Renvela

Renvela

sevelamer

Manufacturer:

sanofi-aventis

Distributor:

DKSH
Full Prescribing Info
Contents
Sevelamer carbonate.
Description
Renvela contains the following excipients: Hypromellose, diacetylated monoglycerides, microcrystalline cellulose, sodium chloride and zinc stearate. The tablet imprint contains black iron oxide ink.
The active ingredient of Renvela, sevelamer carbonate, is 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 2 salts, the polymer itself, the active moiety, is the same.
Renvela (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.
Action
Pharmacology: Patients with chronic kidney disease (CKD) retain phosphorus and can develop hyperphosphatemia. When the product of serum calcium and phosphorus concentrations (Ca x P) exceeds 4.44 mmol2/L2, 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 carbonate taken with meals has been shown to control serum phosphorus concentrations in patients with CKD who are on dialysis.
Mechanism of Action: Renvela contains sevelamer carbonate, a non-absorbed phosphate-binding crosslinked polymer, free of metal and calcium. It contains multiple amines separated by 1 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 carbonate lowers the phosphate concentration in the serum.
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 eg, A, D and K. In clinical trials of sevelamer hydrochloride, both the mean total and low-density lipoprotein (LDL)-cholesterol declined by 15-31%. This effect is observed after 2 weeks. Triglycerides, high-density lipoprotein (HDL)-cholesterol and albumin did not change.
Pharmacokinetics: 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.
Toxicology: Nonclinical Toxicology: 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 sevelamer hydrochloride 0.5, 1.5 or 4.5 g/kg/day 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).
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 1 clinical trial used sevelamer carbonate. The sevelamer hydrochloride studies include 1 double-blind, placebo-controlled 2-week study (sevelamer N=24); 2 open-label, uncontrolled, 8-week studies (sevelamer N=220) and 3 active-controlled open-label studies with treatment durations of 8-52 weeks (sevelamer N=256). The sevelamer carbonate study was a double-blind, active-controlled, cross-over study in hemodialysis patients with two 8-week treatment periods (N=79). Four of the active-controlled studies are described as follows (1 sevelamer carbonate and 3 sevelamer hydrochloride studies).
Crossover Study of Sevelamer Carbonate (Renvela) 800-mg Tablets and Sevelamer Hydrochloride (Renagel) 800-mg Tablets: Stage 5 CKD patients on hemodialysis were entered into a 5-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 8 weeks each, with no intervening washout. Study dose during the crossover period was determined based on the sevelamer hydrochloride dose during the run-in period on a gram per gram basis. The phosphate levels at the end of each of the 2 crossover periods were similar. Average actual daily dose was 6 g/day for both treatments. Thirty-nine of those completing the crossover portion of the study were entered into a 2-week washout period during which patients were instructed not to take any phosphate binders; this confirmed the activity of sevelamer in this study.
Sevelamer Hydrochloride Versus Active-Control, Crossover Study in Hemodialysis Patients: Eighty-four CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus >1.94 mmol/L) following a 2-week phosphate binder washout period were randomized in a crossover design to receive in random order sevelamer hydrochloride and active-control for 8 weeks each. Treatment periods were separated by a 2-week phosphate binder washout period. Patients started on treatment 3 times per day with meals. Over each 8-week treatment period, at 3 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 phosphate control. Both treatments significantly decreased mean serum phosphorus by about 0.65 mmol/L. (See Table 1 and Figure 1.)

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

Sevelamer Hydrochloride Versus Active-Control in Hemodialysis Patients: Two hundred CKD patients on hemodialysis who were hyperphosphatemic (serum phosphorus >1.78 mmol/L) following a 2-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. (See Table 2.)

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Sixty-one percent of sevelamer hydrochloride patients and 73% of the control patients completed the full 52 weeks of treatment.
Figure 2, a plot of phosphorus change from baseline for the completers, illustrates the durability of response who are able to remain on treatment. (See Figure 2.)

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Sevelamer Hydrochloride Versus Active-Control in Peritoneal Dialysis Patients: One hundred and forty-three patients on peritoneal dialysis who were hyperphosphatemic (serum phosphorus >1.78 mmol/L) following a 2-week phosphate binder washout period were randomized to receive Renagel (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 0.8-14.3 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 (-0.52 mmol/L from baseline of 2.42 mmol/L), similar to the active-control.
An Open-Label, Dose Titration Study of Sevelamer Carbonate Tablets Dosed 3 Times a Day in Hyperphosphatemic Chronic Kidney Disease (CKD) Patients Not on Dialysis: An open-label, single-arm, dose titration study was conducted with sevelamer carbonate tablets in hyperphosphatemic CKD patients not on dialysis. The study included a washout period for those on binder, an 8-week treatment period followed by a post-treatment washout period for all patients. All patients were supplemented with a daily dose of native vitamin D 400 IU to be taken separately from the dose of sevelamer carbonate. Sevelamer carbonate tablets were dosed 3 times daily and mean serum phosphorus level decreased from 2 mmol/L at baseline to 1.6 mmol/L at the end of treatment. The decrease in serum phosphorus level was statistically significant (mean 0.5 mmol/L, p<0.001).
During the post-treatment washout period, there was a statistically significant increase in mean serum phosphorus levels of 0.6 mmol/L (p<0.001) confirming the efficacy of sevelamer carbonate in hyperphosphatemic CKD patients not on dialysis.
Indications/Uses
Control of hyperphosphataemia in adult patients receiving hemodialysis or peritoneal dialysis, and with chronic kidney disease not on dialysis with serum phosphorus ≥1.78 mmol/L.
Renvela should be used within the context of a multiple therapeutic approach, which could include calcium supplement, 1,25-dihydroxyvitamin D3 or 1 of its analogues to control the development of renal bone disease.
Dosage/Direction for Use
Starting Dose: One or two 800-mg tab 3 times daily with meals.
Because of the rapid disintegration of the carbonate salt tablet and its rapid reaction with the hydrochloric acid in the stomach, the dosing of Renvela is anticipated to be similar to that of the hydrochloride salt.
Patients Not Taking a Phosphate Binder: Recommended Starting Dose: 800-1600 mg, which can be administered as 1 or 2 Renvela 800-mg tablets, with meals based on serum phosphorus level. The table as follows provides the recommended starting doses of Renvela for patients not taking a phosphate binder. (See Table 3.)

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Patients Switching From Sevelamer Hydrochloride: For patients switching from sevelamer hydrochloride, sevelamer carbonate should be prescribed on a gram per gram basis. Further titration to the desired phosphate levels may be necessary. The highest daily dose of sevelamer carbonate studied was 14 g in chronic kidney disease (CKD) patients on dialysis.
Patients 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 and calcium acetate. Table 4 gives recommended starting doses of Renvela based on a patient’s current calcium acetate dose. (See Table 4.)

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Dose Titration for All Patients Taking Renvela: The dose should be increased or decreased by 1 tab/meal at 2-week intervals, as necessary, with the goal of controlling serum phosphorus within the target range of 1.13-1.78 mmol/L.
Overdosage
Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been given to normal healthy volunteers in doses of up to 14 g/day for 8 days with no adverse effects. In chronic kidney disease patients on dialysis, the maximum dose studied was sevelamer carbonate 14 g and sevelamer hydrochloride 13 g. 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.
Contraindications
Hypophosphatemia or bowel obstruction.
Special Precautions
Caution in Patients with Gastrointestinal Disorders: The safety of Renvela has not been established in patients with dysphagia, swallowing disorders, severe gastrointestinal motility disorders including severe constipation or major gastrointestinal tract surgery. Use with caution in patients with these gastrointestinal disorders.
Monitor Serum Chemistries: Bicarbonate and chloride levels should be monitored.
Monitor for Reduced 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 6-10 times the recommended human dose. In short-term clinical trials, there was no evidence of reduction in serum levels of vitamins. However, in a 1-year clinical trial, 25-hydroxyvitamin D (normal range 24.96-137.28 nmol/L) fell from 97.34±54.91 nmol/L to 84.86±54.91 nmol/L (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. It is recommended that chronic kidney disease (CKD) patients not on dialysis are given vitamin D supplements (approximately native vitamin D 400 IU daily) which can be part of a multivitamin preparation to be taken apart from their dose of Renvela. In patients undergoing peritoneal dialysis, additional monitoring of fat-soluble vitamins and folic acid is recommended, since vitamin A, D, E and K levels were not measured in a clinical study in these patients.
Use in pregnancy: 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 Pharmacology: Toxicology under Actions.)
Labor and Delivery: No sevelamer hydrochloride treatment-related effects on labor and delivery were seen in animal studies. The effects of sevelamer carbonate on labor and delivery on humans is unknown. (See Pharmacology: Toxicology under Actions.)
Use in children: The safety and efficacy of Renvela has not been established in pediatric patients. Renvela is not recommended for use in children below 18 years.
Use in the elderly: Clinical studies of Renvela did not include sufficient numbers of subjects aged 65 years and older 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.
Use In Pregnancy & Lactation
Use in pregnancy: 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 Pharmacology: Toxicology under Actions.)
Labor and Delivery: No sevelamer hydrochloride treatment-related effects on labor and delivery were seen in animal studies. The effects of sevelamer carbonate on labor and delivery on humans is unknown. (See Pharmacology: Toxicology under Actions.)
Adverse Reactions
Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug can not be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The safety of sevelamer (as either carbonate and hydrochloride salts) has been investigated in numerous clinical trials involving a total of 969 hemodialysis patients with treatment duration of 4-50 weeks (724 patients treated with sevelamer hydrochloride and 245 with sevelamer carbonate), 97 peritoneal dialysis patients with treatment duration of 12 weeks (all treated with sevelamer hydrochloride) and 128 patients with chronic kidney disease (CKD) not on dialysis with treatment duration of 8-12 weeks (79 patients treated with sevelamer hydrochloride and 49 with sevelamer carbonate).
The most frequently occurring (≥5% of patients) undesirable effects possibly or probably related to sevelamer were all in the gastrointestinal disorders system organ class. Most of these adverse reactions were mild to moderate in intensity. Data possibly or probably related to sevelamer from these studies are listed by frequency as follows. The reporting rate is classified as: Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1,000, <1/100); rare (≥1/10,000, <1/1,000); very rare (<1/10,000); not known (cannot be estimated from available data).
Gastrointestinal Disorders: Very Common: Nausea, vomiting, upper abdominal pain, constipation. Common: Diarrhea, dyspepsia, flatulence, abdominal pain.
Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of sevelamer hydrochloride, which has the same active moiety as sevelamer carbonate: 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. Patients should be cautioned to report new onset or worsening of existing constipation promptly to their physician.
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.
Drug Interactions
Sevelamer carbonate has been studied in 2 human drug-drug interaction studies. In interaction studies in healthy volunteers, sevelamer carbonate did not affect the bioavailability of either warfarin or digoxin. Sevelamer hydrochloride, which contains the same active moiety as sevelamer carbonate, has been studied in human drug-drug interaction studies with ciprofloxacin, digoxin, warfarin, enalapril, metoprolol and iron.
Ciprofloxacin: In a study of 15 healthy subjects, a co-administered single dose of sevelamer hydrochloride 2.8 g decreased the bioavailability of ciprofloxacin by approximately 50%.
Digoxin: In 19 healthy subjects receiving sevelamer hydrochloride 2.4 g 3 times daily with meals for 2 days, sevelamer did not alter the pharmacokinetics of a single dose of digoxin.
Warfarin: In 14 healthy subjects receiving sevelamer hydrochloride 2.4 g 3 times daily with meals for 2 days, sevelamer did not alter the pharmacokinetics of a single dose of warfarin.
Enalapril: In 28 healthy subjects, sevelamer hydrochloride 2.4 g single dose did not alter the pharmacokinetics of a single dose of enalapril.
Metoprolol: In 31 healthy subjects, a single dose of sevelamer hydrochloride 2.4 g did not alter the pharmacokinetics of a single dose of metoprolol.
Iron: In 23 healthy subjects, a single dose of sevelamer hydrochloride 2.8 g did not alter the absorption of a single oral dose of iron as exsiccated ferrous sulfate 200-mg tablet.
Other Concomitant Drug Therapy: There are no empirical data on avoiding drug interactions between Renvela and most concomitant drugs. During post-marketing experience, very rare cases of increased thyroid-stimulating hormone (TSH) levels have been reported in patients co-administered sevelamer hydrochloride and levothyroxine. Closer monitoring of TSH levels is therefore recommended in patients receiving both medications. When administering an oral medication where a reduction in the bioavailability of that medication would have a clinically significant effect on its safety or efficacy, the drug should be administered at least 1 hr before or 3 hrs after Renvela, or the physician should consider monitoring blood levels of the drug. Patients taking antiarrhythmic medications for the control of arrhythmias and antiseizure medications for the control of seizure disorders were excluded from the clinical trials. Special precautions should be taken when prescribing Renvela to patients also taking these medications.
Storage
Store at 30°C (86°F). Excursions permitted to 25°-40°C (77°-104°F). Protect from moisture.
ATC Classification
V03AE02 - sevelamer ; Belongs to the class of drugs used in the treatment of hyperkalemia and hyperphosphatemia.
Presentation/Packing
FC tab (white, oval, compressed, imprinted with "RENVELA 800") 800 mg x 180's.
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