of administration. consider monitoring clinical responses or blood levels of the concomitant medication ( 7 ) 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.

trol serum phosphorus levels. the highest daily dose studied in a phase 3 clinical trial in esrd patients was 6 tablets (3,000 mg) per day. administration velphoro 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 a missed dose.

modialysis 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%). 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 disorder: rash

of administration. consider monitoring clinical responses or blood levels of the concomitant medication ( 7 ) 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.

/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.

16 times the maximum recommended clinical dose.

er 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.

s 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.

osomal 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).

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).

ithin 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. dose titration study in study-05a, 1,055 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 * 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). 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 dose velphoro 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 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)* 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 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, e and k) with velphoro. there was no evidence of accumulation of iron during one year treatment. figure 1