SODIUM ZIRCONIUM CYCLOSILICATE: 2,294 Adverse Event Reports & Safety Profile

LOKELMA is a powder for oral suspension. The active ingredient in LOKELMA is sodium zirconium cyclosilicate, a potassium binder. Sodium zirconium cyclosilicate is a non-absorbed zirconium silicate that preferentially exchanges potassium for hydrogen and sodium. LOKELMA is an odorless, insoluble white to grey powder for oral suspension. It has a mean particle size of 20 µm and includes no more than 3% of particles with a diameter below 3 µm.

Each

5 g of sodium zirconium cyclosilicate contains 400 mg of sodium. The chemical formula of sodium zirconium cyclosilicate is Na ~1.5 H ~0.5 ZrSi 3 O 9

• 2–3H 2 O.

Figure

1: Crystal Structure of Sodium Zirconium Cyclosilicate Figure 1

AND USAGE LOKELMA is indicated for the treatment of hyperkalemia in adults. Limitation of Use LOKELMA should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action [see Clinical Pharmacology (12.2) and Clinical Studies (14) ] . LOKELMA is a potassium binder indicated for the treatment of hyperkalemia in adults. ( 1 ) Limitation of Use LOKELMA should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action. ( 1 )

AND ADMINISTRATION

• Recommended starting dose is 10 g administered three times a day for up to 48 hours. ( 2.1 )
• For maintenance treatment, recommended dose is 10 g once daily. Adjust dose at one-week intervals as needed (by 5 g daily) to obtain desired serum potassium target range. ( 2.1 ) Patients on Chronic Hemodialysis
• Recommended starting dose is 5 g once daily on non-dialysis days. ( 2.2 ) See full Prescribing Information for additional dosing instructions, as well as reconstitution and administration instructions for the oral suspension.

2.1 Recommended Dosage For initial treatment of hyperkalemia, the recommended dose of LOKELMA is 10 g administered three times a day for up to 48 hours. Administer LOKELMA orally as a suspension in water <span class="opacity-50 text-xs">[see Dosage and Administration (2.3) ]</span> . For continued treatment, the recommended dose is 10 g once daily. Monitor serum potassium and adjust the dose of LOKELMA based on the serum potassium level and desired target range. During maintenance treatment, up-titrate based on the serum potassium level at intervals of 1-week or longer and in increments of 5 g. Decrease the dose of LOKELMA or discontinue if the serum potassium is below the desired target range. The recommended maintenance dose range is from 5 g every other day to 15 g daily.

2.2 Dosage Adjustment for Patients on Chronic Hemodialysis For patients on chronic hemodialysis, administer LOKELMA only on non-dialysis days. The recommended starting dose is 5 g once daily on non-dialysis days. Consider a starting dose of 10 g once daily on non-dialysis days in patients with serum potassium greater than 6.5 mEq/L. Monitor serum potassium and adjust the dose of LOKELMA based on the pre-dialysis serum potassium value after the long inter-dialytic interval and desired target range. During initiation and after a dose adjustment, assess serum potassium after one week. The recommended maintenance dose range is from 5 g to 15 g once daily, on non-dialysis days. Discontinue or decrease the dose of LOKELMA if:

• serum potassium falls below the desired target range based on the pre-dialysis value after the long interdialytic interval, or;
• the patient develops clinically significant hypokalemia

2.3 Reconstitution and Administration In general, other oral medications should be administered at least 2 hours before or 2 hours after LOKELMA <span class="opacity-50 text-xs">[see Drug Interactions (7) ]</span> . Instruct patients to empty the entire contents of the packet(s) into a drinking glass containing approximately 3 tablespoons of water or more if desired. Stir well and drink immediately. If powder remains in the drinking glass, add water, stir and drink immediately. Repeat until no powder remains to ensure the entire dose is taken.

None. None. ( 4 )

REACTIONS The following adverse reactions are discussed in greater detail elsewhere in the label:

• Edema [see Warnings and Precautions (5.2) ] . Most common adverse reactions with LOKELMA: mild to moderate edema. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact AstraZeneca at 1-800-236-9933 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1 Clinical Studies 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 LOKELMA in the safety and efficacy clinical trials of patients not on dialysis with hyperkalemia was 1,760 patients with 652 patients exposed to LOKELMA 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 LOKELMA 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 LOKELMA compared to 2.4% of patients receiving placebo. In longer-term uncontrolled trials in which most patients were maintained on doses &lt;15 g once daily, adverse reactions of edema (edema, generalized edema and peripheral edema) were reported in 8% to 11% of patients. In a pooled analysis of clinical studies conducted in countries with a predominantly Asian population, constipation occurred in patients receiving LOKELMA with an estimated incidence of 9% and 5% for the 10 g and 5 g dose respectively. Constipation was resolved with dose adjustment or treatment discontinuation. No cases of constipation were reported in patients receiving placebo.

Laboratory

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

AND PRECAUTIONS

• Gastrointestinal Adverse Events in Patients with Motility Disorders. ( 5.1 )
• Edema. ( 5.2 )
• Hypokalemia in patients on hemodialysis. ( 5.3 )
• LOKELMA has radio-opaque properties and, therefore, may give the appearance typical of an imaging agent during abdominal X-ray procedures. ( 5.4 )

5.1 Gastrointestinal Adverse Events in Patients with Motility Disorders Avoid use of LOKELMA in patients with severe constipation, bowel obstruction or impaction, including abnormal post-operative bowel motility disorders, because LOKELMA has not been studied in patients with these conditions and may be ineffective and may worsen gastrointestinal conditions.

5.2 Edema Each 5 g dose of LOKELMA contains approximately 400 mg of sodium, but the extent of absorption by the patient is unknown. In clinical trials of LOKELMA in patients who were not on dialysis, edema was observed and was generally mild to moderate in severity and was more commonly seen in patients treated with 15 g once daily. Monitor for signs of edema, particularly in patients who should restrict their sodium intake or are prone to fluid overload (e.g., heart failure or renal disease). Advise patients to adjust dietary sodium, if appropriate. Increase the dose of diuretics as needed <span class="opacity-50 text-xs">[see Adverse Reactions (6) ]</span> . In a clinical trial of LOKELMA in patients on chronic hemodialysis in which most patients were treated with doses of 5 to 10 g once daily on non-dialysis days, there was no difference in the mean change from baseline in interdialytic weight gain (a measure of fluid retention) between the LOKELMA and placebo groups.

5.3 Hypokalemia in Patients on Hemodialysis Patients on hemodialysis may be prone to acute illness that can increase the risk of hypokalemia on LOKELMA (e.g., illnesses associated with decreased oral intake, diarrhea). Consider adjusting Lokelma dose based on potassium levels in these settings.

5.4 Diagnostic Tests LOKELMA has radio-opaque properties and, therefore, may give the appearance typical of an imaging agent during abdominal X-ray procedures .

INTERACTIONS LOKELMA can transiently increase gastric pH. As a result, LOKELMA can change the absorption of co-administered drugs that exhibit pH-dependent solubility, potentially leading to altered efficacy or safety of these drugs when taken close to the time LOKELMA is administered. In general, other oral medications should be administered at least 2 hours before or 2 hours after LOKELMA [see Dosage and Administration (2.3) and Clinical Pharmacology (12.3) ] . LOKELMA is not expected to impact systemic exposure of drugs that do not exhibit pH-dependent solubility and so spacing is not needed if it has been determined that the concomitant medication does not exhibit pH-dependent solubility. In general, other oral medications should be administered at least 2 hours before or 2 hours after LOKELMA. ( 2.3 , 7 , 12.3 )

Drug Interactions

Thirty-six (36) drugs were tested in-vitro to determine potential interactions with LOKELMA. Sixteen (16) drugs tested did not show an in vitro interaction with LOKELMA (allopurinol, apixaban, aspirin, captopril, cyclosporine, digoxin, ethinyl estradiol, lisinopril, magnesium, metformin, phenytoin, prednisone, propranolol, quinapril, spironolactone and ticagrelor). Nine (9) of the 20 drugs that showed an in vitro interaction were subsequently tested in vivo with LOKELMA 10 g in healthy volunteers. Losartan, glipizide and levothyroxine did not show any changes in exposure when co-administered with LOKELMA. However, there was an increase in systemic exposure to weak acids such as furosemide and atorvastatin, and a decrease in systemic exposure to weak bases such as dabigatran when co-administered with LOKELMA, as shown in Figure 2. These changes are consistent with the hypothesis that LOKELMA, by elevating gastric pH, affects the systemic exposure of co-administered drugs whose solubility is pH-dependent [see Drug Interactions (7) ] . In another drug-drug interaction study in healthy volunteers, co-administration of LOKELMA 15 g decreased the systemic exposures of tacrolimus (Figure 2), likely due to LOKELMA’s action on elevating gastric pH. In the same study, co-administration of LOKELMA and cyclosporine did not show a clinically meaningful interaction.

Figure

2: Effects of LOKELMA 10 g or 15 g on the Pharmacokinetic Exposures of Other Orally Administered Medications figure_2