Sevelamer Hydrochloride: Package Insert and Label Information (Page 2 of 2)

12.2 Pharmacodynamics

In addition to effects on serum phosphate levels, sevelamer hydrochloride has been shown to bind bile acids in vitro and in vivo in experimental animal models. Bile acid binding by ion exchange resins is a well-established method of lowering blood cholesterol. 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%. 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 AUC_{0 to 12h} 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.

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, 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 hydrochloride to lower serum phosphorus in CKD patients on dialysis was demonstrated in six clinical trials: one double-blind placebo-controlled 2-week study (sevelamer hydrochloride N=24); two open-label uncontrolled 8-week studies (sevelamer hydrochloride N=220) and three active-controlled open-label studies with treatment durations of 8 to 52 weeks (sevelamer hydrochloride N=256). Three of the active-controlled studies are described here. One is a crossover study with two 8-week periods comparing sevelamer hydrochloride to an active control. The second is a 52-week parallel study comparing sevelamer hydrochloride with active control. The third is a 12-week parallel study comparing sevelamer hydrochloride and active-control in peritoneal dialysis patients.

14.1 Active-Control, Cross-Over Study in Hemodialysis Patients

Eighty-four CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus >6 mg/dL) following a two-week phosphate-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
Endpoint	6.4	5.9
Change from Baseline at Endpoint (95% Confidence Interval)	-2* (-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 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	Active-Control
	(N=94)	(N=98)
Phosphorus Baseline	7.5	7.3
Change from Baseline at Endpoint	-2.1	-1.8
Ca × 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 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.

16. HOW SUPPLIED/STORAGE AND HANDLING

Sevelamer Hydrochloride Tablets, 800 mg are supplied as off-white to pale yellow, modified capsule shaped, biconvex film-coated tablets, imprinted with ‘G447’ on one side and plain on the other side and are supplied as follows:

Bottles of 180 tablets with child-resistant closures: NDC 72603-148-01

Storage: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Do not use sevelamer hydrochloride tablets after the expiration date on the bottle.

Dispense in a tight container.

Protect from moisture and store in a dry place. Keep tablets in original/pharmacy container.

17 PATIENT COUNSELING INFORMATION

Advise patients to take sevelamer hydrochloride tablets with meals and adhere to their prescribed diets.

Provide instructions on concomitant medications that should be dosed apart from sevelamer hydrochloride tablets.

Advise patients to report new onset or worsening of existing constipation or bloody stools promptly to their healthcare provider [see Warnings and Precautions (5.1)].

Manufactured for:

Northstar Rx LLC

Memphis, TN 38141.

Manufactured by:

Glenmark Pharmaceuticals Limited
Pithampur, Madhya Pradesh 454775, India

May 2023

Package/Label Display Panel

NDC 72603-148-01

Sevelamer Hydrochloride Tablets

800 mg

Bottle Label

SEVELAMER HYDROCHLORIDE sevelamer hydrochloride tablet, film coated

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:72603-148 Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SEVELAMER HYDROCHLORIDE (SEVELAMER) SEVELAMER HYDROCHLORIDE 800 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE TALC ZINC STEARATE DIACETYLATED MONOGLYCERIDES FERROSOFERRIC OXIDE HYPROMELLOSE, UNSPECIFIED MANNITOL LACTOSE MONOHYDRATE HYPROMELLOSE 2910 (50 MPA.S) BUTYL ALCOHOL ISOPROPYL ALCOHOL PROPYLENE GLYCOL AMMONIA STARCH, CORN SHELLAC

Product Characteristics Color WHITE (off-white to pale yellow) Score no score Shape OVAL Size 19mm Flavor Imprint Code G447 Contains

Packaging # Item Code Package Description Multilevel Packaging 1 NDC:72603-148-01 180 TABLET, FILM COATED in 1 BOTTLE None

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA204724 05/23/2023

Labeler — NorthStar RxLLC (830546433)

Establishment
Name	Address	ID/FEI	Operations
Glenmark Pharmaceuticals Limited		862603186	ANALYSIS (72603-148), MANUFACTURE (72603-148)

Revised: 05/2023 NorthStar RxLLC