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1. Indications And Usage
Sevelamer hydrochloride tablets are indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis. The safety and efficacy of sevelamer hydrochloride tablets in CKD patients who are not on dialysis have not been studied.
2. Dosage And Administration
Patients Not Taking a Phosphate Binder. The recommended starting dose of sevelamer hydrochloride tablets is 800 to 1600 mg, which can be administered as one or two 800 mg sevelamer hydrochloride tablets or two to four 400 mg sevelamer hydrochloride tablets, with meals based on serum phosphorus level. Table 1 provides recommended starting doses of sevelamer hydrochloride tablets for patients not taking a phosphate binder. Table 1. Starting Dose for Dialysis Patients Not Taking a Phosphate Binder Serum PhosphorusSevelamer Hydrochloride Tablets 800 mgSevelamer Hydrochloride Tablets 400 mg> 5.5 and < 7.5 mg/dL1 tablet three times daily with meals2 tablets three times daily with meals≥ 7.5 and < 9 mg/dL2 tablets three times daily with meals3 tablets three times daily with meals≥ 9 mg/dL2 tablets three times daily with meals4 tablets three times daily with mealsPatients Switching From Calcium Acetate. In a study in 84 CKD patients on hemodialysis, 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 TabletsCalcium Acetate 667 mg (Tablets per meal)Sevelamer Hydrochloride Tablets 800 mg(Tablets per meal)Sevelamer Hydrochloride Tablets 400 mg(Tablets per meal)1 tablet1 tablet2 tablets2 tablets2 tablets3 tablets3 tablets3 tablets5 tabletsDose Titration for All Patients Taking Sevelamer Hydrochloride Tablets. Dosage should be adjusted based on the serum phosphorus concentration with a goal of lowering serum phosphorus to 5.5 mg/dL or less. The dose may be increased or decreased 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 mg/dL or less was approximately three sevelamer hydrochloride 800 mg tablets per meal. The maximum average daily sevelamer hydrochloride tablets dose studied was 13 grams. Table 3. Dose Titration GuidelineSerum 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
3. Dosage Forms And Strengths
800 mg and 400 mg Tablets.
Sevelamer hydrochloride is contraindicated in patients with bowel obstruction.Sevelamer hydrochloride tablets are contraindicated in patients with known hypersensitivity to sevelamer hydrochloride or to any of the excipients.
5.1 Gastrointestinal Adverse 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 hydrochloride clinical studies.
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.
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.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 one hundred and forty-three 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 post-approval use of sevelamer hydrochloride: 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.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.
7. Drug Interactions
There are no empirical data on avoiding drug interactions between sevelamer hydrochloride 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 4. Sevelamer Drug InteractionsOral drugs for which sevelamer did not alter the pharmacokinetics when administered concomitantlyDigoxinEnalaprilIronMetoprololWarfarinOral drugs that have demonstrated interaction with sevelamer and are to be dosed separately from sevelamer hydrochlorideDosing RecommendationsCiprofloxacinTake at least 2 hours before or 6 hours after sevelamerMycophenolate mofetilTake at least 2 hours before sevelamer
Pregnancy Category C: The effect of sevelamer hydrochloride on the absorption of vitamins and other nutrients has not been studied in pregnant women. Requirements for vitamins and other nutrients are increased in pregnancy. In pregnant rats given doses 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 pregnant rabbits given oral doses of sevelamer hydrochloride by gavage during organogenesis, an increase of early resorptions occurred. [See NONCLINICAL TOXICOLOGY (13.1)]
8.2 Labor And Delivery
No sevelamer hydrochloride treatment-related effects on labor and delivery were seen in animal studies. The effects of sevelamer hydrochloride on labor and delivery in humans are not known. [See NONCLINICAL TOXICOLOGY (13.1)]
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.
Sevelamer hydrochloride has been given to normal healthy volunteers in doses of up to 14 grams per day for eight days with no adverse effects. Sevelamer hydrochloride has been given in average doses up to 13 grams per day to hemodialysis patients. There are no reports of overdosage with sevelamer hydrochloride in patients. Since sevelamer hydrochloride is not absorbed, the risk of systemic toxicity is low.
The active ingredient in Sevelamer Hydrochloride Tablets is sevelamer hydrochloride, a polymeric amine that binds phosphate and is meant for oral administration. Sevelamer hydrochloride is poly(allylamine hydrochloride) crosslinked with epichlorohydrin in which forty percent of the amines are protonated. It is known chemically as poly(allylamine-co-N,N'-diallyl-1,3-diamino-2-hydroxypropane) hydrochloride. Sevelamer hydrochloride is hydrophilic, but insoluble in water. The structure is represented in Figure 1.Figure 1. Chemical Structure of Sevelamer Hydrochloridea, b = number of primary amine groups a + b = 9 c = number of crosslinking groups c = 1 n = fraction of protonated amines n = 0.4 m = large number to indicate extended polymer network The primary amine groups shown in the structure are derived directly from poly(allylamine hydrochloride). The crosslinking groups consist of two secondary amine groups derived from poly(allylamine hydrochloride) and one molecule of epichlorohydrin.Sevelamer Hydrochloride Tablets: Sevelamer HydrochlorideTablets: Each film-coated tablet of sevelamer hydrochloride contains either 800 mg or 400 mg of sevelamer hydrochloride on an anhydrous basis. The inactive ingredients are colloidal silicon dioxide, corn starch, diacetylated monoglycerides, hypromellose, lactose monohydrate, mannitol, talc and zinc stearate. The imprinting ink for sevelamer hydrochloride tablets has the following components: black iron oxide, butyl alcohol, isopropyl alcohol, propylene glycol, ammonium hydroxide and shellac.
12. Clinical Pharmacology
Patients with chronic kidney disease (CKD) on dialysis retain phosphorus and can develop hyperphosphatemia. High serum phosphorus can precipitate serum calcium resulting in ectopic calcification. When the product of serum calcium and phosphorus concentrations (Ca × P) exceeds 55 mg2/dL2, there is an increased risk that ectopic calcification will occur. Hyperphosphatemia plays a role in the development of secondary hyperparathyroidism in renal insufficiency. Treatment of hyperphosphatemia includes reduction in dietary intake of phosphate, inhibition of intestinal phosphate absorption with phosphate binders, and removal of phosphate with dialysis. Sevelamer hydrochloride taken with meals has been shown to decrease serum phosphorus concentrations in patients with CKD who are on dialysis.
12.1 Mechanism Of Action
Sevelamer hydrochloride tablets contain sevelamer hydrochloride, a non-absorbed binding crosslinked polymer. 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 dietary tract and decreasing absorption, sevelamer hydrochloride lowers the phosphate concentration in the serum.
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.
A mass balance study using 14C-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 InteractionsIn vivoSevelamer 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.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 a single dose 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.
13.1 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). 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 less than 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).
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 Washout8.48Endpoint6.45.9Change 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 TabletsActive-Control(N=94)(N=98)Phosphorus Baseline 7.57.3Change from Baseline at Endpoint -2.1-1.8Ca x Phosphorus Ion Product Baseline70.568.4Change from Baseline at Endpoint-19.4-14.2Sixty-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 TreatmentAverage 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, 400 mg, are supplied as off-white to pale yellow, oval shaped, biconvex film coated tablets, imprinted with ‘G446’ on one side and plain on the other side and are supplied as follows: Bottle of 30 tablets: NDC 68462-446-30Bottle of 360 tablets: NDC 68462-446-26 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: Bottle of 30 tablets: NDC 68462-447-30Bottle of 180 tablets: NDC 68462-447-18Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].Do not use Sevelamer Hydrochloride Tablets after the expiration date on the bottle. Protect from moisture.
17 Patient Counseling Information
Dosing RecommendationsThe prescriber should inform patients to take sevelamer hydrochloride tablets with meals and adhere to their prescribed diets. Instructions should be given on concomitant medications that should be dosed apart from sevelamer hydrochloride tablets.Adverse ReactionsSevelamer hydrochloride tablets may cause constipation that if left untreated, may lead to severe complications. Patients should be cautioned to report new onset or worsening of existing constipation promptly to their physician. Manufactured by:Glenmark Pharmaceuticals Ltd.Plot No. 2, Phase-2, Pharma Zone SEZPithampur, Dist.- DharMadhya Pradesh 454 775, IndiaManufactured for:Glenmark Pharmaceuticals Inc., USAMahwah, NJ 07430Questions? 1(888)721-7115www.glenmarkpharma.com/usaApril 2018
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