s 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

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 [see adverse reactions (6) ] . 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.

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 [see drug interactions (7) ] . 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.

ars, 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 <15 g once daily, adverse reactions of edema (edema, generalized edema and peripheral edema) were reported in 8% to 11% of patients. 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.

s 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

ium 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. 12.3 pharmacokinetics 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 gin 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

h lokelma 10 gin 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

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). 14.2 study 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 doses (5, 10 and 15 g) of once daily lokelma maintained mean potassium at lower levels than placebo (mean serum potassium was 4.8, 4.5, and 4.4 meq/l for the 5, 10 and 15 g dose groups, respectively, vs. 5.1 meq/l in the placebo group, p ≤0.001 for all doses, figure 3, right ). a greater proportion of patients had mean serum potassium levels in the normal range (3.5 to 5 meq/l) while on lokelma than while on placebo (80%, 90% and 94% at the 5, 10 and 15 g doses, respectively, vs. 46% on placebo). figure 3: study 2 - mean serum potassium levels in the acute and randomized withdrawal phases intent-to-treat population includes subjects with at least one valid serum potassium measurement on or after day 8 figure_3 14.3 eleven-month extension study patients who completed the 28-day randomized withdrawal phase had the option to continue treatment with lokelma, taken just before breakfast, in an open-label extension phase for up to 11 months (n=123; nct02107092). figure 4 shows that the treatment effect on serum potassium was maintained during continued therapy. figure 4: 11-month open-label extension phase of study 2 - mean serum potassium (meq/l) figure 4 14.4 study 3 lokelma was evaluated in an open-label 12-month study in 751 hyperkalemic patients (nct02163499). the mean baseline potassium level in this study was 5.6 meq/l. following the acute phase treatment of lokelma 10 g three times a day, patients who achieved normokalemia (3.5-5.0 meq/l) within 72 hours (n=746; 99%) entered the maintenance phase. for maintenance treatment, the initial dosage of lokelma was 5 g once daily and was adjusted to a minimum of 5 g every other day up to maximum of 15 g once daily, based on serum potassium level. the treatment effect on serum potassium was maintained during continued therapy. 14.5 study 4 the effectiveness of lokelma in lowering serum potassium was studied in a double-blind, placebo-controlled trial of 196 chronic hemodialysis patients (mean age 58 years, range 20 to 86 years) with persistent pre-dialysis hyperkalemia (mean baseline potassium 5.8 meq/l) who were randomized to receive lokelma 5 g or placebo once daily on non-dialysis days (nct03303521). during the dose adjustment period (initial 4 weeks), the dose was adjusted weekly in 5 g increments up to 15 g once daily based on pre-dialysis serum potassium measurement after the long inter-dialytic interval to achieve a pre-dialysis serum potassium level between 4.0-5.0 meq/l. the dose reached at the end of the dose-adjustment period was maintained throughout the subsequent 4-week evaluation period. the primary endpoint in the trial was the proportion of responders, defined as patients who maintained a pre-dialysis serum potassium between 4.0 and 5.0 meq/l on at least 3 out of 4 dialysis treatments after the long inter-dialytic interval and who did not receive rescue therapy during the evaluation period. a greater proportion of patients were responders in the lokelma arm as compared to placebo (41% vs 1%, respectively; p<0.001). the treatment effect on mean pre-dialysis serum potassium levels was maintained during continued treatment. mean pre-dialysis serum potassium levels during the study are presented in figure 5. figure 5: mean pre-dialysis serum potassium levels over time in patients on chronic hemodialysis f/u - follow-up period the displayed error bars correspond to 95% confidence intervals. n = number of patients with non-missing potassium measurements at a particular visit. figure_5

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