · has-warning-information · PDF-Seite 3

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. 3 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 Lokelma, 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.