SEVELAMER CARBONATE- s evelamer carbonate tablet, film coated

Marlex Pharmaceuticals Inc

----------

HIGHLIGHT S OF PRESCRIBING INFORMAT ION

T hese hig hlig hts do no t include all the info rmatio n needed to use SEVELAMER CARBONAT E T ABLET S safely
and effectively. See full prescribing info rmatio n fo r SEVELAMER CARBONAT E T ABLET S.
SEVELAMER CARBONAT E tablets, fo r o ral use
Initial U.S. Appro val: 20 0 0
RECENT MAJOR CHANGES

Indications and Usage (1) 11/2016

Dosage and Administration (2) 11/2016
Contraindications (4) 03/2016

INDICAT IONS AND USAGE

Sevelamer carbonate tablets are a phosphate binder indicated for the control of serum phosphorus in adults with
chronic kidney disease on dialysis. (1)

DOSAGE AND ADMINIST RAT ION

Starting dose of sevelamer carbonate tablets is 0.8 or 1.6 grams administered orally three times per day with meals
based on serum phosphorus levels for adult patients (2.1)
Titrate by 0.8 g per meal in two week intervals for adult patients as needed to obtain serum phosphorus target. (2.1)

DOSAGE FORMS AND ST RENGT HS

Tablets: 800 mg (3)

CONT RAINDICAT IONS

Bowel obstruction. (4)
Known hypersensitivity to sevelamer carbonate, sevelamer hydrochloride, or any of the excipients. (4)

WARNINGS AND PRECAUT IONS

Serious cases of dysphagia, bowel obstruction and perforation have been associated with sevelamer use, some
requiring hospitalization and surgery. (5.1)

ADVERSE REACT IONS

Most of the safety experience is with sevelamer tablets and sevelamer hydrochloride. In long-term studies with
sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, the most common adverse
events included: vomiting (22%), nausea (20%), diarrhea (19%), dyspepsia (16%), abdominal pain
(9%), flatulence (8%) and constipation (8%). (6.1)

T o repo rt SUSPECT ED ADVERSE REACT IONS, co ntact FDA at 1-8 0 0 -FDA-10 8 8 o r www.fda.g o v/medwatch
DRUG INT ERACT IONS
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)

Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets and Renvela
(sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing exclusivity rights, these drug
products are not labeled with that pediatric information.
See 17 fo r PAT IENT COUNSELING INFORMAT ION.
Revised: 5/20 18
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
2 DOSAGE AND ADMINISTRATION
2.1 General Dos ing Information
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Gas trointes tinal Advers e Events
5.2 Reductions in Vitamins D, E, K (clotting factors ) and Folic Acid Levels
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience
6.2 Pos tmarketing Experience
7 DRUG INTERACTIONS
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.2 Lactation
8.4 Pediatric Us e
8.5 Geriatric Us e
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanis m of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenes is , Mutagenes is , Impairment of Fertility
14 CLINICAL STUDIES
14.1 Cros s -Over Study of Sevelamer Carbonate 800 mg Tablets and Sevelamer
Hydrochloride (Renagel® ) 800 mg Tablets
14.2 Cros s -Over Study of Sevelamer Carbonate Powder and Sevelamer Hydrochloride
(Renagel® ) Tablets
14.4 Sevelamer Hydrochloride Vers us Active-Control, Cros s -Over Study in
Hemodialys is Patients
14.5 Sevelamer Hydrochloride Vers us Active-Control in Hemodialys is Patients
14.6 Sevelamer Hydrochloride Vers us Active-Control in Peritoneal Dialys is Patients
14.7 Once a Day Vers us Three Times a Day Dos ing
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
* Sections or subsections omitted from the full prescribing information are not listed.

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Sevelamer carbonate tablets are indicated for the control of serum phosphorus in adults with chronic
kidney disease (CKD) on dialysis.
Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets
and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing
exclusivity rights, these drug products are not labeled with that pediatric information.

2 DOSAGE AND ADMINISTRATION

2.1 General Dos ing Information

Starting Dose for Adult Patients Not Taking a Phosphate Binder. The recommended starting dose of
sevelamer carbonate tablets is 0.8 to 1.6 g taken orally with meals based on serum phosphorus level.
Table 1 provides recommended starting doses of sevelamer carbonate tablets for adult patients not
taking a phosphate binder.

Table 1. Starting Dos e for Adult Dialys is Patients Not Taking a Phos phate Binder
Serum Phos phorus Sevelamer Carbonate
> 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 Tablets. Titrate the sevelamer carbonate
tablets 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.
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
tablets based on a patient’s current calcium acetate dose.

Table 3. Starting Dos e for Dialys is Patients Switching From Calcium Acetate to Sevelamer
Carbonate
Calcium Acetate 667 mg (Tablets per meal) Sevelamer Carbonate
1 tablet 0.8 g
2 tablets 1.6 g
3 tablets 2.4 g

Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets
and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing
exclusivity rights, these drug products are not labeled with that pediatric information.

3 DOSAGE FORMS AND STRENGTHS

Sevelamer carbonate tablets, 800 mg, are supplied as off-white to light yellow colored, oval shaped,
biconvex, film-coated tablet, imprinted “AN058” with black ink on one side and plain on the other side.

4 CONTRAINDICATIONS
Sevelamer carbonate is contraindicated in patients with bowel obstruction.
Sevelamer carbonate tablets are contraindicated in patients with known hypersensitivity to sevelamer
carbonate, sevelamer hydrochloride, or to any of the excipients.
5 WARNINGS AND PRECAUTIONS

5.1 Gas trointes tinal Advers e Events

Cases of dysphagia and esophageal tablet retention have been reported in association with use of the
tablet formulation of sevelamer, some requiring hospitalization and intervention. Consider using
sevelamer suspension in patients with a history of swallowing disorders.
Cases of bowel obstruction and perforation have also been reported with sevelamer use.
Patients with dysphagia, swallowing disorders, severe gastrointestinal (GI) motility disorders including
severe constipation, or major GI tract surgery were not included in the sevelamer carbonate clinical
studies.

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.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

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.
There are limited clinical trial data on the safety of sevelamer carbonate. However, because it contains
the same active ingredient as the hydrochloride salt, the adverse 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 Pos tmarketing 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 post-approval use of sevelamer
hydrochloride or sevelamer carbonate: hypersensitivity, pruritus, rash, abdominal pain, 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.

7 DRUG INTERACTIONS
There are no empirical data on avoiding drug interactions between sevelamer carbonate and most
concomitant oral drugs. For oral medication where a reduction in the bioavailability of that medication
would have a clinically significant effect on its safety or efficacy (e.g., cyclosporine, tacrolimus,
levothyroxine), consider separation of the timing of the administration of the two drugs [see Clinical
Pharmacology (12.3)]. The duration of 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
clinical responses and/or blood levels of concomitant drugs that have a narrow therapeutic range.

Table 5. Sevelamer Drug Interactions

Oral drugs for which s evelamer did not alter the pharmacokinetics when adminis tered
concomitantly
Digoxin Enalapril Iron Metoprolol
Warfarin
Oral drugs that have demons trated interaction with s evelamer and are to be dos ed s eparately
from s evelamer carbonate
Dos ing Recommendations
Ciprofloxacin Mycophenolate
Take at least 2 hours before or 6 hours after sevelamer Take at least 2
mofetil
hours before sevelamer

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy
Risk Summary
Sevelamer carbonate is not absorbed systemically following oral administration and maternal use is not
expected to result in fetal exposure to the drug.
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.
Data
Animal Data
In pregnant rats given dietary doses of 0.5, 1.5 or 4.5 g/kg/day of sevelamer hydrochloride during
organogenesis, reduced or irregular ossification of fetal bones, probably due to a reduced absorption
of fat-soluble vitamin D, occurred in mid- and high-dose groups (human equivalent doses approximately
equal to 3-4 times the maximum clinical trial dose of 13 g). In pregnant rabbits given oral doses of 100,
500 or 1000 mg/kg/day of sevelamer hydrochloride by gavage during organogenesis, an increase of
early resorptions occurred in the high-dose group (human equivalent dose 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 Us e
Sevelamer carbonate has not been studied in pediatric patients below 6 years of age.
Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets
and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing
exclusivity rights, these drug products are not labeled with that pediatric information.

8.5 Geriatric Us e
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.

10 OVERDOSAGE
In CKD patients on dialysis, the maximum dose studied was 14 grams of sevelamer carbonate and 13
grams of sevelamer hydrochloride. There are no reports of overdosage with sevelamer carbonate or
sevelamer hydrochloride in patients. Since sevelamer is not absorbed, the risk of systemic toxicity is
low.

11 DESCRIPTION
The active ingredient in sevelamer carbonate tablets is sevelamer carbonate, a polymeric amine that
binds phosphate and is meant for oral administration. It was developed as a pharmaceutical alternative to
sevelamer hydrochloride (Renagel ® ). Sevelamer carbonate is an anion exchange resin, with the same
polymeric structure as sevelamer hydrochloride, in which carbonate replaces chloride as the
counterion. While the counterions differ for the two salts, the polymer itself, the active moiety involved
in phosphate binding, is the same.
Sevelamer carbonate is known chemically as poly(allylamine-co-N,N’-diallyl-1,3-diamino-2-
hydroxypropane) carbonate salt. Sevelamer carbonate is hygroscopic, but insoluble in water. The
structure is represented in Figure 1.
 Fig ure 1. Chemical Structure of Sevelamer Carbonate

a, b = number of primary amine groups a + b = 9 c = number of crosslinking groups c=1

m = large number to indicate extended polymer network
Sevelamer carbonate tablets : Each film-coated tablet of sevelamer carbonate contains 800 mg of
sevelamer carbonate on an anhydrous basis. The inactive ingredients are diacetylated monoglycerides,
hypromellose, microcrystalline cellulose, silicon dioxide and zinc stearate. Imprinting ink contains
ammonium hydroxide, iron oxide black, propylene glycol and shellac.

12 CLINICAL PHARMACOLOGY

12.1 Mechanis m of Action

Sevelamer carbonate tablet contains sevelamer carbonate, a non-absorbed phosphate binding crosslinked
polymer, free of metal and calcium. It contains multiple amines separated by one carbon from the
polymer backbone. These amines exist in a protonated form in the intestine and interact with phosphate
molecules through ionic and hydrogen bonding. By binding phosphate in the gastrointestinal tract and
decreasing absorption, sevelamer carbonate lowers the phosphate concentration in the serum (serum
phosphorus).

12.2 Pharmacodynamics
In addition to effects on serum phosphorus levels, sevelamer hydrochloride has been shown to bind bile
acids in vitro and in vivo in experimental animal models. Because sevelamer binds bile acids, it may
interfere with normal fat absorption and thus may reduce absorption of fat soluble vitamins such as A, D
and K. In clinical trials of sevelamer hydrochloride, both the mean total and LDL cholesterol 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 (2.4-2.8 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.
Co-administered 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 Cmax and AUC0-12h by 36% and 26% respectively.
Sevelamer carbonate or sevelamer hydrochloride did not alter the pharmacokinetics of enalapril,
digoxin, iron, metoprolol and warfarin when co-administered.
During postmarketing experience, cases of increased thyroid stimulating hormone (TSH) levels have
been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Reduction in
concentrations of cyclosporine and tacrolimus leading to dose increases has also been reported in
transplant patients when co-administered with sevelamer hydrochloride without any clinical
consequences (for example, graft rejection). The possibility of an interaction cannot be excluded with
these drugs.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenes is , Mutagenes is , Impairment of Fertility

Standard lifetime carcinogenicity bioassays were conducted in mice and rats. Rats were given
sevelamer hydrochloride by diet at 0.3, 1, or 3 g/kg/day. There was an increased incidence of urinary
bladder transitional cell papilloma in male rats of the high-dose group (human equivalent dose twice the
maximum clinical trial dose of 13 g). Mice received dietary administration of sevelamer hydrochloride
at doses of up to 9 g/kg/day (human equivalent dose 3 times the maximum clinical trial dose). There was
no increased incidence of tumors observed in mice.
In an in vitro mammalian cytogenetic test with metabolic activation, sevelamer hydrochloride caused a
statistically significant increase in the number of structural chromosome aberrations. Sevelamer
hydrochloride was not mutagenic in the Ames bacterial mutation assay.
Sevelamer hydrochloride did not impair the fertility of male or female rats in a dietary administration
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).

14 CLINICAL STUDIES
The ability of sevelamer to control serum phosphorus in CKD patients on dialysis was predominantly
determined from the effects of the hydrochloride salt to bind phosphate. Six clinical trials used
sevelamer hydrochloride and three clinical trials used sevelamer carbonate. The sevelamer
hydrochloride studies include one double-blind, placebo-controlled 2-week study (sevelamer N=24);
two open-label, uncontrolled, 8-week studies (sevelamer N=220) and three active-controlled open-label
studies with treatment durations of 8 to 52 weeks (sevelamer N=256). The sevelamer carbonate studies
include one double-blind, active-controlled, cross-over study with two 8-week treatment periods using
sevelamer carbonate tablets (N=79), one open-label, active-controlled, cross-over study with two 4-
week treatment periods using sevelamer carbonate powder (N=31) and one randomized, parallel, open-
label study using sevelamer carbonate powder (N=144) dosed once daily or sevelamer hydrochloride
tablets (N=73) dosed three times daily for 24 weeks. Six of the active-controlled studies are described
here (three sevelamer carbonate and three sevelamer hydrochloride studies).

14.1 Cros s -Over Study of Sevelamer Carbonate 800 mg Tablets and Sevelamer
®
Hydrochloride (Renagel® ) 800 mg Tablets
Stage 5 CKD patients on hemodialysis were entered into a five-week sevelamer hydrochloride run-in
period and 79 patients received, in random order, sevelamer carbonate 800 mg tablets and sevelamer
hydrochloride 800 mg tablets for eight 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 both treatments. Thirty-nine of
those completing the cross-over portion of the study were entered into a two-week washout period
during which patients were instructed not to take any phosphate binders; this confirmed the activity of
sevelamer in this study.

14.2 Cros s -Over Study of Sevelamer Carbonate Powder and Sevelamer Hydrochloride
(Renagel® ) 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 6.0 g/day divided among meals for sevelamer carbonate powder
and 6.4 g/day divided among meals for sevelamer hydrochloride tablets.
Pediatric use information is approved for Genzyme Corporation’s Renvela (sevelamer carbonate) tablets
and Renvela (sevelamer carbonate) for oral suspension. However, due to Genzyme Corporation’s marketing
exclusivity rights, these drug products are not labeled with that pediatric information.

14.4 Sevelamer Hydrochloride Vers us Active-Control, Cros s -Over Study in Hemodialys is

Patients
Eighty-four CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus > 6
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 Phos phorus (mg/dL) at Bas eline and Endpoint
Sevelamer Active
Hydrochloride Control
(N=81) (N=83)
Baseline at End of Washout 8.4 8
Endpoint 6.4 5.9
Change from Baseline at Endpoint (95% -2* -2.1*
Confidence Interval) (-2.5, -1.5) (-2.6, -1.7)
*p<0.0001, within treatment group comparison

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.
Fig ure 3. Percentag e of patients (Y-axis ) attaining a phos phorus reduction from bas eline (mg /dL) At leas t
as g reat 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).

14.5 Sevelamer Hydrochloride Vers us Active-Control in Hemodialys is 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 Phos phorus (mg/dL) and Ion Product at Bas eline and Change
from Bas eline to End of Treatment
Sevelamer HCl Active-Control
(N=94) (N=98)
Phosphorus Baseline 7.5 7.3
Change from Baseline at Endpoint -2.1 -1.8
Ca x Phosphorus Ion Product Baseline 70.5 68.4
Change from Baseline at Endpoint -19.4 -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.
 Fig ure 4 . Mean Phos phorus Chang e from Bas eline 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).

14.6 Sevelamer Hydrochloride Vers us Active-Control in Peritoneal Dialys is 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 a Day Vers us Three Times a Day Dos ing

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

Sevelamer carbonate tablets, 800 mg, are supplied as off-white to light yellow colored, oval shaped,
biconvex, film-coated tablet, imprinted with “AN058” with black ink on one side and plain on the other
side. They are available as follows:
Bottle of 270 Tablets: NDC 10135-0660-68
Storage: Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F)
[see USP Controlled Room Temperature]. Protect from moisture.

17 PATIENT COUNSELING INFORMATION

Inform patients to take sevelamer carbonate with meals and adhere to their prescribed diets.
For patients using an oral medication where a reduction in the bioavailability of that medication would
have a clinically significant effect on its safety or efficacy, advise the patient to take the oral medication
at least one hour before or three hours after sevelamer carbonate.
Advise patients to report new onset or worsening of existing constipation promptly to their physician.
Trademarks are the property of their respective owners.
Manufactured for:
Marlex Pharmaceuticals, Inc.
New Castle, DE 19720
Distributed by:
Marlex Pharmaceuticals, Inc.
New Castle, DE 19720
Rev. 05/18AN

PRINCIPAL DISPLAY PANEL

NDC 10135-0660-68
Sevelamer
Carbonate
Tablets
800 mg
270 TABLETS
Rx Only

SEVELAMER CARBONATE
sevelamer carbonate tablet, film coated

Product Information
Prod uct T yp e HUMAN PRESCRIPTIO N DRUG Ite m Cod e (S ource ) NDC:10 135-6 6 0 (NDC:6 516 2-0 58 )

Route of Ad minis tration O RAL

Active Ing redient/Active Moiety

Ing redient Name Basis o f Streng th Streng th
SEVELAMER CARBO NATE (UNII: 9 YCX42I8 IU) (SEVELAMER - UNII:9 41N5DUU5C) SEVELAMER CARBO NATE 8 0 0 mg

Inactive Ing redients

Ing redient Name Streng th
DIACETYLATED MO NO GLYCERIDES (UNII: 5Z1738 6 USF)
HYPRO MELLO SES (UNII: 3NXW29 V3WO )
CELLULO SE, MICRO CRYSTALLINE (UNII: O P1R32D6 1U)
SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)
ZINC STEARATE (UNII: H9 2E6 Q A4FV)
AMMO NIA (UNII: 5138 Q 19 F1X)
FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)
PRO PYLENE GLYCO L (UNII: 6 DC9 Q 16 7V3)
SHELLAC (UNII: 46 N10 7B71O )

Product Characteristics
Color WHITE (o ff-white to light ye llo w) S core no sc o re
S hap e O VAL S iz e 20 mm
Flavor Imp rint Cod e AN0 58
Contains

Packag ing
# Item Co de Packag e Descriptio n Marketing Start Date Marketing End Date
1 NDC:10 135-6 6 0 -6 8 270 in 1 BO TTLE; Type 0 : No t a Co mbina tio n Pro duc t 0 5/0 1/20 18

Marketing Information
Marke ting Cate gory Ap p lication Numb e r or Monograp h Citation Marke ting S tart Date Marke ting End Date
ANDA ANDA20 728 8 0 5/0 1/20 18

Labeler - Marlex Pharmaceuticals Inc (782540215)

Revised: 5/2018 Marlex Pharmaceuticals Inc