that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer hydrochloride ciprofloxacin mycophenolate mofetil dosing recommendations take at least 2 hours before or 6 hours after sevelamer take at least 2 hours before sevelamer. when clinically significant drug interactions are expected, separate the timing of administration and 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 binds ciprofloxacin and mycophenolate mofetil; dose these drugs separately from sevelamer hydrochloride tablets. ( 7 )

scontinuation. treatment with sevelamer hydrochloride should be re-evaluated in patients who develop severe gastrointestinal symptoms. 5.2 monitor serum chemistries bicarbonate and chloride levels should be monitored. 5.3 monitor for reduced vitamins d, e, k (clotting factors) and folic acid levels in preclinical studies in rats and dogs, sevelamer hydrochloride 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 received vitamin supplements, which is typical of patients on dialysis.

s, a similar reduction in serum phosphorus was seen with equivalent doses (approximately mg for mg) of sevelamer hydrochloride tablets and calcium acetate. table 2 gives recommended starting doses of sevelamer hydrochloride tablets based on a patient's current calcium acetate dose. table 2: starting dose for dialysis patients switching from calcium acetate to sevelamer hydrochloride tablets calcium acetate 667 mg (tablets per meal) sevelamer hydrochloride tablets 800 mg (tablets per meal) sevelamerhydrochloride tablets 400 mg (tablets per meal) 1 tablet 1 tablet 2 tablets 2 tablets 2 tablets 3 tablets 3 tablets 3 tablets 5 tablets dose titration for all patients taking sevelamer hydrochloride tablets . adjust dosage based on the serum phosphorus concentration with a goal of lowering serum phosphorus to 5.5 mg/dl or less. increase or decrease by one tablet per meal at two-week intervals as necessary. table 3 gives a dose titration guideline. the average dose in a phase 3 trial designed to lower serum phosphorus to 5.0 mg/dl or less was approximately three sevelamer hydrochloride 800 mg tablets per meal. the maximum average daily sevelamer hydrochloride dose studied was 13 g. table 3: dose titration guideline serum phosphorus sevelamer hydrochloride tablets dose >5.5 mg/dl increase 1 tablet per meal at 2-week intervals 3.5 to 5.5 mg/dl maintain current dose <3.5 mg/dl decrease 1 tablet per meal starting dose is one or two 800 mg or two to four 400 mg tablets three times per day with meals. ( 2 ) adjust by one tablet per meal in two-week intervals as needed to obtain serum phosphorus target (3.5 to 5.5 mg/dl). ( 2 )

reflect the rates observed in practice. 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-control 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, most 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. patients on peritoneal dialysis should be closely monitored to ensure the reliable use of appropriate aseptic technique with the prompt recognition and management of any signs and symptoms associated with peritonitis. 6.2 postmarketing experience the following adverse reactions have been identified during postapproval use of sevelamer hydrochloride: 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. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or to establish a causal relationship to drug exposure.

that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer hydrochloride ciprofloxacin mycophenolate mofetil dosing recommendations take at least 2 hours before or 6 hours after sevelamer take at least 2 hours before sevelamer. when clinically significant drug interactions are expected, separate the timing of administration and 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 binds ciprofloxacin and mycophenolate mofetil; dose these drugs separately from sevelamer hydrochloride tablets. ( 7 )

times the maximum clinical trial dose based on 60 kg body weight). 8.2 lactation risk summary sevelamer hydrochloride is not absorbed systemically by the mother following oral administration and breastfeeding is not expected to result in exposure of the child to sevelamer hydrochloride. clinical considerations sevelamer hydrochloride may decrease serum levels of fat soluble vitamins and folic acid in lactating women [see clinical pharmacology ( 12.2 )] . consider supplementing with these vitamins. 8.4 pediatric use the safety and efficacy of sevelamer hydrochloride has not been established in pediatric patients. 8.5 geriatric use clinical studies of sevelamer hydrochloride 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.

ial dose based on 60 kg body weight).

eclined by 15% to 31%. this effect is observed after 2 weeks. 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 g 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 g 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 g 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 auc0-12 h by 36% and 26%, respectively. sevelamer carbonate or sevelamer hydrochloride did not alter the pharmacokinetics of a single dose 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 (e.g., graft rejection). the possibility of an interaction cannot be excluded with these drugs.

atric patients decreased the mean mpa c max and auc0-12 h by 36% and 26%, respectively. sevelamer carbonate or sevelamer hydrochloride did not alter the pharmacokinetics of a single dose 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 (e.g., 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).

sphate-binder washout period received sevelamer hydrochloride and active control for eight weeks each in random order. 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 1 capsule or tablet per meal (3 per day) to control serum phosphorus, the dose of active control could also be altered to attain phosphate control. both treatments significantly decreased mean serum phosphorus by about 2 mg/dl (table 5). table 5: mean serum phosphorus (mg/dl) at baseline and endpoint sevelamer hydrochloride tablets (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) *p<0.0001, within treatment group comparison the distribution of responses is shown in figure 2. 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 2: 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 0.0 to 12.6 g). 14.2 active-control, parallel study 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). the two treatments produced similar decreases in serum phosphorus. at week 52, using last observation carried forward, sevelamer hydrochloride and active control both significantly decreased mean serum phosphorus (table 6). table 6: mean serum phosphorus (mg/dl) and ion product at baseline and change from baseline to end of treatment sevelamer hydrochloride tablets (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 3, 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 3. 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). 14.3 active-control, parallel study 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). 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. 02 03