ral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer carbonate ciprofloxacin mycophenolate mofetil dosing recommendations take at least 2 hours before or 6 hours after sevelamer take at least 2 hours before sevelamer for oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, consider separation of the timing of administration and/or monitor clinical responses or blood levels of the concomitant medication. ( 7 ) sevelamer did not alter the pharmacokinetics of digoxin, enalapril, iron, metoprolol and warfarin. ( 7 ) sevelamer has demonstrated interaction with ciprofloxacin, mycophenolate mofetil, and therefore, these drugs should be dosed separately from sevelamer carbonate. ( 7 )

amer carbonate discontinuation. treatment with sevelamer carbonate should be re-evaluated in patients who develop severe gastrointestinal symptoms. 5.2 reductions in vitamins d, e, k (clotting factors) and folic acid levels in preclinical studies in rats and dogs, sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, reduced vitamins d, e, and k (coagulation parameters) and folic acid levels at doses of 6 to 10 times the recommended human dose. in short-term clinical trials, there was no evidence of reduction in serum levels of vitamins. however, in a one-year clinical trial, 25-hydroxyvitamin d (normal range 10 to 55 ng/ml) fell from 39 ± 22 ng/ml to 34 ± 22 ng/ml (p<0.01) with sevelamer hydrochloride treatment. most (approximately 75%) patients in sevelamer hydrochloride clinical trials were receiving vitamin supplements.

t taking a phosphate binder serum phosphorus sevelamer carbonate for oral suspension >5.5 and <7.5 mg/dl 0.8 g three times daily with meals ≥7.5 mg/dl 1.6 g three times daily with meals dose titration for adult patients taking sevelamer carbonate for oral suspension . titrate the sevelamer carbonate for oral suspension dose by 0.8 g three times per day with meals at two-week intervals as necessary to achieve target serum phosphorus levels. based on clinical studies, the average prescribed adult daily dose of sevelamer carbonate is approximately 7.2 g per day. the highest daily adult dose of sevelamer carbonate studied was 14 grams in ckd patients on dialysis. starting dose for pediatric patients not taking a phosphate binder. the recommended starting dose for pediatric patients 6 years of age and older is 0.8 g to 1.6 g taken three times per day with meals based on the patient’s body surface area (bsa) category; see table 2. table 2: recommended starting dosage and titration increment based on pediatric patient’s body surface area (m 2 ) bsa (m 2 ) starting dose per meal/snack titration increases/decreases per dose ≥0.75 to <1.2 0.8 g titrate by 0.4 g ≥1.2 1.6 g titrate by 0.8 g dose titration for pediatric patients taking sevelamer carbonate for oral suspension. titrate the sevelamer carbonate for oral suspension dose as needed to achieve target levels at two-week intervals based on bsa category, as shown in table 2. switching from sevelamer hydrochloride tablets. for adult patients switching from sevelamer hydrochloride tablets to sevelamer carbonate tablets or powder, use the same dose in grams. switching between sevelamer carbonate tablets and powder. use the same dose in grams. switching from calcium acetate . table 3 gives recommended starting doses of sevelamer carbonate for oral suspension based on a patient’s current calcium acetate dose. table 3: starting dose for dialysis patients switching from calcium acetate to sevelamer carbonate for oral suspension calcium acetate 667 mg (tablets per meal) sevelamer carbonate for oral suspension 1 tablet 0.8 g 2 tablets 1.6 g 3 tablets 2.4 g 2.2 sevelamer carbonate powder preparation instructions sevelamer carbonate powder is available in 0.8 or 2.4 g pouches. for dose increments of 0.4 g, use one half of a 0.8 g pouch. place the sevelamer carbonate powder in a cup and suspend in the amount of water described in table 4. table 4: sevelamer carbonate powder preparation instructions amount of sevelamer carbonate powder minimum amount of water for dose preparation (either ounces, ml, or tablespoon) ounces ml tablespoons 0.4 g 1 30 2 0.8 g 1 30 2 2.4 g 2 60 4 instruct patients to stir the mixture vigorously (it does not dissolve), resuspend, if necessary, right before administration, and drink the entire preparation within 30 minutes. as an alternative to water, the entire contents of the pouch may be pre-mixed with a small amount of food or beverage and consumed immediately (within 30 minutes) as part of the meal. do not heat sevelamer carbonate powder (e.g., microwave) or add to heated foods or liquids.

dverse event profiles of the two salts are expected to be similar. in a cross-over study in hemodialysis patients with treatment durations of eight weeks each and no washout, and another cross-over study in hemodialysis patients with treatment durations of four weeks each and no washout between treatment periods, the adverse reactions on sevelamer carbonate powder were similar to those reported for sevelamer hydrochloride. in a parallel design study of sevelamer hydrochloride with treatment duration of 52 weeks, adverse reactions reported for sevelamer hydrochloride (n=99) were similar to those reported for the active-comparator group (n=101). overall adverse reactions among those treated with sevelamer hydrochloride occurring in >5% of patients included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain (9%), flatulence (8%), and constipation (8%). a total of 27 patients treated with sevelamer and 10 patients treated with comparator withdrew from the study due to adverse reactions. based on studies of 8 to 52 weeks, the most common reason for withdrawal from sevelamer hydrochloride was gastrointestinal adverse reactions (3% to 16%). in 143 peritoneal dialysis patients studied for 12 weeks using sevelamer hydrochloride, most common adverse reactions were similar to adverse reactions observed in hemodialysis patients. the most frequently occurring treatment emergent serious adverse reaction was peritonitis (8 reactions in 8 patients [8%] in the sevelamer group and 2 reactions in 2 patients [4%] on active control). thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. 6.2 postmarketing experience because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or to establish a causal relationship to drug exposure. the following adverse reactions have been identified during postapproval use of sevelamer hydrochloride or sevelamer carbonate: hypersensitivity, pruritus, rash, abdominal pain, bleeding gastrointestinal ulcers, colitis, ulceration, necrosis, fecal impaction, and uncommon cases of ileus, intestinal obstruction, and intestinal perforation . appropriate medical management should be given to patients who develop constipation or have worsening of existing constipation to avoid severe complications.

ral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer carbonate ciprofloxacin mycophenolate mofetil dosing recommendations take at least 2 hours before or 6 hours after sevelamer take at least 2 hours before sevelamer for oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, consider separation of the timing of administration and/or monitor clinical responses or blood levels of the concomitant medication. ( 7 ) sevelamer did not alter the pharmacokinetics of digoxin, enalapril, iron, metoprolol and warfarin. ( 7 ) sevelamer has demonstrated interaction with ciprofloxacin, mycophenolate mofetil, and therefore, these drugs should be dosed separately from sevelamer carbonate. ( 7 )

twice the maximum clinical trial dose). 8.2 lactation risk summary sevelamer carbonate is not absorbed systemically by the mother following oral administration, and breastfeeding is not expected to result in exposure of the child to sevelamer carbonate. clinical considerations sevelamer carbonate may decrease serum levels of fat soluble vitamins and folic acid in pregnant women [see clinical pharmacology (12.2) ] . consider supplementation. 8.4 pediatric use the safety and efficacy of sevelamer carbonate in lowering serum phosphorus levels was studied in patients 6 years of age and older with ckd. in this study, sevelamer carbonate was apparently less effective in children with a low baseline serum phosphorus, which described children <13 years of age and children not on dialysis. given its mechanism of action, sevelamer carbonate is expected to be effective in lowering serum phosphorus levels in pediatric patients with ckd. most adverse events that were reported as related, or possibly related, to sevelamer carbonate were gastrointestinal in nature. no new risks or safety signals were identified with the use of sevelamer carbonate in the trial. sevelamer carbonate has not been studied in pediatric patients below 6 years of age. 8.5 geriatric use clinical studies of sevelamer carbonate did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.

al dose).

ol declined by 15% to 31%; the clinical significance of this finding, which was observed after 2 weeks, is unclear. triglycerides, hdl cholesterol, and albumin did not change. 12.3 pharmacokinetics a mass balance study using 14 c-sevelamer hydrochloride, in 16 healthy male and female volunteers showed that sevelamer hydrochloride is not systemically absorbed. no absorption studies have been performed in patients with renal disease. drug interactions in vivo sevelamer carbonate has been studied in human drug-drug interaction studies (9.6 grams once daily with a meal) with warfarin and digoxin. sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been studied in human drug-drug interaction studies (2.4 to 2.8 grams single dose or three times daily with meals or two times daily without meals) with ciprofloxacin, digoxin, enalapril, iron, metoprolol, mycophenolate mofetil, and warfarin. coadministered single dose of 2.8 grams of sevelamer hydrochloride in fasted state decreased the bioavailability of ciprofloxacin by approximately 50% in healthy subjects. concomitant administration of sevelamer and mycophenolate mofetil in adult and pediatric patients decreased the mean mpa c max and auc 0-12h by 36% and 26%, respectively. sevelamer carbonate or sevelamer hydrochloride did not alter the pharmacokinetics of enalapril, digoxin, iron, metoprolol, and warfarin when coadministered. during postmarketing experience, cases of increased thyroid stimulating hormone (tsh) levels have been reported in patients coadministered sevelamer hydrochloride and levothyroxine. reduction in concentrations of cyclosporine and tacrolimus leading to dose increases has also been reported in transplant patients when coadministered with sevelamer hydrochloride without any clinical consequences (for example, graft rejection). the possibility of an interaction cannot be excluded with these drugs.

dult and pediatric patients decreased the mean mpa c max and auc 0-12h by 36% and 26%, respectively. sevelamer carbonate or sevelamer hydrochloride did not alter the pharmacokinetics of enalapril, digoxin, iron, metoprolol, and warfarin when coadministered. during postmarketing experience, cases of increased thyroid stimulating hormone (tsh) levels have been reported in patients coadministered sevelamer hydrochloride and levothyroxine. reduction in concentrations of cyclosporine and tacrolimus leading to dose increases has also been reported in transplant patients when coadministered with sevelamer hydrochloride without any clinical consequences (for example, graft rejection). the possibility of an interaction cannot be excluded with these drugs.

dministration study in which the females were treated from 14 days prior to mating through gestation and the males were treated for 28 days prior to mating. the highest dose in this study was 4.5 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose of 13 g).

ch the females were treated from 14 days prior to mating through gestation and the males were treated for 28 days prior to mating. the highest dose in this study was 4.5 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose of 13 g).

carbonate and three sevelamer hydrochloride studies). 14.2 cross-over study of sevelamer carbonate powder and sevelamer hydrochloride tablets stage 5 ckd patients on hemodialysis were entered into a four-week sevelamer hydrochloride run-in period and 31 patients received, in random order, sevelamer carbonate powder and sevelamer hydrochloride tablets for four weeks each with no intervening washout. study dose during the cross-over period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram-per-gram basis. the phosphorus levels at the end of each of the two cross-over periods were similar. average actual daily dose was 6 g/day divided among meals for sevelamer carbonate powder and 6.4 g/day divided among meals for sevelamer hydrochloride tablets. 14.3 clinical study of sevelamer carbonate powder in pediatric patients a clinical study with sevelamer carbonate was conducted in 101 patients 6 to 18 years of age with chronic kidney disease. this study included a washout period for patients on a phosphate binder, a 2-week, double-blind, fixed-dose period (fdp) in which patients were randomized to sevelamer carbonate (n=50) or placebo (n=51), and a 26-week, open-label, sevelamer carbonate dose titration period (dtp). most patients were 13 to 18 years of age (73%) and had a bsa ≥1.2 m 2 (84%). approximately 78% of patients were ckd patients on dialysis. sevelamer carbonate significantly reduced serum phosphorus through week 2 (primary endpoint) by an ls mean difference of -0.90 (se 0.27) mg/dl compared to placebo (p=0.001). a similar treatment response was observed in patients who received sevelamer carbonate during the 6-month open-label dtp. approximately 30% of subjects reached their target serum phosphorus. the median prescribed daily dose was approximately 7 g per day during the titration period. the results of the primary efficacy endpoint were consistent by bsa subgroup. in contrast, a treatment effect was not observed in subjects with a baseline serum phosphorus below 7 mg/dl, many of whom were the subjects 6 to <13 years of age or the subjects not on dialysis (figure 2). figure 2: change in serum phosphorus (mg/dl) from baseline to week 2 by subgroup [a]: ls mean difference of sevelamer carbonate – placebo, based on ancova within subgroup and with treatment as fixed effect and screening bsa and baseline serum phosphorus as covariates. figure 2. change in serum phosphorus (mg/dl) from baseline to week 2 by subgroup 14.4 sevelamer hydrochloride versus active-control, cross-over study in hemodialysis patients eighty-four ckd patients on hemodialysis who were hyperphosphatemic (serum phosphorus >6.0 mg/dl) following a two-week phosphate binder washout period were randomized in a cross-over design to receive in random order sevelamer hydrochloride and active control for eight weeks each. treatment periods were separated by a two-week phosphate binder washout period. patients started on treatment three times per day with meals. over each eight-week treatment period, at three separate time points the dose of sevelamer hydrochloride could be titrated up to control serum phosphorus, the dose of active control could also be altered to attain phosphorus control. both treatments significantly decreased mean serum phosphorus by about 2 mg/dl (table 6). table 6: mean serum phosphorus (mg/dl) at baseline and endpoint * p<0.0001, within treatment group comparison sevelamer hydrochloride (n=81) active control (n=83) baseline at end of washout 8.4 8.0 endpoint 6.4 5.9 change from baseline at endpoint (95% confidence interval) -2.0* (-2.5, -1.5) -2.1* (-2.6, -1.7) the distribution of responses is shown in figure 3. the distributions are similar for sevelamer hydrochloride and active control. the median response is a reduction of about 2 mg/dl in both groups. about 50% of subjects have reductions between 1 and 3 mg/dl. figure 3: percentage of patients (y-axis) attaining a phosphorus reduction from baseline (mg/dl) at least as great as the value of the x-axis average daily sevelamer hydrochloride dose at the end of treatment was 4.9 g (range of 0 to 12.6 g). figure 3: percentage of patients (y-axis) attaining a phosphorus reduction from baseline (mg/dl) at least as great as the value of the x-axis 14.5 sevelamer hydrochloride versus active control in hemodialysis patients two hundred ckd patients on hemodialysis who were hyperphosphatemic (serum phosphorus >5.5 mg/dl) following a two-week phosphate-binder washout period were randomized to receive sevelamer hydrochloride 800 mg tablets (n=99) or an active control (n=101). at week 52, using last observation carried forward, sevelamer and active control both significantly decreased mean serum phosphorus (table 7). table 7: mean serum phosphorus (mg/dl) and ion product at baseline and change from baseline to end of treatment sevelamer hydrochloride (n=94) active control (n=98) phosphorus baseline change from baseline at endpoint 7.5 -2.1 7.3 -1.8 ca x phosphorus ion product baseline change from baseline at endpoint 70.5 -19.4 68.4 -14.2 sixty-one percent of sevelamer hydrochloride patients and 73% of the control patients completed the full 52 weeks of treatment. figure 4, a plot of the phosphorus change from baseline for the completers, illustrates the durability of response for patients who are able to remain on treatment. figure 4: mean phosphorus change from baseline for patients who completed 52 weeks of treatment average daily sevelamer hydrochloride dose at the end of treatment was 6.5 g (range of 0.8 to 13 g). figure 4. mean phosphorus change from baseline for patients who completed 52 weeks of treatment 14.6 sevelamer hydrochloride versus active control in peritoneal dialysis patients one hundred and forty-three patients on peritoneal dialysis who were hyperphosphatemic (serum phosphorus >5.5 mg/dl) following a two-week phosphate binder washout period were randomized to receive sevelamer hydrochloride (n=97) or active control (n=46) open label for 12 weeks. average daily sevelamer hydrochloride dose at the end of treatment was 5.9 g (range 0.8 to 14.3 g). thirteen patients (14%) in the sevelamer group and 9 patients (20%) in the active-control group discontinued, mostly for gastrointestinal adverse reactions. there were statistically significant changes in serum phosphorus (p<0.001) for sevelamer hydrochloride (-1.6 mg/dl from baseline of 7.5 mg/dl), similar to the active control. 14.7 once-daily versus three-times-per-day dosing stage 5 ckd patients on hemodialysis with a serum phosphate level of >5.5 mg/dl after washout from baseline therapies were randomized in a 2:1 ratio to receive either sevelamer carbonate powder once daily (n=144) or sevelamer hydrochloride as a tablet with the dose divided three times per day (n=73) for 24 weeks. the initial dose for the two groups was 4.8 g/day. at the end of the study, the total daily dose was 6.2 g/day of sevelamer carbonate powder once daily and 6.7 g/day of sevelamer hydrochloride tablets three times per day. a greater percentage of subjects on the once-daily dose than three-times-per-day regimen discontinued therapy prematurely, 35% versus 15%. the reasons for discontinuation were largely driven by adverse events and withdrawal of consent in the once-daily dosing regimen. serum phosphate levels and calcium-phosphate product were better controlled on the three-times- per-day regimen than on the once-daily regimen. mean serum phosphorus decreased 2.0 mg/dl for sevelamer carbonate powder once daily and 2.9 mg/dl for sevelamer hydrochloride tablets three times per day.