PDL DRUG REVIEW Proprietary Name: Lokelma® Common Name: sodium zirconium cyclosilicate PDL Category: K Removing Resins

Comparable Products Preferred Drug List Status Sodium Preferred Veltassa Non‐Preferred with Conditions

Summary

Pharmacology/Usage: Sodium zirconium cyclosilicate, the active ingredient of Lokelma®, is a potassium binder. It is non‐absorbed binder that preferentially exchanges potassium for hydrogen and sodium. In vitro, Lokelma® has a high affinity for potassium ions, even in the presence of other cations such as calcium and magnesium. It increases fecal potassium excretion through binding of potassium in the lumen of the GI tract.

Indication: For the treatment of in adults. It should not be used as an emergency treatment for life‐ threatening hyperkalemia because of its delayed onset of action.

There is no pregnancy category for this medication; however, the risk summary indicates that Lokelma® is not absorbed systemically after oral administration and maternal use is not expected to result in fetal exposure to the drug. The safety and efficacy of use in the pediatric population have not been established.

Dosage Forms: Oral Suspension: 5g or 10g of white powder in a foil‐lined packet; Administer as a suspension in water

Recommended Dosage: Empty the entire content of the packet(s) into a glass containing 3 tablespoons of water or more if desired. Stir well and drink immediately. If powder remains in the glass, add water, stir, and drink immediately. Repeat until no powder remains to ensure the entire dose is taken. For initial treatment of hyperkalemia, the recommended dose is 10g PO given TID for up to 48 hours. For continued treatment, the recommended dose is 10g QD.

Monitor serum potassium and adjust the dose based on the serum potassium level and desired target range. During maintenance treatment, the dose may be up‐titrated based on the serum potassium level at intervals of 1 week or longer and in increments of 5g. The dose should be decreased or discontinued if the serum potassium is below the desired target range. The recommended maintenance dose range is 5g every other day to 15g daily.

Drug Interactions: Lokelma® can transiently increase gastric pH. Thus, Lokelma® can change the absorption of co‐ administered drugs that have pH‐dependent solubility, possibly leading to altered efficacy or safety of these drugs when taken close to when Lokelma® is administered. In general, other oral medications should be administered at least 2 hours before or 2 hours after Lokelma®.

Common Adverse Drug Reactions: Listed % incidence for adverse drug reactions= reported % incidence for drug (Lokelma® 5g/10g/15g) minus reported % incidence for placebo. Please note that an incidence of 0% means the incidence was the same as or that the active drug was less than placebo. The most frequently reported adverse events included edema (2%/3.5%/13.7%). In clinical trials, edema was generally mild to moderate in severity and was more commonly seen in patients treated with higher doses. Monitor for signs of edema, especially in patients who should restrict their sodium intake or are prone to fluid overload (e.g. heart failure or renal disease). In addition, advise patients to adjust dietary sodium, if appropriate. Increase the dose of diuretics as needed. 1 Use of Lokelma® should be avoided in patients with severe constipation, bowel obstruction or impaction, including abnormal post‐operative bowel motility disorders, as Lokelma® has not been studied in patients with these conditions and may be ineffective and may worsen gastrointestinal conditions.

Contraindications: There are no contraindications listed with this product.

Manufacturer: AstraZeneca

Analysis: The efficacy of Lokelma® in lowering serum potassium was demonstrated in a two‐part, double‐blind, randomized, placebo‐controlled study that included patients with hyperkalemia (5 to 6.5mEq/L, mean potassium 5.3mEq/L). In the first phase or the acute phase, patients were randomized to receive 1 of 4 doses of Lokelma® or placebo for the initial 48 hours with meals (N=753). The mean age of patients was 66 years and about 60% had (CKD), 10% had heart failure (HF), 62% had DM, and 67% were on renin angiotension aldosterone system (RAAS) inhibitor therapy at baseline.

The primary endpoint was the difference in the exponential rate of change in serum potassium levels during the initial 48 hours of study drug treatment. The study met its primary endpoint demonstrating a greater reduction in serum potassium levels for the 2.5, 5, and 10g (TID) dose groups compared to placebo (p˂0.001). For the secondary endpoint of potassium change from baseline, Lokelma® demonstrated dose‐dependent reductions in serum potassium at 2.5, 5, and 10g. Patients with higher starting potassium levels had a greater response to Lokelma®. Also, Lokelma® was effective in lowering potassium levels in patients with CKD, HF, DM, and those taking RAAS inhibitor therapy. The table below illustrates the results of the acute phase of this study, which was adapted from the prescribing information.

Mean serum potassium change mEq/L Placebo 1.25g TID 2.5g TID 5g TID 10g TID ‐0.2 ‐0.3 ‐0.5 ‐0.5 ‐0.7 All patients (N=158) (N=150) (N=137) (N=152) (N=140) ‐0.4 ‐0.3 ‐0.6 ‐0.9 ‐1.1 Baseline serum potassium ˃5.5mEq/L (N=40) (N=40) (N=37) (N=29) (N=22)

Patients who achieved a potassium level between 3.5 and 5mEq/L after receiving Lokelma® during the acute phase were re‐randomized to receive placebo QD or 1.25, 2.5, 5, or 10g of once daily Lokelma® for 12 days together with breakfast. The primary endpoint in the maintenance phase was the difference in the exponential rate of change in serum potassium levels over the 12‐day treatment interval, comparing patients receiving Lokelma® and patients receiving placebo. The study met the primary efficacy endpoint at the 5g and 10g doses when compared with their respective placebo groups (p˂0.01 and p˂0.001, respecvely). No further data was provided in the prescribing information.

Study 2 was also a two‐part trial with an open‐label acute phase and a month‐long randomized, double‐blind, placebo‐controlled withdrawal phase. In the acute phase (N=258), patients with hyperkalemia (baseline mean 5.6mEq/L, range 5.1 to 7.4mEq/L) received 10g of Lokelma® administered TID with meals for 48 hours. Average serum potassium levels decreased from 5.6 to 4.5mEq/L during treatment with Lokelma®. After the acute phase, there was a randomized, double‐blind withdrawal phase where patients who achieved potassium levels between 3.5 and 5mEq/L were randomized to 1 of 3 doses of Lokelma® administered once daily for 28 days or placebo. Of those enrolled in the acute phase, 92% achieved a potassium level within this range and were enrolled into the second phase of the trial.

The primary endpoint in the withdrawal phase was the mean serum potassium value over the period from day 8 to day 29, comparing Lokelma® and placebo. All 3 doses (5, 10, and 15g) of once daily Lokelma® maintained mean potassium at lower levels than placebo (mean serum potassium was 4.8, 4.5, and 4.4mEq/L for the 5g, 10g, and 15g dose groups, respectively as compared with 5.1mEq/L in the placebo group; p≤0.001 for all doses). In addition, a greater proportion of patients had mean serum potassium levels in the normal range (3.5 to 5mEq/L) while on Lokelma® than while on placebo (80%, 90%, and 94% at the 5, 10, and 15g doses, respectively vs 46% on placebo).

2 Patients who completed the 28‐day randomized withdrawal phase had the option to continue treatment with Lokelma® in an open‐label extension phase for up to 11 months (N=123). The treatment effect on serum potassium was maintained during continued therapy.

Lokelma® was assessed in an open‐label 12‐month study that included hyperkalemic patients (N=751) with the mean baseline potassium level being 5.6mEq/L. After the acute phase treatment of Lokelma® 10g TID, patients who achieved normokalemia (3.5‐5mEq/L) within 72 hours (N=746, 99%) entered the maintenance phase. For maintenance treatment, the initial dosage of Lokelma® was 5g QD and was adjusted to a minimum of 5g every other day up to 15g once daily, per serum potassium levels. The treatment effect on serum potassium was maintained during continued therapy.

Place in Therapy: Lokelma® is an oral non‐absorbable potassium binder indicated for the treatment of hyperkalemia in adults. Lokelma® should not be used as an emergency treatment for life‐threatening hyperkalemia due to its delayed onset of action. In clinical trials, Lokelma® was effective for lowering potassium in both the acute and maintenance phases.

In a 2017 systematic review and meta‐analysis by Meaney et al2, the safety and efficacy of (brand name Veltassa®) and sodium zirconium cyclosilicate (ZS‐9, Lokelma®) were assessed for the treatment of hyperkalemia. There were 3 trials included for patiromer. The primary endpoint was the change in potassium at 4 weeks and the secondary endpoint was the change in potassium at 3 days. Results suggested a change of ‐0.70mEq/L for the primary endpoint and ‐0.36mEq/L for the secondary endpoint. During the maintenance phase, 74‐95% of patients were maintained in the normal potassium range. There were 3 trials with sodium zirconium cyclosilicate. The primary endpoint was the change in potassium for 48 hours and results suggested a change of ‐0.67mEq/L. A secondary endpoint was a change in potassium at 1 hour, which was ‐0.17mEq/L. In one trial, 71‐85% of patients were maintained in the normal potassium range by the end of the 4‐week randomized phase. Regarding safety, GI adverse effects and electrolyte abnormalities were more common in those treated with patiromer. Discontinuation due to an adverse effect occurred in 8% of those treated with patiromer and 1% of patients treated with sodium zirconium cyclosilicate during maintenance phases of the trials. QTc interval prolongation and edema occurred in patients receiving Lokelma®. The authors concluded that both treatments resulted in statistically and clinically significant reductions in potassium; however, sodium zirconium cyclosilicate had fewer adverse events (less frequent GI effects) and a faster onset of action. The authors also indicate that while “...the clinical niche for these drugs remain to be seen, patiromer appears more likely to play more of a role in the chronic management of hyperkalemia, whereas ZS‐9 may be better suited for acute therapy.”2

Like the other nonabsorbable potassium binders used for the treatment of hyperkalemia, sodium polystyrene sulfonate and patiromer, Lokelma® effectively reduces elevated serum potassium levels. There is some evidence from a 2017 meta‐analysis to suggest that Lokelma® is safer and has less adverse events, including electrolyte abnormalities and adverse GI effects, as compared with patiromer. Lokelma® has been associated with QT prolongation, however. Due to its more rapid onset and shorter duration of action, Lokelma® may be preferable to patiromer for the treatment of acute hyperkalemia. Because of its pharmacokinetic properties and its longer clinical trials, patiromer may be preferable for the management of chronic hyperkalemia. Because of its rapid onset and short duration of action and its high cost Lokelma® should be non‐preferred with authorization only for the treatment of acute hyperkalemia in patients unable to tolerate sodium polystyrene sulfonate.

PDL Placement: † Preferred : Non‐Preferred with Conditions

References

1 Lokelma [package insert]. Wilmington, DE: AstraZeneca; 2018. 2 Meaney CJ, Beccari MV, Yang Y, et al. Systematic review and meta‐analysis of patiromer and sodium zirconium cyclosilicate: a new armamentarium for the treatment of hyperkalemia. Pharmacotherapy. 2017; 37(4): 410‐411.

Prepared By: IME Date: 09/17/2018 Property of IME and may not be reproduced without permission 3