ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most common adverse drug reactions to Velphoro chewable tablets in clinical trials were discolored feces (12%) and diarrhea (6%). 6.1) To report SUSPECTED ADVERSE REACTIONS, contact Fresenius Medical Care North America at 1-800-323-5188 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. The most common adverse drug reactions to Velphoro chewable tablets in clinical trials were discolored feces (12%) and diarrhea (6%). 6.1) 6.1 Clinical Trial Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety data derived from Velphoro clinical trials reflect exposure to Velphoro in active-controlled clinical studies involving total of 778 patients on hemodialysis and 57 patients on peritoneal dialysis exposed for up to 55 weeks. Dosage regimens ranged from 250 mg to 3,000 mg per day.In parallel design, dose-finding study of Velphoro with treatment duration of weeks in hemodialysis patients, adverse reactions for Velphoro (N=128) were similar to those reported for the active-control group (sevelamer hydrochloride) (N=26), with the exception of discolored feces (12%) which did not occur in the active-control group. Diarrhea was reported in 6% of patients treated with Velphoro. In 55-week, open-label, active-controlled, parallel design, safety and efficacy study involving 968 hemodialysis patients and 86 peritoneal dialysis patients treated with either Velphoro (N=707 including 57 peritoneal dialysis patients) or the active-control (sevelamer carbonate) (N=348 including 29 peritoneal dialysis patients), adverse reactions occurring in more than 5% in the Velphoro group were diarrhea (24%), discolored feces (16%), and nausea (10%). The majority of diarrhea events in the Velphoro group were mild and transient, occurring soon after initiation of treatment, and resolving with continued treatment. Adverse reactions occurred at similar rates in hemodialysis and peritoneal dialysis patients. The most common adverse reactions (>1%) leading to withdrawal were diarrhea (4%), product taste abnormal (2%), and nausea (2%).. 6.2 Postmarketing Experience. The following adverse reactions have been identified during post-approval use of Velphoro that are not included in other sections of labeling. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure.Gastrointestinal Disorders: tooth discolorationSkin and Subcutaneous Tissue Disorder: rash.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, 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 carcinogenic effect in mice. Mucosal hyperplasia, with diverticulum/cyst formation was observed in the colon and caecum of mice after 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).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism 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 consequence of the reduced dietary phosphate absorption.. 12.2 Pharmacodynamics. In vitro studies have demonstrated 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). 12.3 Pharmacokinetics. The active moiety of Velphoro, polynuclear iron (III)-oxyhydroxide (pn-FeOOH), is practically insoluble 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 day, was investigated in 16 chronic kidney disease patients (8 pre-dialysis and hemodialysis patients) and 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 vitroIn 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 37C for 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 vivoFive 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 times 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 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. The ability of Velphoro to lower serum phosphorus in ESRD patients on dialysis was demonstrated in randomized clinical trials: one 6-week, open-label, active-controlled (sevelamer hydrochloride), dose-finding study; and one 55-week, open-label, active-controlled (sevelamer carbonate), parallel-group, safety and efficacy study.In clinical trials, control of serum phosphorus levels was demonstrated at doses starting from 1,000 mg (2 tablets) per day with treatment effect being observed as early as 1-2 weeks after starting Velphoro.. Fixed-dose StudyIn Study-03A, 154 ESRD patients on hemodialysis who were hyperphosphatemic (serum phosphorus >5.5 mg/dL but <7.75 mg/dL) following 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, and K) were generally not clinically meaningful and showed no apparent trends across the treatment groups. Velphoro had similar GI adverse event profile [see Adverse Reactions 6.1)] to sevelamer hydrochloride, and no dose-dependent trend in GI events was observed. Dose Titration StudyIn Study-05A, 1,055 patients on hemodialysis (N=968) or peritoneal dialysis (N=87) with serum phosphorus >=6 mg/dL following 2-4 week phosphate binder washout period, were randomized and treated with either Velphoro, at 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 non-effective low dose control 250 mg/day, N=49) of Velphoro for further weeks. At Week 27, 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 Mean (SD) Serum Phosphorus and Change from Baseline to End of Treatment 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 covariance analysis (MIXED Model).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. Mean (SD) Serum Phosphorus (mg/dL)Velphoro Maintenance DoseVelphoro Low Dose Control(1,000 to 3,000 mg/day)(250 mg/day)(N=44)(N=49)Week 24 (BL)4.7 (1.03)5.0 (1.14)Week 254.7 (0.91)6.3 (1.44)Week 264.7 (1.21)6.6 (1.91)Week 27/End of Treatment5.0 (1.07)6.8 (1.63)Change from BL to End of Treatment0.3 (1.22)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 1Mean change (+-SEM) from baseline in serum phosphorus over time in Study05A and extension Study-05B. Insert showing the mean change (+-SEM) from baseline in serum phosphorus during the withdrawal phase of the study (Weeks 24 to 27) for Velphoro non-effective low dose control (250 mg /day) versus Velphoro maintenance dose.Age, gender, race, or dialysis modality did not affect the efficacy of Velphoro.There were no clinically meaningful changes for serum iron, ferritin, TSAT levels, vitamins (A, D, and K) with Velphoro. There was no evidence of accumulation of iron during one year treatment.. Figure 1.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Velphoro chewable tablets should be chewed or crushed. Do not swallow whole.. Chew or crush Velphoro tablets, do not swallow whole. 2) The recommended starting dose of Velphoro is tablets (1,500 mg) per day, administered as tablet (500 mg) times daily with meals. 2) Adjust by tablet per day as needed until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. Titrate as often as weekly. 2) Chew or crush Velphoro tablets, do not swallow whole. 2) The recommended starting dose of Velphoro is tablets (1,500 mg) per day, administered as tablet (500 mg) times daily with meals. 2) Adjust by tablet per day as needed until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. Titrate as often as weekly. 2) Starting DoseThe recommended starting dose of Velphoro is tablets (1,500 mg) per day, administered as tablet (500 mg) times daily with meals.. Titration and MaintenanceMonitor serum phosphorus levels and titrate the dose of Velphoro in decrements or increments of 500 mg (1 tablet) per day as needed until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. Titrate as often as weekly.Based on clinical studies, on average patients required to tablets (1,500 mg to 2,000 mg) day to control serum phosphorus levels.The highest daily dose studied in Phase clinical trial in ESRD patients was tablets (3,000 mg) per day.. AdministrationVelphoro must be administered with meals. To maximize the dietary phosphate binding, distribute the total daily dose among meals. No additional fluid above the amount usually taken by the patient is required.If one or more doses of Velphoro are missed, the medication should be resumed with the next meal. Do not attempt to replace missed dose.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Table Oral drugs that can be administered concomitantly with VelphoroCalcitriol Ciprofloxacin Digoxin Enalapril Furosemide HMG-CoA reductase inhibitors Hydrochlorothiazide Losartan Metoprolol Nifedipine Omeprazole Quinidine Warfarin Oral drugs that are to be separated from VelphoroDosing RecommendationsDoxycycline Acetylsalicylic acid Cephalexin Take at least hour before Velphoro. LevothyroxineTake at least hours before Velphoro. Velphoro can be administered concomitantly with oral calcitriol, ciprofloxacin, digoxin, enalapril, furosemide, HMG-CoA reductase inhibitors, hydrochlorothiazide, losartan, metoprolol, nifedipine, omeprazole, quinidine and warfarin. 7) Take acetylsalicylic acid, cephalexin and doxycycline at least hour before Velphoro. 7) Take levothyroxine at least hours before Velphoro. 7) For oral medications not listed above where reduction of bioavailability would be clinically significant consider separation of the timing of administration. Consider monitoring clinical responses or blood levels of the concomitant medication 7) Velphoro can be administered concomitantly with oral calcitriol, ciprofloxacin, digoxin, enalapril, furosemide, HMG-CoA reductase inhibitors, hydrochlorothiazide, losartan, metoprolol, nifedipine, omeprazole, quinidine and warfarin. 7) Take acetylsalicylic acid, cephalexin and doxycycline at least hour before Velphoro. 7) Take levothyroxine at least hours before Velphoro. 7) For oral medications not listed above where reduction of bioavailability would be clinically significant consider separation of the timing of administration. Consider monitoring clinical responses or blood levels of the concomitant medication 7) Oral medications not listed in Table There are no empirical data on avoiding drug interactions between Velphoro and most concomitant oral drugs. For oral medications where reduction in the bioavailability of that medication would have clinically significant effect on its safety or efficacy, consider separating the administration of the two drugs. The necessary separation depends upon the absorption characteristics of the medication concomitantly administered, such as the time to reach peak systemic levels and whether the drug is an immediate release or an extended release product. Where possible, consider monitoring for clinical response and/or blood levels of concomitant medications that have narrow therapeutic range.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, 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 carcinogenic effect in mice. Mucosal hyperplasia, with diverticulum/cyst formation was observed in the colon and caecum of mice after 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).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. The active moiety of Velphoro, polynuclear iron (III)-oxyhydroxide (pn-FeOOH), is practically insoluble 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 day, was investigated in 16 chronic kidney disease patients (8 pre-dialysis and hemodialysis patients) and 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 vitroIn 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 37C for 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 vivoFive 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 times 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 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.

PREGNANCY SECTION.

8.1 Pregnancy. Velphoro is not systemically absorbed following oral administration and maternal use is not expected to result in fetal exposure to the drug.. Data. Animal DataIn pregnant rats given up to 800 mg/kg/day Velphoro by oral gavage from Days to 17 post-mating, no embryo-fetal development toxicity was observed. This dose corresponds to 16 times the maximum recommended clinical dose.In pregnant rabbits given 50, 100 or 200 mg/kg/day Velphoro by oral gavage, from Days to 19 post-mating, the number of fetuses with incomplete/unossified epiphyses and metacarpals/phalanges was increased at the highest dose (corresponding to times the recommended maximum clinical dose). Litter parameters were not adversely affected.In pregnant rats given Velphoro at 100, 280, or 800 mg/kg/day by oral gavage from Day post-mating to lactation Day 20, offspring body weight gain was lower at age 5-13 weeks and neuromuscular function was delayed at the dose of 800 mg/kg/day. This dose represented 16 times the maximum recommended clinical dose.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Velphoro is not systemically absorbed following oral administration and maternal use is not expected to result in fetal exposure to the drug.. Data. Animal DataIn pregnant rats given up to 800 mg/kg/day Velphoro by oral gavage from Days to 17 post-mating, no embryo-fetal development toxicity was observed. This dose corresponds to 16 times the maximum recommended clinical dose.In pregnant rabbits given 50, 100 or 200 mg/kg/day Velphoro by oral gavage, from Days to 19 post-mating, the number of fetuses with incomplete/unossified epiphyses and metacarpals/phalanges was increased at the highest dose (corresponding to times the recommended maximum clinical dose). Litter parameters were not adversely affected.In pregnant rats given Velphoro at 100, 280, or 800 mg/kg/day by oral gavage from Day post-mating to lactation Day 20, offspring body weight gain was lower at age 5-13 weeks and neuromuscular function was delayed at the dose of 800 mg/kg/day. This dose represented 16 times the maximum recommended clinical dose.. 8.2 Lactation. Velphoro is not absorbed systemically following oral administration and breastfeeding is not expected to result in exposure of the child to Velphoro.. 8.4 Pediatric Use. The safety and efficacy of Velphoro have not been established in pediatric patients.. 8.5 Geriatric Use. Of the total number of subjects in two active-controlled clinical studies of Velphoro (N=835), 29.7% (n=248) were 65 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Patients with peritonitis during peritoneal dialysis, significant gastric or hepatic disorders, history of recent major gastrointestinal surgery, or with history of hemochromatosis or other diseases with iron accumulation have not been included in clinical studies with Velphoro. Monitor effect and iron homeostasis in such patients. 5.1) Patients with peritonitis during peritoneal dialysis, significant gastric or hepatic disorders, history of recent major gastrointestinal surgery, or with history of hemochromatosis or other diseases with iron accumulation have not been included in clinical studies with Velphoro. Monitor effect and iron homeostasis in such patients. 5.1) 5.1 Monitoring in Patients with Gastrointestinal Disorders or Iron Accumulation Disorders. Each chewable tablet contains 500 mg iron (equivalent to 2,500 mg sucroferric oxyhydroxide) [see Clinical Pharmacology 12.3)] .Patients with peritonitis during peritoneal dialysis, significant gastric or hepatic disorders, following major gastrointestinal (GI) surgery, or with history of hemochromatosis or other diseases with iron accumulation have not been included in clinical studies with Velphoro. Monitor effect and iron homeostasis in such patients.