Sucroferric Oxyhydroxide

1 INDICATIONS AND USAGE Velphoro is indicated for the control of serum phosphorus levels in adults and pediatric patients 9 years of age and older with chronic kidney disease (CKD) on dialysis. Velphoro is a phosphate binder indicated for the control of serum phosphorus levels in adult and pediatric patients 9 years of age and older with chronic kidney disease on dialysis. ( 1 )

2 DOSAGE AND ADMINISTRATION Chew or crush Velphoro tablets, do not swallow whole. ( 2.2 ) The recommended starting dose for adults and pediatric patients 12 years of age and older is one 500 mg tablet three times daily with meals. ( 2.1 ) The recommended starting dose for pediatric patients 9 to <12 years of age is one 500 mg tablet two times daily with meals. ( 2.1 ) Adjust dosage by one 500 mg tablet per day as needed until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. Titrate as often as weekly. ( 2.1 ) 2.1 General Dosing Information The recommended starting dose of Velphoro in adults and pediatric patients 12 years of age and older is one 500 mg tablet three times daily with meals. The recommended starting dose of Velphoro in pediatric patients 9 to <12 years of age is one 500 mg tablet two times daily with meals. Monitor serum phosphorus levels and titrate the dose of Velphoro in decrements or increments of one 500 mg tablet per day as needed until an acceptable serum phosphorus level is reached, with regular monitoring afterwards. Titrate as often as weekly. If the recommended daily dose cannot be divided equally among meals, administer the larger dose with the largest meal of the day. In clinical studies, on average, adult patients and pediatric patients 12 years of age and older required 1,500 mg to 2,000 mg (3 to 4 tablets) a day to control serum phosphorus levels; pediatric patients 9 to <12 years of age required on average 1,500 mg (3 tablets) to control serum phosphorus levels. Daily doses as high as 3,000 mg per day have been studied in adults and pediatric patients 9 years of age and older. 2.2 Administration Velphoro chewable tablets should be chewed or crushed. Do not swallow whole. Velphoro chewable tablets must be administered with meals. If one or more doses of Velphoro are missed, the medication should be resumed with the next food intake.

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 . 6.1 Clinical Trial Experience Adult Patients Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 2 active-controlled clinical studies involving a total of 778 adult patients on hemodialysis and 57 adult patients on peritoneal dialysis exposed for up to 55 weeks. Dosage regimens ranged from 250 mg to 3,000 mg per day. In a parallel design, dose-finding study of Velphoro with a treatment duration of 6 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 a 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%). Pediatric Patients In an open-label, randomized study, with a 10-week dose titration period and 24-week safety extension, 60 patients 6 to 18 years of age received at least one dose of Velphoro, including 30 patients (50%) exposed for at least 19 weeks [see Clinical Studies ( 14.3 )] . The safety profile of Velphoro in pediatric patients was similar to that observed in adult patients. Velphoro is not approved in pediatric patients 6 years to less than 9 years of age because of the lack of an appropriate dosage strength. 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 a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal Disorders: tooth discoloration Skin and Subcutaneous Tissue Disorders: rash

12.3 Pharmacokinetics 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.