Velphoro

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.

4 CONTRAINDICATIONS None. None ( 4 )

5 WARNINGS AND PRECAUTIONS Patients with peritonitis during peritoneal dialysis, significant gastric or hepatic disorders, history of recent major gastrointestinal surgery, or with a 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 a 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.

7 DRUG INTERACTIONS Table 1 Oral drugs that can be administered concomitantly with Velphoro Calcitriol Ciprofloxacin Digoxin Enalapril Furosemide HMG-CoA reductase inhibitors Hydrochlorothiazide Losartan Metoprolol Nifedipine Omeprazole Quinidine Warfarin Oral drugs that are to be separated from Velphoro Dosing Recommendations Doxycycline Acetylsalicylic acid Cephalexin Take at least 1 hour before Velphoro. Levothyroxine Take at least 4 hours before Velphoro Oral medications not listed in Table 1 There are no empirical data on avoiding drug interactions between Velphoro and most concomitant oral drugs. For oral medications where a reduction in the bioavailability of that medication would have a 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 a narrow therapeutic range. 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 1 hour before Velphoro. ( 7 ) Take levothyroxine at least 4 hours before Velphoro. ( 7 ) For oral medications not listed above where a 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 )

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 Renal Therapies Group, LLC 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

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 Data In pregnant rats given up to 800 mg/kg/day Velphoro by oral gavage from Days 6 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 6 to 19 post-mating, the number of fetuses with incomplete/unossified epiphyses and metacarpals/phalanges was increased at the highest dose (corresponding to 4 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 6 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.