Sodium Zirconium Cyclosilicate (Lokelma)
sodium zirconium cyclosilicate — potassium binder
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Treatment of hyperkalemia | Adults (including patients on chronic hemodialysis) | Oral monotherapy or adjunctive | FDA Approved |
Sodium zirconium cyclosilicate (SZC) is a non-absorbed, inorganic zirconium silicate that preferentially captures potassium ions in the gastrointestinal lumen in exchange for hydrogen and sodium. It has a high selectivity for potassium even in the presence of other cations such as calcium and magnesium. By increasing fecal potassium excretion, SZC reduces the concentration of free potassium in the GI tract, thereby lowering serum potassium levels. SZC was approved by the FDA in 2018 for hyperkalemia in adults, with an expanded label in 2020 adding specific dosing guidance for patients on chronic hemodialysis based on the DIALIZE trial.
Lokelma should NOT be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action. While serum potassium reductions are observed within 1 hour of initiation, the full clinical effect develops over the initial 48-hour treatment period. Emergency measures (IV calcium, insulin/glucose, dialysis) remain the standard of care for acute, life-threatening hyperkalemia.
Dosing
Non-Hemodialysis Patients
| Phase | Dose | Frequency | Duration | Notes |
|---|---|---|---|---|
| Initial (acute correction) | 10 g | Three times daily | Up to 48 hours | Administer as oral suspension in water Serum K reduction observed within 1 hour; mean K reduction −0.7 mEq/L at 48h with 10 g TID |
| Maintenance | 10 g once daily | Once daily | Ongoing | Titrate at ≥1-week intervals by 5 g increments based on serum K Range: 5 g every other day to 15 g daily |
Chronic Hemodialysis Patients
| Clinical Scenario | Starting Dose | Maintenance Range | Notes |
|---|---|---|---|
| Pre-dialysis K+ ≤6.5 mEq/L | 5 g once daily on non-dialysis days | 5–15 g once daily | Non-dialysis days only; assess K after 1 week; adjust weekly in 5 g increments; base on pre-dialysis K after long interdialytic interval |
| Pre-dialysis K+ >6.5 mEq/L | 10 g once daily on non-dialysis days | 5–15 g once daily | Same rules as above; decrease or discontinue if K falls below target |
Empty the entire packet contents into a glass containing approximately 3 tablespoons (45 mL) of water or more. Stir well and drink immediately. If powder remains, add more water, stir, and drink again until no powder remains. SZC can be taken with or without food. Separate all other oral medications by at least 2 hours (before or after) because SZC can transiently increase gastric pH, potentially altering absorption of pH-dependent drugs.
Each 5 g dose contains approximately 400 mg of sodium. For patients on a 15 g daily maintenance dose, this equals 1,200 mg of additional sodium daily. Advise patients to adjust dietary sodium accordingly, especially those with heart failure, fluid overload, or sodium-restricted diets. Diuretic doses may need to be increased.
Pharmacology
Mechanism of Action
Sodium zirconium cyclosilicate is an inorganic, non-polymer crystalline compound with a uniform microporous structure that functions as a highly selective potassium ion trap. SZC preferentially captures K+ ions in the GI lumen — throughout the entire gastrointestinal tract — in exchange for hydrogen (H+) and sodium (Na+) ions. The crystal lattice dimensions closely match the ionic radius of potassium, conferring high selectivity even in the presence of competing cations like calcium and magnesium. By binding potassium in the intestinal lumen, SZC increases fecal potassium excretion in a dose-dependent manner, with corresponding decreases in urinary potassium excretion and serum potassium levels. In healthy subjects, 5 g and 10 g once daily for 4 days produced dose-dependent increases in fecal K+ excretion and decreases in serum K+ (FDA PI).
Pharmacokinetic Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | Not absorbed systemically. In clinical studies, zirconium blood and urine concentrations were similar in treated and untreated patients (either undetectable or at the lower limit of quantification). In vivo rat mass balance confirmed complete fecal recovery with no systemic absorption. | No systemic drug exposure; no hepatic or renal dose adjustments needed; no pregnancy or lactation exposure concerns |
| Distribution | Not applicable — remains in the GI lumen | No volume of distribution or protein binding considerations |
| Metabolism | Inorganic compound; not subject to enzymatic metabolism; no CYP involvement | No metabolic drug-drug interactions; no active metabolites |
| Elimination | Entirely in feces as unchanged compound | No renal elimination; safe across all levels of renal function including dialysis |
| Pharmacodynamics | Dose-dependent increase in serum bicarbonate: +1.1 mmol/L at 5 g, +2.3 mmol/L at 10 g, +2.6 mmol/L at 15 g (vs +0.6 mmol/L placebo). Onset of K+ reduction within 1 hour. K+ continued to decline over 48 h of initial treatment. | Bicarbonate rise may be beneficial in CKD patients with metabolic acidosis; clinical significance unclear per FDA PI. Rapid onset but NOT a substitute for emergency hyperkalemia treatment. |
Side Effects
The total safety exposure in clinical trials was 1,760 non-dialysis patients, with 652 exposed for at least 6 months and 507 for at least 1 year. The placebo-controlled population (n=1,009) included patients aged 22–96 years with hyperkalemia associated with CKD, heart failure, and diabetes mellitus. The most notable adverse reaction is edema, directly related to the sodium content of SZC.
| SZC Dose | Edema Incidence | Clinical Note |
|---|---|---|
| 15 g once daily | 16.1% | Vs 2.4% placebo; highest incidence at this dose; driven by sodium content (1,200 mg Na/day) |
| 10 g once daily | 5.9% | Vs 2.4% placebo; moderate excess; most common maintenance dose |
| 5 g once daily | 4.4% | Vs 2.4% placebo; minimal excess over placebo |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Edema (edema, generalized edema, peripheral edema) | 8–11% | In uncontrolled trials where most patients received <15 g daily; generally mild to moderate |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Hypokalemia (K+ <3.5 mEq/L) — non-dialysis | 4.1% | During maintenance; dose-dependent | Resolved with dose reduction or discontinuation; monitor serum K regularly |
| Hypokalemia (K+ <3.5 mEq/L) — hemodialysis | 5% (vs 5% placebo); K+ <3.0: 3% vs 1% | May be precipitated by acute illness, decreased oral intake, or diarrhea | Adjust dose based on K levels; extra caution during intercurrent illness; discontinue if clinically significant |
| Fluid overload / volume expansion | Related to sodium content (400 mg/5 g dose) | Days to weeks, particularly at higher doses | Monitor for edema; adjust dietary sodium; increase diuretic dose as needed; exercise caution in heart failure and renal disease |
| GI adverse events in motility disorders | Not quantified; avoided per FDA warning | Variable | Avoid use in severe constipation, bowel obstruction, or impaction; SZC has not been studied in these populations |
Drug Interactions
SZC is inorganic and not subject to CYP metabolism. It does not inhibit or induce any CYP enzymes. However, SZC can transiently increase gastric pH, which can alter the absorption of co-administered drugs whose solubility is pH-dependent. In general, other oral medications should be given at least 2 hours before or 2 hours after SZC. Spacing is not needed for drugs confirmed to lack pH-dependent solubility. Thirty-nine drugs were tested; 16 showed no in vitro interaction.
Monitoring
- Serum PotassiumDuring initial titration and after each dose change; at least weekly
RoutineCore monitoring parameter. Adjust or discontinue SZC if K falls below target range. In HD patients, base adjustments on pre-dialysis K after the long interdialytic interval. - Signs of EdemaEach visit; ongoing
RoutineMonitor for peripheral edema, weight gain, and fluid overload, particularly in patients with heart failure, renal disease, or on sodium-restricted diets. More common at 15 g daily. Increase diuretics as needed. - Volume Status (HD Patients)Each dialysis session
RoutineMonitor interdialytic weight gain. In the DIALIZE trial, no significant difference in mean interdialytic weight gain was observed between SZC and placebo groups at 5–10 g daily doses. - Intercurrent Illness (HD Patients)Triggered by illness
Trigger-basedAcute illnesses with decreased oral intake or diarrhea increase hypokalemia risk in HD patients on SZC. Consider dose adjustment during such episodes. - Concomitant MedicationsAt each medication reconciliation
Trigger-basedEnsure 2-hour separation for pH-dependent oral drugs. Confirm whether new medications require spacing.
Contraindications & Cautions
Absolute Contraindications
- None listed in the FDA prescribing information.
Warnings & Precautions (Avoid or Use with Caution)
- Severe constipation, bowel obstruction, or impaction — avoid use; SZC has not been studied in these populations and may worsen GI conditions (FDA PI Sec 5.1).
- Abnormal post-operative bowel motility disorders — avoid use per FDA PI; may be ineffective.
- Patients prone to fluid overload (heart failure, renal disease, sodium-restricted diets) — each 5 g dose contains 400 mg sodium; monitor for edema; increase diuretics as needed (FDA PI Sec 5.2).
- Hypokalemia risk in hemodialysis patients — particularly during acute illness, decreased oral intake, or diarrhea; adjust dose based on K+ levels (FDA PI Sec 5.3).
- Radio-opaque properties — SZC may appear as an imaging agent on abdominal X-rays; inform radiology if patient is on SZC (FDA PI Sec 5.4).
SZC has a delayed onset of full therapeutic effect and should never be used as the sole treatment for acute, life-threatening hyperkalemia. Standard emergency interventions (IV calcium gluconate for cardiac membrane stabilization, insulin/glucose for intracellular K+ shift, and urgent dialysis for definitive removal) remain the cornerstones of acute management.
Patient Counselling
Purpose of Therapy
Lokelma is a potassium binder that works in your intestines to remove excess potassium from your body. High potassium can be dangerous for your heart, and Lokelma helps keep your potassium levels in a safe range. It is not for emergency treatment of very high potassium — if you feel your heart racing, have chest pain, or feel very weak, seek emergency care immediately.
Sources
- Lokelma (sodium zirconium cyclosilicate) for Oral Suspension — Full Prescribing Information. AstraZeneca Pharmaceuticals LP. Revised 02/2024. Drugs.comPrimary regulatory source for all dosing, adverse reactions, pharmacology, and drug interaction data. Includes original 2018 approval data and 2020 hemodialysis dosing supplement.
- Lokelma (sodium zirconium cyclosilicate) — FDA Label. DailyMedDailyMed full label with clinical study data tables, drug interaction forest plots, and package information.
- Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222–231. doi:10.1056/NEJMoa1411487Study 1 (NCT01737697): pivotal phase 3 trial, n=753; demonstrated dose-dependent K reduction with 10 g TID producing −0.7 mEq/L at 48h. Source of Table 1 (PI Sec 14.1).
- Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223–2233. doi:10.1001/jama.2014.15688Study 2 (HARMONIZE, NCT02088073): open-label acute + randomized withdrawal; 92% achieved normokalemia in 48h; 5/10/15 g maintained mean K at 4.8/4.5/4.4 vs 5.1 mEq/L (placebo).
- Spinowitz BS, Fishbane S, Pergola PE, et al. Sodium zirconium cyclosilicate among individuals with hyperkalemia: a 12-month phase 3 study. Clin J Am Soc Nephrol. 2019;14(6):798–809. doi:10.2215/CJN.12651018Study 3 (ZS-005, NCT02163499): 751 patients followed for 12 months; 99% achieved normokalemia within 72h; maintained on 5 g QOD to 15 g daily.
- Roger SD, Spinowitz BS, Lerma EV, et al. Efficacy and safety of sodium zirconium cyclosilicate for treatment of hyperkalemia: an 11-month open-label extension of HARMONIZE. Am J Nephrol. 2019;50(6):473–480. doi:10.1159/00050371211-month OLE (NCT02107092) of HARMONIZE; n=123; confirmed sustained K-lowering effect with continued therapy.
- Fishbane S, Ford M, Fukagawa M, et al. A phase 3b, randomized, double-blind, placebo-controlled study of sodium zirconium cyclosilicate for reducing the incidence of predialysis hyperkalemia. J Am Soc Nephrol. 2019;30(9):1723–1733. doi:10.1681/ASN.2019050450DIALIZE trial (NCT03303521): 196 chronic HD patients; basis for 2020 FDA label update with HD-specific dosing.
- Stavros F, Yang A, Leon A, Nuttall M, Rasmussen HS. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLoS One. 2014;9(12):e114686. doi:10.1371/journal.pone.0114686Foundational study characterizing the crystal structure and ion-selectivity mechanism of sodium zirconium cyclosilicate (ZS-9).
- Palmer BF. Potassium binders for hyperkalemia in chronic kidney disease — diet, renin-angiotensin-aldosterone system inhibitor therapy, and hemodialysis. Mayo Clin Proc. 2020;95(2):339–354. doi:10.1016/j.mayocp.2019.05.019Comprehensive review comparing potassium binders (SZC, patiromer, SPS) and their role in enabling RAAS inhibitor therapy in CKD.
- KDIGO 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int. 2024;105(4S):S117–S314. doi:10.1016/j.kint.2023.10.018Updated KDIGO guideline for CKD management including potassium monitoring and management strategies.
- Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol. 2022;79(17):e263–e421. doi:10.1016/j.jacc.2021.12.012Heart failure guideline recognizing potassium binders as tools to enable RAAS inhibitor continuation in patients with hyperkalemia.