Veltassa patiromer 25.2 g Powder, For Suspension, 30 packets — NDC 53436-252-30 (Billing 53436-0252-30)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action Veltassa is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol counterion. Veltassa 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, resulting in a reduction of serum potassium levels.

12.2Pharmacodynamics In a Phase 1 study in healthy adult subjects (6 to 8 subjects per group), Veltassa (0 grams to 50.4 grams per day) administered three times a day for 8 days caused a dose-dependent increase in fecal potassium excretion. A corresponding dose-dependent decrease in urinary potassium excretion with no change in serum potassium were also observed. Compared to placebo, Veltassa doses of 25.2 and 50.4 grams per day significantly decreased mean daily urinary potassium excretion.

In a Phase 1, open-label, multiple-dose crossover study in 12 healthy subjects, 25.2 grams of patiromer per day was administered orally as a once daily, twice daily or thrice daily regimen for 6 days in a randomly assigned order. A significant increase in mean daily fecal potassium excretion and concomitant decrease in mean daily urinary potassium excretion were observed during the treatment periods for all three dosing regimens. The mean increase in fecal potassium excretion ranged from 1283 to 1550 mg/day, and the mean decrease in urinary potassium excretion ranged from 1438 to 1534 mg/day across the three dosing regimens.

No significant differences were observed among the dosing regimens with respect to mean daily fecal potassium and urinary potassium excretion. This was true for the overall comparison among the three dosing regimens, as well as for the pairwise comparisons. In an open-label, uncontrolled study, 25 patients with hyperkalemia (mean baseline serum potassium of 5.9 mEq/L) and chronic kidney disease were given a controlled potassium diet for 3 days, followed by 16.8 grams patiromer daily (as divided doses) for 2 days while the controlled diet was continued.

A statistically significant reduction in serum potassium (-0.2 mEq/L) was observed at 7 hours after the first dose. Serum potassium levels continued to decline during the 48-hour treatment period (-0.8 mEq/L at 48 hours after the first dose). Potassium levels remained stable for 24 hours after the last dose, then rose during the 4-day observation period following discontinuation of Veltassa.

12.3Pharmacokinetics Absorption In radiolabeled ADME studies in rats and dogs, patiromer was not systemically absorbed and was excreted in the feces. Quantitative whole-body autoradiography analysis in rats demonstrated that radioactivity was limited to the gastrointestinal tract, with no detectable level of radioactivity in any other tissues or organs. Effect of Food Veltassa can be taken with or without food.

In an open-label study, 114 patients with hyperkalemia were randomized to Veltassa once daily with food or without food. Serum potassium at the end of treatment, the change from baseline in serum potassium, and the mean dose of Veltassa were similar between groups. Drug Interactions Veltassa has the potential to bind some oral co-administered medications, which could decrease their gastrointestinal absorption.

Fifty-six (56) drugs were tested in-vitro to determine the potential for interaction with Veltassa [see Drug Interactions (7) ]. For oral drug products not listed in Table 3, administration of patiromer should be separated by at least 3 hours as a precautionary measure. Twelve (12) drugs that showed an in vitro interaction were subsequently tested in vivo .

These studies in healthy volunteers showed that Veltassa did not alter the systemic exposure of amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil or warfarin when coadministered with Veltassa. Veltassa decreased the systemic exposure of coadministered ciprofloxacin, l… [Excerpted — this section continues on DailyMed.]

12.1Mechanism of Action Veltassa is a non-absorbed, cation exchange polymer that contains a calcium-sorbitol counterion. Veltassa 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, resulting in a reduction of serum potassium levels.

12.3Pharmacokinetics Absorption In radiolabeled ADME studies in rats and dogs, patiromer was not systemically absorbed and was excreted in the feces. Quantitative whole-body autoradiography analysis in rats demonstrated that radioactivity was limited to the gastrointestinal tract, with no detectable level of radioactivity in any other tissues or organs. Effect of Food Veltassa can be taken with or without food.

In an open-label study, 114 patients with hyperkalemia were randomized to Veltassa once daily with food or without food. Serum potassium at the end of treatment, the change from baseline in serum potassium, and the mean dose of Veltassa were similar between groups. Drug Interactions Veltassa has the potential to bind some oral co-administered medications, which could decrease their gastrointestinal absorption.

Fifty-six (56) drugs were tested in-vitro to determine the potential for interaction with Veltassa [see Drug Interactions (7) ]. For oral drug products not listed in Table 3, administration of patiromer should be separated by at least 3 hours as a precautionary measure. Twelve (12) drugs that showed an in vitro interaction were subsequently tested in vivo .

These studies in healthy volunteers showed that Veltassa did not alter the systemic exposure of amlodipine, cinacalcet, clopidogrel, furosemide, lithium, metoprolol, trimethoprim, verapamil or warfarin when coadministered with Veltassa. Veltassa decreased the systemic exposure of coadministered ciprofloxacin, levothyroxine and metformin. However, there was no interaction when Veltassa and these drugs were taken 3 hours apart (Figure 2) [see Drug Interactions (7) ] .

Figure 2: Effects of Veltassa on the Pharmacokinetic Exposures of Other Orally Administered Medications with No Dosing Separation and with a 3-Hour Separation Figure 2

12.2Pharmacodynamics In a Phase 1 study in healthy adult subjects (6 to 8 subjects per group), Veltassa (0 grams to 50.4 grams per day) administered three times a day for 8 days caused a dose-dependent increase in fecal potassium excretion. A corresponding dose-dependent decrease in urinary potassium excretion with no change in serum potassium were also observed. Compared to placebo, Veltassa doses of 25.2 and 50.4 grams per day significantly decreased mean daily urinary potassium excretion.

In a Phase 1, open-label, multiple-dose crossover study in 12 healthy subjects, 25.2 grams of patiromer per day was administered orally as a once daily, twice daily or thrice daily regimen for 6 days in a randomly assigned order. A significant increase in mean daily fecal potassium excretion and concomitant decrease in mean daily urinary potassium excretion were observed during the treatment periods for all three dosing regimens. The mean increase in fecal potassium excretion ranged from 1283 to 1550 mg/day, and the mean decrease in urinary potassium excretion ranged from 1438 to 1534 mg/day across the three dosing regimens.

No significant differences were observed among the dosing regimens with respect to mean daily fecal potassium and urinary potassium excretion. This was true for the overall comparison among the three dosing regimens, as well as for the pairwise comparisons. In an open-label, uncontrolled study, 25 patients with hyperkalemia (mean baseline serum potassium of 5.9 mEq/L) and chronic kidney disease were given a controlled potassium diet for 3 days, followed by 16.8 grams patiromer daily (as divided doses) for 2 days while the controlled diet was continued.

A statistically significant reduction in serum potassium (-0.2 mEq/L) was observed at 7 hours after the first dose. Serum potassium levels continued to decline during the 48-hour treatment period (-0.8 mEq/L at 48 hours after the first dose). Potassium levels remained stable for 24 hours after the last dose, then rose during the 4-day observation period following discontinuation of Veltassa.

14 CLINICAL STUDIES

14.1Two-Part, Randomized Withdrawal Study The efficacy of Veltassa was demonstrated in a two-part, single-blind randomized withdrawal study that evaluated Veltassa in hyperkalemic patients with CKD on stable doses of at least one renin-angiotensin-aldosterone system inhibitor (i.e., angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, or aldosterone antagonist). In Part A, 243 patients were treated with Veltassa for 4 weeks. Patients with a baseline serum potassium of 5.1 mEq/L to < 5.5 mEq/L received a starting Veltassa dose of 8.4 grams patiromer per day (as a divided dose) and patients with a baseline serum potassium of 5.5 mEq/L to < 6.5 mEq/L received a starting Veltassa dose of 16.8 grams patiromer per day (as a divided dose).

The dose of Veltassa was titrated, as needed, based on the serum potassium level, assessed starting on Day 3 and then at weekly visits (Weeks 1, 2 and 3) to the end of the 4-week treatment period, with the aim of maintaining serum potassium in the target range (3.8 mEq/L to < 5.1 mEq/L). The mean age of patients was 64 years, 58% of patients were men, and 98% were white. Approximately 97% of patients had hypertension, 57% had type 2 diabetes, and 42% had heart failure.

Results for the Part A primary endpoint, the change in serum potassium from Baseline to Week 4, are summarized in Table 4. Mean serum potassium over time for the intent-to-treat population is displayed in Figure 3. For the Part A secondary endpoint, 76% (95% CI: 70%, 81%) of patients had a serum potassium in the target range of 3.8 mEq/L to < 5.1 mEq/L at Week 4.

The mean daily doses of Veltassa were 13 grams and 21 grams in patients with serum potassium of 5.1 to < 5.5 mEq/L and 5.5 to < 6.5 mEq/L, respectively. Table 4: Veltassa Treatment Phase (Part A): Primary Endpoint Baseline, mean (SD) Week 4 Change from Baseline, Mean ± SE (95% CI) p -value Baseline Potassium 5.1 to <5.5 mEq/L (n=90) Serum Potassium (mEq/L) 5.31 (0.57) -0.65 ± 0.05 (-0.74, -0.55) Baseline Potassium 5.5 to <6.5 mEq/L (n=147) 5.74 (0.40) -1.23 ± 0.04 (-1.31, -1.16) Overall Population (n=237) 5.58 (0.51) -1.01 ± 0.03 (-1.07, -0.95) < 0.001 Figure 3: Estimated Mean (95% CI) of Central Serum Potassium (mEq/L) Over Time In Part B, 107 patients with a Part A baseline serum potassium of 5.5 mEq/L to < 6.5 mEq/L and whose serum potassium was in the target range (3.8 mEq/L to < 5.1 mEq/L) at Part A Week 4 and still receiving RAAS inhibitor medication were randomized to continue Veltassa or to receive placebo to evaluate the effect of withdrawing Veltassa on serum potassium.

In patients randomized to Veltassa, the mean daily dose was 21 grams at the start of Part B and during Part B. The Part B primary endpoint was the change in serum potassium from Part B baseline to the earliest visit at which the patient's serum potassium was first outside of the range of 3.8 to < 5.5 mEq/L, or to Part B Week 4 if the patient's serum potassium remained in the range. In Part B, serum potassium rose by 0.72 mEq/L in patients who were switched to placebo, versus no change in patients who remained on Veltassa.

Results are summarized in Table 5. Table 5: Randomized, Placebo-Controlled Withdrawal Phase (Part B): Primary Endpoint Placebo (n=52) Veltassa (n=55) Difference Estimate (95% CI) p -value Estimated Median Change in Serum Potassium from Baseline (mEq/L) 0.72 0.00 0.72 (0.46, 0.99) < 0.001 More placebo patients (91%; 95% CI: 83%, 99%) developed a serum potassium ≥ 5.1 mEq/L at any time during Part B than Veltassa patients (43%; 95% CI: 30%, 56%), p < 0.001. More placebo patients (60%; 95% CI: 47%, 74%) developed a serum potassium ≥ 5.5 mEq/L at any time during Part B than Veltassa patients (15%; 95% CI: 6%, 24%), p < 0.001.

Figure 3

14.2One-Year Study The effect of treatment with Veltassa for up to 52 weeks was evaluated in an open-label study of 304 hyperkalemic patients with CKD and type 2 diabetes mellitus on RAAS inhibitor therapy. Figur… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Patiromer was not genotoxic in the reverse mutation test (Ames assay), chromosome aberration or rat micronucleus assays. Carcinogenicity studies have not been performed. Patiromer did not impair the fertility in male or female rats at doses up to 10-fold the maximum recommended human dose (MRHD).