Sodium zirconium cyclosilicate

Risk Summary

Sodium zirconium cyclosilicate is not absorbed systemically following oral administration and maternal use is not expected to result in fetal exposure to the drug.

Risk Summary

Sodium zirconium cyclosilicate is not absorbed systemically following oral administration, and breastfeeding is not expected to result in exposure of the child to sodium zirconium cyclosilicate.

The following tests for mutagenic potential of sodium zirconium cyclosilicate were negative: (1) the Ames (S. typhimurium and E. coli) test; (2) chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells; and (3) in vivo rat micronucleus assay. Given that zirconium cyclosilicate is not genotoxic, not absorbed from the gastrointestinal tract, and did not cause local gastrointestinal alterations in a chronic toxicity study in dogs, carcinogenicity studies in animals to evaluate tumorigenic potential of sodium zirconium cyclosilicate were not deemed to be necessary.

Fertility in male and female rats has been assessed at doses up to a Human Equivalent Dose (HED) of 58 g per day (the maximum feasible dose) with no adverse effects.

• Edema

Clinical Trials Experience

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

The total exposure to sodium zirconium cyclosilicate in the safety and efficacy clinical trials of patients not on dialysis with hyperkalemia was 1,760 patients with 652 patients exposed to sodium zirconium cyclosilicate for at least 6 months and 507 patients exposed for at least one year.

The population (n=1,009) in the placebo-controlled trials included patients aged 22 to 96 years, females (n=454), Caucasians (n=859) and Blacks (n=130). Patients had hyperkalemia in association with comorbid diseases such as chronic kidney disease, heart failure, and diabetes mellitus.

In placebo-controlled trials in which patients who were not on dialysis were treated with once daily doses of sodium zirconium cyclosilicate for up to 28 days, edema was reported in 4.4% of patients receiving 5 g, 5.9% of patients receiving 10 g and 16.1% of patients receiving 15 g sodium zirconium cyclosilicate compared to 2.4% of patients receiving placebo. In longer-term uncontrolled trials in which most patients were maintained on doses <15 g once daily, adverse reactions of edema (edema, generalized edema and peripheral edema) were reported in 8% to 11% of patients.

Laboratory Abnormalities

In clinical trials in patients who were not on dialysis, 4.1% of sodium zirconium cyclosilicate-treated patients developed hypokalemia with a serum potassium value less than 3.5 mEq/L, which resolved with dosage reduction or discontinuation of sodium zirconium cyclosilicate. In a clinical trial of sodium zirconium cyclosilicate in patients on chronic hemodialysis, 5% of patients developed pre-dialysis hypokalemia (serum potassium <3.5 mEq/L) in both the sodium zirconium cyclosilicate and placebo groups; 3% and 1% of patients developed a serum potassium <3.0 mEq/L in the sodium zirconium cyclosilicate and placebo groups, respectively.