The Medical Letter ®

on Drugs and Therapeutics

Volume 60 December 3, 2018

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ISSUE No.
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1561
Sodium Zirconium Cyclosilicate (Lokelma) for Hyperkalemia ...............................................p 197
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The Medical Letter
on Drugs and Therapeutics
Volume 60 (Issue 1561)
▶ Sodium Zirconium Cyclosilicate
(Lokelma) for Hyperkalemia
The FDA has approved sodium zirconium cyclosilicate
(Lokelma – AstraZeneca), an oral potassium binder that
exchanges hydrogen and sodium for potassium in the
gastrointestinal (GI) lumen, for treatment of non-life-
threatening hyperkalemia in adults. Sodium zirconium
cyclosilicate (SZC) is the third drug to be approved
for this indication; sodium polystyrene sulfonate and
patiromer (Veltassa)1 were approved earlier.
Pronunciation Key
Lokelma: low kel’ ma
HYPERKALEMIA — Risk factors for hyperkalemia
include renal disease, diabetes, and heart failure. The
risk is increased with use of drugs that inhibit the
renin-angiotensin-aldosterone system (RAAS) such
as angiotensin-converting enzyme (ACE) inhibitors,
angiotensin receptor blockers (ARBs), direct renin
inhibitors, and aldosterone antagonists. Dosage
reduction or discontinuation of RAAS inhibitors
because of hyperkalemia is sometimes required.
Some other drugs, such as nonsteroidal anti-
inflammatory drugs (NSAIDs) and trimethoprim, can
also increase serum potassium levels.2
STANDARD TREATMENT — Sodium polystyrene
sulfonate, a resin that exchanges sodium for
potassium in the gastrointestinal lumen, has been
available in the US since 1958. It is sometimes used
to treat asymptomatic mild to moderate hyperkalemia
not adequately corrected by dietary restrictions and/
or use of a diuretic, but its effectiveness in chronic
hyperkalemia has never been established in controlled
trials, and its use has been associated with serious
adverse effects, including intestinal necrosis.3
Patiromer, a nonabsorbed polymer that exchanges
calcium for potassium in the GI lumen, is effective in
reducing serum potassium concentrations in patients
with non-life-threatening hyperkalemia, and may permit
patients with comorbid conditions to continue taking
RAAS inhibitors. Adverse effects of patiromer include
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December 3, 2018
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hypomagnesemia (patiromer also binds to magnesium),
constipation, diarrhea, nausea, abdominal discomfort,
and flatulence.4 Patiromer reduces the systemic expo-
sure of ciprofloxacin, levothyroxine, and metformin. The
prescribing information recommends taking other drugs
at least 3 hours before or 3 hours after patiromer.
Severe hyperkalemia (e.g., clinical signs or symptoms,
serum potassium >6.5 mEq/L), which can result in
paralysis and potentially fatal cardiac arrhythmias,
requires emergency treatment with rapid-acting IV
therapies, such as calcium, beta-agonists, and/or
insulin with glucose.5
CLINICAL STUDIES — FDA approval of SZC was
based on the results of two published, randomized,
placebo-controlled trials and one unpublished,
open-label trial.
In Study 1, 753 patients with hyperkalemia were
randomized to receive initial treatment with SZC 1.25,
2.5, 5, or 10 g or placebo three times daily. At 48 hours,
serum potassium levels were statistically significantly
lower with the 2.5-, 5-, and 10-g doses than with
placebo (see Table 1). Patients who received SZC and
were normokalemic at 48 hours were rerandomized to
once-daily treatment with their original SZC dose or
placebo; those who continued to receive 5- and 10-g
doses of SZC were significantly more likely to remain
normokalemic at day 14 than those who were switched
to placebo.6
In Study 2 (HARMONIZE), 258 patients with
hyperkalemia initially received open-label treatment
with SZC 10 g three times daily. After 48 hours, the 237
Table 1. Study 1 Results at 48 Hours1
Treatment of Hyperkalemia
Regimen Mean Serum Potassium (mEq/L)
Baseline 5.3
SZC 1.25 g tid (n=154) 5.1
SZC 2.5 g tid (n=141) 4.9*
SZC 5 g tid (n=157) 4.8*
SZC 10 g tid (n=143) 4.6*
Placebo tid (n=158) 5.1
*p<0.05 vs placebo
1. DK Packham et al. N Engl J Med 2015; 372:222.
197
 The Medical Letter ®
Vol. 60 (1561) December 3, 2018

Table 2. Study 2 (HARMONIZE) Results on Days 8-291
Maintenance of Normokalemia
Regimen Mean Serum Potassium (mEq/L)
Baseline 5.5
SZC 5 g once/day (n=45) 4.8*
SZC 10 g once/day (n=51) 4.5*
SZC 15 g once/day (n=56) 4.4*
Placebo once/day (n=85) 5.1
*p<0.05 vs placebo
1. Patients who achieved normokalemia following open-label treatment
with SZC 10 g tid were subsequently randomized to receive double-blind
treatment with SZC 5, 10, or 15 g or placebo once daily for 28 days
(M Kosiborod et al. JAMA 2014; 312:2223).
patients who were normokalemic were randomized to
receive double-blind treatment with SZC 5, 10, or 15 g
or placebo once daily for 28 days. Serum potassium
concentrations were significantly significantly lower
on days 8-29 with all three doses of SZC than with
placebo (see Table 2).7
In a 12-month trial (unpublished; summarized in
the package insert), 751 patients with hyperkalemia
received SZC 10 g three times daily. Within 72
hours, 99% of patients were normokalemic. These
patients then began maintenance treatment with
SZC at an initial dosage of 5 g once daily; the dosage
was adjusted throughout the trial to maintain
normokalemia (range 5 g every other day to 15 g once
daily). The treatment effect was maintained with
continued therapy.
Heart Failure – A subgroup analysis evaluated the
efficacy of SZC in patients with heart failure who
were enrolled in HARMONIZE. Those taking RAAS
inhibitors continued on their current dosages during
the trial. After a 48-hour open-label SZC treatment
phase, 87 patients with heart failure who became
normokalemic were randomized to receive SZC
treatment or placebo for 28 days. On days 8-29,
serum potassium concentrations were significantly
lower and the proportion of patients who remained
normokalemic was significantly higher with SZC
therapy than with placebo.8
ADVERSE EFFECTS — Like sodium polystyrene
sulfonate, SZC releases sodium into the GI tract.
In clinical trials, SZC was associated with a dose-
dependent risk of edema that was generally mild to
moderate in severity; patients with heart failure or
renal impairment may be at increased risk.
SZC has not been studied in patients with severe
constipation, bowel obstruction, or postoperative
motility disorders; its use should be avoided in such
patients.
DRUG INTERACTIONS — SZC can temporarily
increase gastric pH, which may alter the absorption
of coadministered drugs with acid-dependent
solubility, such as some azole antifungals and
antiretroviral drugs.9 Oral medications with acid-
dependent solubility should not be taken within 2
hours of SZC.
PREGNANCY AND LACTATION — Because SZC is
not systemically absorbed, its use by pregnant or
breastfeeding women is not expected to expose the
fetus or the breastfed infant to the drug.
DOSAGE AND ADMINISTRATION — Lokelma is
formulated as a tasteless, odorless powder for oral
suspension and is available in 5- and 10-g packets.
The starting dosage is 10 g three times daily for up to
48 hours, followed by 10 g once daily. Doses of SZC
can be adjusted based on response in 5-g increments
at intervals of ≥1 week. The usual maintenance
dosage of SZC ranges from 5 g every other day to
15 g once daily. The contents of each packet should
be dissolved in 3 tablespoons (45 mL) of water and
consumed immediately.
CONCLUSION — Sodium zirconium cyclosilicate
(Lokelma) can reduce serum potassium concentrations
in patients with non-life-threatening hyperkalemia. It
appears to be safer than sodium polystyrene sulfonate,
but it may exacerbate edema in patients with heart
failure or renal impairment. A head-to-head trial with
patiromer (Veltassa) would be welcome. ■

Table 3. Some Oral Drugs for Treatment of Non-Life-Threatening Hyperkalemia

Drug Formulations Usual Dosage Cost1
Sodium zirconium cyclosilicate – 5, 10 g powder in foil packets2 10 g tid for up to 48 hrs, then $655.00
Lokelma (AstraZeneca) 10 g once/day3
Patiromer – Veltassa (Relypsa) 8.4, 16.8, 25.2 g powder in foil packets2 8.4-25.2 g once/day4 820.80
Sodium polystyrene sulfonate5 – generic 454 g powder in jars2 15 g 1-4x/day 83.50
1. Approximate WAC for 1 month’s treatment at the lowest recommended usual or maintenance dosage. WAC = wholesaler acquisition cost, or manufacturer’s
published price to wholesalers; WAC represents published catalogue or list prices and may not represent an actual transactional price. Source: AnalySource®
Monthly. November 5, 2018. Reprinted with permission by First Databank, Inc. All rights reserved. ©2018. www.fdbhealth.com/policies/drug-pricing-policy.
2. Powder is dissolved in water immediately before drinking (3 tablespoons for Lokelma; one-third cup for Veltassa; 3-4 mL/g for sodium polystyrene sulfonate).
3. Recommended maintenance dosage range is 5 g every other day to 15 g once/day. Dose can be adjusted in 5-g increments at intervals of ≥1 week.
4. Dose can be adjusted in 8.4-g increments at intervals of ≥1 week up to a maximum of 25.2 g once daily.
5. Sodium polystyrene sulfonate can also be reconstituted for rectal administration.

198
 The Medical Letter ®
Vol. 60 (1561) December 3, 2018

1. Patiromer (Veltassa) for hyperkalemia. Med Lett Drugs Ther

2016; 58:23.
2. PA Sarafidis et al. Advances in treatment of hyperkalemia in
chronic kidney disease. Expert Opin Pharmacother 2015; 16:2205.
3. A Henneman et al. Emerging therapies for the management
of chronic hyperkalemia in the ambulatory care setting. Am J
Health Syst Pharm 2016; 73:33.
4. M Chaitman et al. Potassium-binding agents for the clinical
management of hyperkalemia. P T 2016; 41:43.
5. B Long et al. Controversies in management of hyperkalemia. J
Emerg Med 2018; 55:192.
6. DK Packham et al. Sodium zirconium cyclosilicate in
hyperkalemia. N Engl J Med 2015; 372:222.
7. M Kosiborod et al. Effect of sodium zirconium cyclosilicate
on potassium lowering for 28 days among outpatients with
hyperkalemia: the HARMONIZE randomized clinical trial. JAMA
2014; 312:2223.
8. SD Anker et al. Maintenance of serum potassium with sodium
zirconium cyclosilicate (ZS-9) in heart failure patients: results
from a phase 3 randomized, double-blind, placebo-controlled
trial. Eur J Heart Fail 2015; 17:1050.
9. C Palleria et al. Pharmacokinetic drug-drug interaction and their
implication in clinical management. J Res Med Sci 2013; 18:601.

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