Velphoro sucroferric oxyhydroxide 500 mg Tablet, Chewable, 90-count — NDC 49230-645-51 (Billing 49230-0645-51)

12 CLINICAL PHARMACOLOGY

12.1Mechanism of Action In the aqueous environment of the GI tract, phosphate binding takes place by ligand exchange between hydroxyl groups and/or water in sucroferric oxyhydroxide and the phosphate in the diet. The bound phosphate is eliminated with feces. Both serum phosphorus levels and calcium-phosphorus product levels are reduced as a consequence of the reduced dietary phosphate absorption.

12.2Pharmacodynamics In vitro studies have demonstrated a robust phosphate binding capacity of Velphoro over the physiologically relevant pH range of the GI tract (1.2-7.5). The phosphate binding capacity of Velphoro peaked at pH 2.5, resulting in 96% of the available phosphate being adsorbed (phosphorus:iron concentration ratio 0.4:1).

12.3Pharmacokinetics The active moiety of Velphoro, polynuclear iron (III)-oxyhydroxide (pn-FeOOH), is practically insoluble in water and therefore not absorbed and not metabolized. Its degradation product, mononuclear iron species, can however be released from the surface of pn-FeOOH and be absorbed. Because of the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out.

The sucrose and starch components of Velphoro can be digested to glucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in the blood. The iron uptake from radiolabeled Velphoro drug substance, 2,000 mg in 1 day, was investigated in 16 chronic kidney disease patients (8 pre-dialysis and 8 hemodialysis patients) and 8 healthy volunteers with low iron stores (serum ferritin <100 mcg/L).

In healthy subjects, the median uptake of radiolabeled iron in the blood was 0.43% on Day 21. In chronic kidney disease patients, the median uptake was much less, 0.04% on Day 21. Drug Interaction Studies In vitro In vitro interactions were studied in aqueous solutions which mimic the physico-chemical conditions of the gastro-intestinal tract with or without the presence of phosphate (400 mg).

The study was conducted at pH 3.0, 5.5 and 8.0 with incubation at 37°C for 6 hours. Interaction with Velphoro was seen with the following drugs: alendronate, doxycycline, acetylsalicylic acid, cephalexin, levothyroxine, and paricalcitol. The following drugs did not show interaction with Velphoro: ciprofloxacin, enalapril, hydrochlorothiazide, metoprolol, nifedipine, and quinidine.

In vivo Five in vivo drug interaction studies (N=40/study) were conducted with losartan, furosemide, digoxin, omeprazole and warfarin in healthy subjects receiving 1,000 mg Velphoro 3 times a day with meals. Velphoro did not alter the systemic exposure as measured by the area under the curve (AUC) of the tested drugs when co-administered with Velphoro or given 2 hours later. Data from the clinical studies (Study-05A and Study-05B) show that Velphoro does not affect the lipid lowering effects of HMG-CoA reductase inhibitors or the PTH lowering effect of calcitriol.

12.1Mechanism of Action In the aqueous environment of the GI tract, phosphate binding takes place by ligand exchange between hydroxyl groups and/or water in sucroferric oxyhydroxide and the phosphate in the diet. The bound phosphate is eliminated with feces. Both serum phosphorus levels and calcium-phosphorus product levels are reduced as a consequence of the reduced dietary phosphate absorption.

12.3Pharmacokinetics The active moiety of Velphoro, polynuclear iron (III)-oxyhydroxide (pn-FeOOH), is practically insoluble in water and therefore not absorbed and not metabolized. Its degradation product, mononuclear iron species, can however be released from the surface of pn-FeOOH and be absorbed. Because of the insolubility and degradation characteristics of Velphoro, no classical pharmacokinetic studies can be carried out.

The sucrose and starch components of Velphoro can be digested to glucose and fructose, and maltose and glucose, respectively. These compounds can be absorbed in the blood. The iron uptake from radiolabeled Velphoro drug substance, 2,000 mg in 1 day, was investigated in 16 chronic kidney disease patients (8 pre-dialysis and 8 hemodialysis patients) and 8 healthy volunteers with low iron stores (serum ferritin <100 mcg/L).

In healthy subjects, the median uptake of radiolabeled iron in the blood was 0.43% on Day 21. In chronic kidney disease patients, the median uptake was much less, 0.04% on Day 21. Drug Interaction Studies In vitro In vitro interactions were studied in aqueous solutions which mimic the physico-chemical conditions of the gastro-intestinal tract with or without the presence of phosphate (400 mg).

The study was conducted at pH 3.0, 5.5 and 8.0 with incubation at 37°C for 6 hours. Interaction with Velphoro was seen with the following drugs: alendronate, doxycycline, acetylsalicylic acid, cephalexin, levothyroxine, and paricalcitol. The following drugs did not show interaction with Velphoro: ciprofloxacin, enalapril, hydrochlorothiazide, metoprolol, nifedipine, and quinidine.

In vivo Five in vivo drug interaction studies (N=40/study) were conducted with losartan, furosemide, digoxin, omeprazole and warfarin in healthy subjects receiving 1,000 mg Velphoro 3 times a day with meals. Velphoro did not alter the systemic exposure as measured by the area under the curve (AUC) of the tested drugs when co-administered with Velphoro or given 2 hours later. Data from the clinical studies (Study-05A and Study-05B) show that Velphoro does not affect the lipid lowering effects of HMG-CoA reductase inhibitors or the PTH lowering effect of calcitriol.

12.2Pharmacodynamics In vitro studies have demonstrated a robust phosphate binding capacity of Velphoro over the physiologically relevant pH range of the GI tract (1.2-7.5). The phosphate binding capacity of Velphoro peaked at pH 2.5, resulting in 96% of the available phosphate being adsorbed (phosphorus:iron concentration ratio 0.4:1).

14 CLINICAL STUDIES

14.1Fixed-dose Study In Study-03A, 154 ESRD adult patients on hemodialysis who were hyperphosphatemic (serum phosphorus >5.5 mg/dL but <7.75 mg/dL) following a 2-week phosphate binder washout period, were randomized to receive Velphoro at 250 mg/day, 1,000 mg/day, 1,500 mg/day, 2,000 mg/day, or 2,500 mg/day or active-control (sevelamer hydrochloride). Velphoro treatment was divided across meals, depending on dose. No dose titration was allowed.

Within each of the groups, the serum phosphorus level at the end of treatment was compared to baseline value. Velphoro was shown to be efficacious (p≤0.016) for all doses except 250 mg/day. There were no patient-reported dose limiting treatment-emergent adverse events.

Mean changes in iron parameters (ferritin, transferrin saturation (TSAT) and transferrin) and vitamins (A, D, E and K) were generally not clinically meaningful and showed no apparent trends across the treatment groups. Velphoro had a similar GI adverse event profile [see Adverse Reactions (6.1) ] to sevelamer hydrochloride, and no dose-dependent trend in GI events was observed.

14.2Dose Titration Study In Study-05A, 1,055 adult patients on hemodialysis (N=968) or peritoneal dialysis (N=87) with serum phosphorus ≥6 mg/dL following a 2-4 week phosphate binder washout period, were randomized and treated with either Velphoro, at a starting dose of 1,000 mg/day (N=707), or active-control (sevelamer carbonate, N=348) for 24 weeks. At the end of Week 24, 93 patients on hemodialysis whose serum phosphorus levels were controlled (<5.5 mg/dL) with Velphoro in the first part of the study, were re-randomized to continue treatment with either their Week 24 maintenance dose (N=44 or a non-effective low dose control 250 mg/day, N=49) of Velphoro for a further 3 weeks.

At Week 27, a superiority analysis of the Velphoro maintenance dose versus low dose was performed. The maximum dose of Velphoro was 3,000 mg/day (6 tablets/day) and the minimum dose was 1,000 mg/day (2 tablets/day). Velphoro was administered with food and the daily dose was divided across the largest meals of the day.

The Velphoro maintenance dose (1,000 to 3,000 mg/day) was statistically significantly superior in sustaining the phosphorus lowering effect in hemodialysis patients at Week 27 (p<0.001) compared with the non-effective low dose control. The results are provided in Table 2. Table 2 Mean (SD) Serum Phosphorus and Change from Baseline to End of Treatment Mean (SD) Serum Phosphorus (mg/dL) Velphoro Maintenance Dose (1,000 to 3,000 mg/day) (N=44) Velphoro Low Dose Control (250 mg/day) (N=49) Notes: BL is Week 24 or latest value available before Week 24 when Week 24 result is missing; End of Treatment is Week 27 value or includes the latest evaluable measurement after Week 24 (i.e., LOCF).

BL = Baseline; LOCF = Last observation carried forward; SD = Standard deviation. Week 24 (BL) 4.7 (1.03) 5.0 (1.14) Week 25 4.7 (0.91) 6.3 (1.44) Week 26 4.7 (1.21) 6.6 (1.91) Week 27/End of Treatment 5.0 (1.07) 6.8 (1.63) Change from BL to End of Treatment 0.3 (1.22) p<0.001 for the difference in least square means of the change from BL to Week 27/End of Treatment (LOCF principle) between Velphoro maintenance dose and low dose using a covariance analysis (MIXED Model). 1.8 (1.47) Following completion of Study-05A, 658 patients (597 on hemodialysis and 61 on peritoneal dialysis) were treated in the 28-week extension study (Study-05B) with either Velphoro (N=391) or sevelamer carbonate (N=267) according to their original randomization.

Serum phosphorus levels declined rapidly during the first few weeks of treatment and remained relatively constant thereafter. The phosphorus lowering effect of Velphoro was consistently maintained and controlled through 12 months of treatment (shown in Figure 1). The proportion of adherent patients for Velphoro was 86% at 52 weeks.

Figure 1 Mean change (±SEM) from baseline in serum phosphorus over time in Study‑05A and extension… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies were performed in mice and rats. In the 2-year carcinogenicity study in mice, animals were given Velphoro by diet at doses of 250, 500 or 1,000 mg/kg/day. There was no clear evidence of a carcinogenic effect in mice.

Mucosal hyperplasia, with diverticulum/cyst formation was observed in the colon and caecum of mice after 2 years treatment. In the 2-year rat carcinogenicity study, animals were given Velphoro by diet at doses of 40, 150 or 500 mg/kg/day. No statistically significantly increased incidences of tumors were found, but there were increased incidences in epithelial hyperplasia with or without submucosal inflammation in duodenum, cecum and colon at the dose of 500 mg/kg/day (10 times the maximum recommended clinical dose).

Velphoro was not mutagenic, clastogenic or DNA damaging in vitro in the Ames bacterial reverse mutation test, or in the Chinese-hamster fibroblast chromosomal aberration test, or in vivo in the rat Comet assay or peripheral blood micronucleus test. In rats, mating performance and fertility were unaffected by Velphoro at oral doses up to 800 mg/kg/day (16 times the maximum recommended clinical dose).