Lokelma sodium zirconium cyclosilicate 5 g/5g Powder, For Suspension — NDC 0310-1105-30 (Billing 00310-1105-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action LOKELMA (sodium zirconium cyclosilicate) is a non-absorbed zirconium silicate that preferentially captures potassium in exchange 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. LOKELMA increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract.

Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, thereby lowering serum potassium levels.

12.2Pharmacodynamics In a study in healthy adult subjects, LOKELMA administered as 5 g or 10 g once daily for four days caused a dose-dependent increase in fecal potassium excretion. Corresponding dose-dependent decreases in urinary potassium excretion and serum potassium were also observed. In patients with hyperkalemia treated with LOKELMA 10 g three times a day for up to 48 hours, reductions in serum potassium were observed one hour after initiation of therapy; serum potassium concentrations continued to decline over the 48-hour treatment period [see Clinical Studies (14.2) ] .

In patients not continuing LOKELMA, potassium levels increased. Patients with higher starting serum potassium levels or receiving a higher dose have greater reductions in serum potassium. LOKELMA causes a small dose-dependent increase in serum bicarbonate concentrations (1.1 mmol/L at 5 g once daily, 2.3 mmol/L at 10 g once daily and 2.6 mmol/L at 15 g once daily as compared with a mean increase of 0.6 mmol/L in patients treated with placebo).

The clinical significance of this finding is unclear.

12.3Pharmacokinetics LOKELMA is an inorganic, insoluble compound that is not subject to enzymatic metabolism. In a clinical study in patients with hyperkalemia in which zirconium concentrations were measured in the urine and blood, zirconium concentrations were similar in treated and untreated patients (i.e., either undetectable or around the lower limit of quantification of the assay). An in vivo mass balance study in rats showed that LOKELMA was recovered in the feces with no evidence of systemic absorption.

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

12.1Mechanism of Action LOKELMA (sodium zirconium cyclosilicate) is a non-absorbed zirconium silicate that preferentially captures potassium in exchange 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. LOKELMA increases fecal potassium excretion through binding of potassium in the lumen of the gastrointestinal tract.

Binding of potassium reduces the concentration of free potassium in the gastrointestinal lumen, thereby lowering serum potassium levels.

12.3Pharmacokinetics LOKELMA is an inorganic, insoluble compound that is not subject to enzymatic metabolism. In a clinical study in patients with hyperkalemia in which zirconium concentrations were measured in the urine and blood, zirconium concentrations were similar in treated and untreated patients (i.e., either undetectable or around the lower limit of quantification of the assay). An in vivo mass balance study in rats showed that LOKELMA was recovered in the feces with no evidence of systemic absorption.

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

12.2Pharmacodynamics In a study in healthy adult subjects, LOKELMA administered as 5 g or 10 g once daily for four days caused a dose-dependent increase in fecal potassium excretion. Corresponding dose-dependent decreases in urinary potassium excretion and serum potassium were also observed. In patients with hyperkalemia treated with LOKELMA 10 g three times a day for up to 48 hours, reductions in serum potassium were observed one hour after initiation of therapy; serum potassium concentrations continued to decline over the 48-hour treatment period [see Clinical Studies (14.2) ] .

In patients not continuing LOKELMA, potassium levels increased. Patients with higher starting serum potassium levels or receiving a higher dose have greater reductions in serum potassium. LOKELMA causes a small dose-dependent increase in serum bicarbonate concentrations (1.1 mmol/L at 5 g once daily, 2.3 mmol/L at 10 g once daily and 2.6 mmol/L at 15 g once daily as compared with a mean increase of 0.6 mmol/L in patients treated with placebo).

The clinical significance of this finding is unclear.

14 CLINICAL STUDIES

14.1Study 1 The effectiveness of LOKELMA in lowering serum potassium was demonstrated in a two-part, double-blind, randomized, placebo-controlled clinical trial (NCT01737697) in patients with hyperkalemia (5 to 6.5 mEq/L, mean potassium 5.3 mEq/L), Study 1. In the first phase of the trial (the acute phase), 753 patients were randomized to receive one of four doses of LOKELMA (1.25, 2.5, 5 or 10 g) or placebo, administered three times daily for the initial 48 hours with meals. The mean age of patients was 66 years, 59% of patients were men, and 86% were Caucasian.

Approximately 60% of patients had chronic kidney disease, 10% had heart failure, 62% had diabetes mellitus and 67% were on renin angiotensin aldosterone system (RAAS) inhibitor therapy at baseline. The primary endpoint in the acute phase was the difference in the exponential rate of change in serum potassium levels during the initial 48 hours of study drug treatment, comparing placebo-treated patients and LOKELMA-treated patients. The study met its primary endpoint demonstrating a greater reduction in serum potassium levels for the 2.5, 5 and 10 g (three times a day) dose groups compared to the placebo group ( p <0.001).

As displayed in Table 1 for the secondary endpoint of potassium change from baseline, LOKELMA showed dose-dependent reductions in serum potassium at 2.5, 5 and 10 g. In patients administered 10 g TID, the mean serum potassium reduction was -0.7 mEq/L at 48 hours. Patients with higher starting potassium levels had a greater response to LOKELMA.

LOKELMA was effective in lowering potassium levels in patients with chronic kidney disease, heart failure, diabetes mellitus and those taking RAAS inhibitor therapy. Table 1: Study 1 - Potassium Change from Baseline to 48 hours Mean Serum Potassium Change mEq/L (95% Confidence Intervals) Sample Size Placebo 1.25 g TID 2.5 g TID 5 g TID 10 g TID All Patients -0.2 (-0.3, -0.2) n=158 -0.3 (-0.4, -0.2) n=150 -0.5 (-0.5, -0.4) n=137 -0.5 (-0.6, -0.5) n=152 -0.7 (-0.8, -0.7) n=140 Baseline Serum Potassium >5.5 mEq/L -0.4 (-0.6, -0.3) n=40 -0.3 (-0.5, -0.2) n=40 -0.6 (-0.7, -0.4) n=37 -0.9 (-1.0, -0.7) n=29 -1.1 (-1.3, -0.9) n=22 Patients who achieved a potassium level between 3.5 and 5 mEq/L after receiving LOKELMA during the acute phase were re-randomized to receive once daily placebo or 1.25, 2.5, 5 or 10 g 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 5 and 10 g doses when compared with their respective placebo groups ( p <0.01 and p <0.001).

14.2Study 2 The efficacy of LOKELMA was also demonstrated in a two-part trial with an open-label acute phase and a month-long randomized, double-blind, placebo-controlled withdrawal phase (Study 2; NCT02088073). In the open-label acute phase of Study 2, 258 patients with hyperkalemia (baseline mean 5.6 mEq/L, range 5.1 to 7.4 mEq/L) received 10 g of LOKELMA administered three times daily with meals for 48 hours. As shown in Figure 3, left , average serum potassium levels decreased from 5.6 to 4.5 mEq/L during treatment with LOKELMA in the acute phase.

Following the acute phase of the study, there was a double-blind randomized withdrawal phase where patients who achieved potassium levels between 3.5 and 5 mEq/L were randomized to one of three doses of LOKELMA administered once-daily for 28 days, or placebo just before breakfast. Of the patients 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 randomized withdrawal phase was the mean serum potassium value over the period from Day 8 to Day 29, comparing LOKELMA-treated and placebo-treated patients.

All three do… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility 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.