Sevelamer (Oral-Local)


VA CLASSIFICATION
Primary: AD900

Commonly used brand name(s): Renagel.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antihyperphosphatemic—

Indications

General considerations
Hyperphosphatemia may occur as a result of phosphorus retention in patients with end-stage renal disease (ESRD). This in turn can lead to ectopic calcification as a result of precipitation of serum calcium, particularly when the product of serum calcium and phosphorus concentrations (Ca × P) exceeds 66. Hyperphosphatemia also contributes to the development of secondary hyperparathyroidism; increased parathyroid hormone (PTH) concentrations are characteristic of patients with chronic renal insufficiency. {01}

Accepted

Hyperphosphatemia (treatment)—Sevelamer is indicated for reduction of serum phosphorus concentrations in patients with ESRD {01}.

Note: Hyperphosphatemia is defined as serum phosphorus concentrations over 6 mg per deciliter (mg/dL) {01}.
Safety and efficacy of sevelamer in the treatment of ESRD patients who are not on hemodialysis have not been established {01}.
Sevelamer treatment has been shown to produce fewer hypercalcemic episodes than produced with calcium acetate treatment {01}.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Solubility
    Hydrophilic, but insoluble in water {01}.

Mechanism of action/Effect:

When sevelamer is taken with meals, it binds with phosphates present in the intestines and inhibits intestinal phosphate absorption, which results in decreased serum phosphorus concentrations {01}.


Other actions/effects:

Sevelamer reduces serum low-density lipoprotein (LDL) and total serum cholesterol concentrations, but does not affect serum triglyceride or high-density lipoprotein (HDL) concentrations {01}.

Absorption:

Not absorbed systemically {01}.


Precautions to Consider

Carcinogenicity

Long-term studies in animals have not been completed. {01}

Mutagenicity

Sevelamer was not found to be mutagenic in the Ames test (bacterial mutation assay); however, sevelamer did cause a statistically significant increase in the number of structural chromosome aberrations in an in vitro mammalian cytogenetics test with metabolic activation. {01}

Pregnancy/Reproduction
Fertility—
Sevelamer did not impair fertility in male or female rats. {01}

Pregnancy—
Adequate and well-controlled studies in humans have not been done. The effect of sevelamer on absorption of vitamins and other nutrients has not been studied in pregnant women. {01} However, in clinical trials, there was no reduction in serum levels of vitamins seen in patients who were supplemented with multivitamins. {01}

Studies in rats at doses of 1.5 and 4.5 grams per kg of body weight (grams/kg) per day (approximately 15 and 45 times, respectively, the recommended human dose based on mg per kg of body weight [mg/kg]) found that sevelamer caused reduced or irregular ossification of fetal bones, probably due to a reduced absorption of fat-soluble vitamin D. Studies in rabbits at a dose of 1 gram/kg per day (approximately 10 times the recommended human dose based on mg/kg) found a slightly increased prenatal mortality due to an increased incidence of early resorptions. {01}

FDA Pregnancy Category C {01}.

Breast-feeding

Since sevelamer is not systemically absorbed, distribution into breast milk is not expected. {01}

Pediatrics

Appropriate studies on the relationship of age to the effects of sevelamer have not been performed in the pediatric population. Safety and efficacy have not been established {01}.


Geriatrics


Appropriate studies on the relationship of age to the effects of sevelamer have not been performed in the geriatric population. However, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected.

Drug interactions and/or related problems
Drug interaction studies have shown that sevelamer has no effect on the bioavailability of single dose of digoxin, enalapril, metoprolol, or warfarin.{03} However, there is a possibility that sevelamer could bind with and decrease the bioavailability of other oral medications administered at the same time{01}. Caution is recommended with medications for which safety or efficacy could be significantly altered by changes in their blood concentrations; administration of such medications at least 1 hour before or 3 hours after sevelamer is recommended{01} or the physician should consider monitoring the blood levels of the drug.{03}

Note: Patients taking anti-arrhythmic and anti-seizure medications were excluded from the drug interaction studies. Special precautions should be taken when prescribing sevelamer to patients who are also taking these medications.{03}



Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

With physiology/laboratory test values
Cholesterol, total {01} , and
Low-density lipoprotein (LDL) {01}    (serum concentrations may be decreased {01})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Risk-benefit should be considered when the following medical problems exist
» Bowel obstruction {01}    (use is not recommended {01})


Dysphagia {01} or
Gastrointestinal (GI) tract motility disorders, severe {01} or
GI tract surgery, major {01} or
Swallowing disorders {01}    (safety and efficacy have not been established; caution is recommended {01})


» Hypophosphatemia {01}    (use is not recommended {01})


» Sensitivity to sevelamer {01}

Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Bicarbonate concentrations, serum {01} and
Calcium concentrations, serum {01} and
Chloride concentrations, serum {01}    (determinations recommended at periodic intervals {01})


» Phosphorus concentrations, serum {01}    (determinations recommended at periodic intervals to guide dosage adjustment {01})




Side/Adverse Effects

Note: Side/adverse effects are similar to those reported for calcium acetate {01}.

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
    
Constipation{01}
    
diarrhea{01}
    
dyspepsia{01} (heartburn)
    
flatulence{01} (bloating or gas)
    
nausea{01}
    
vomiting{01}





Overdose
Overdosage has not been reported with sevelamer. Because the medication is not absorbed systemically, the risk of systemic toxicity is low. {01}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Sevelamer (Oral).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Sensitivity to sevelamer

Pregnancy—It is not known if sevelamer affects the absorption of vitamins in pregnancy; no effect on serum levels of vitamins in patients supplemented with multivitamins was observed in clinical trials; however, decreased absorption of vitamins was reported in animals
Other medical problems, especially bowel obstruction or hypophosphatemia

Proper use of this medication
» Taking with meals

» Compliance with therapy

» Swallowing capsules whole; not breaking or chewing {01}

» Not taking capsules apart prior to administration, because contents expand in water {01}

» Following prescribed diet {01}

» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses

» Proper storage


General Dosing Information

Diet/Nutrition
It is important that each dose be taken with a meal{01}.and the patient should be informed of the importance of adhering to their prescribed diet.{03}


Oral Dosage Forms

SEVELAMER HYDROCHLORIDE CAPSULES

Note: Strength and dose are expressed in terms of anhydrous sevelamer hydrochloride {01}.


Usual adult dose
Hyperphosphatemia
Initial: Oral, 806 to 1612 mg (two to four 403-mg capsules) three times a day, with each meal, depending on the patient's serum phosphorus concentration{01}{03}. The dose is then adjusted gradually based on serum phosphorus concentrations, usually in increments or decrements of one capsule per meal{01}{03}.
Note: The following dosing recommendations were determined from baseline serum phosphorus concentrations obtained after a phosphate-binder-free washout period:{02}{03}
   —Serum phosphorus higher than 6 but less than 7.5 mg per deciliter (mg/dL): Oral, 806 mg (two capsules) three times a day with meals {01}{03}.
   —Serum phosphorus equal to or higher than 7.5 but less than 9 mg/dL: Oral, 1209 mg (three capsules) three times a day with meals {01}{03}.
   —Serum phosphorus 9 mg/dL or higher: Oral, 1612 mg (four capsules) three times a day with meals {01}{03}.

The proper dose is the one that maintains a serum phosphorus concentration of 6 mg per deciliter (mg/dL) or less {01}{03}.
The average dose is four capsules per meal in Phase III clinical trials{03}.
The maximum daily dose used in clinical studies was 12.1 grams (thirty capsules){01}{03}.



Patients switching from Calcium Acetate
The recommended starting doses based on the patient's current calcium acetate dose are listed below   —Oral, 806 mg (two capsules) of sevelamer three times a day for patients currently taking 667 mg of calcium acetate (1 tablet){03}.
   —Oral, 1209 mg (three capsules) of sevelamer three times a day for patients currently taking 1334 mg of calcium acetate (2 tablets) {03}.
   —Oral, 2015 mg (five capsules) of sevelamer three times a day for patients currently taking 2001 mg of calcium acetate (3 tablets) {03}.


Dose Titration
Dosage should be adjusted based on the serum phosphorus concentration with the goal of lowering the serum phosphorus to 6 mg per deciliter (mg/dL) or less.

The dose may be increased or decreased by one tablet or capsule per meal at two week intervals as necessary.
   —Serum phosphorus greater than 6.0 mg/dL: Oral, increase one tablet/capsule per meal at two week intervals.{03}
   —Serum phosphorus between 3.5 mg/dL to 6.0 mg/dL: Oral, maintain current dose.{03}
   —Serum phosphorus less than 3.5 mg/dL: Oral, decrease one tablet/capsule per meal.{03}


Usual pediatric dose
Safety and efficacy have not been established. {01}

Strength(s) usually available
U.S.—


403 mg (anhydrous) (Rx) [Renagel]

Packaging and storage:
Store between 15 and 30 ºC (59 and 86 ºF), preferably at 25 ºC (77 ºF) {01}{03}, unless otherwise specified by manufacturer. Protect from moisture.{01}{03}

Auxiliary labeling:
   • Take with meals.
   • Swallow capsules whole. Do not break or chew.


SEVELAMER HYDROCHLORIDE TABLETS

Note: Strength and dose are expressed in terms of anhydrous sevelamer hydrochloride{03}.


Usual adult dose
Hyperphosphatemia
Initial: Oral, 800 to 1600 mg (two to four 400-mg tablets or one to two 800-mg tablets) three times a day, with each meal, depending on the patient's serum phosphorus concentration{03}. The dose is then adjusted gradually based on serum phosphorus concentrations, usually in increments or decrements of one tablet per meal.{03}
Note: The following dosing recommendations were determined from baseline serum phosphorus concentrations obtained after a phosphate-binder-free washout period or for patients not currently taking a phosphate binder:{02}{03}
   —Serum phosphorus higher than 6 mg/dL but less than 7.5 mg per deciliter (mg/dL): Oral, 800 mg (two 400 mg tablets or one 800 mg tablet) three times a day with meals{03}.
   —Serum phosphorus equal to or higher than 7.5 mg/dL but less than 9 mg/dL: Oral, 1200 mg to 1600 mg (three 400 mg tablets or two 800 mg tablets) three times a day with meals{03}.
   —Serum phosphorus 9 mg/dL or higher: Oral, 1600 mg (four 400 mg tablets or two 800 mg tablets) three times a day with meals{03}.

The proper dose is the one that maintains a serum phosphorus concentration of 6 mg per deciliter (mg/dL) or less {03}.



Patients switching from Calcium Acetate
The recommended starting dose based on the patient's current calcium acetate dose are listed below   —Oral, 800 mg (two 400 mg tablets or one 800 mg tablet) of sevelamer three times a day for patients currently taking 667 mg of calcium acetate (1 tablet){03}.
   —Oral, 1200 to 1600 mg (three 400 mg tablets or two 800 mg tablets) of sevelamer three times a day for patients currently taking 1334 mg of calcium acetate (2 tablets){03}.
   —Oral, 2000 to 2400 mg (five 400 mg tablets or three 800 mg tablets) of sevelamer three times a day for patients currently taking 2001 mg of calcium acetate (3 tablets){03}.


Dose Titration
See Sevelamer Hydrochloride Capsules


Usual pediatric dose
Safety and efficacy have not been established. {03}

Strength(s) usually available
U.S.—


400 mg (anhydrous) (Rx) [Renagel ( colloidal silicon dioxide) (diacetylated monoglyceride ) (hydroxypropyl methylcellulose) (stearic acid)]{03}


800 mg (anhydrous) (Rx) [Renagel (colloidal silicon dioxide) (diacetylated monoglyceride) (hydroxypropyl methylcellulose) (stearic acid)]{03}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), preferably at 25 °C (77 °F) {03}, unless otherwise specified by manufacturer. Protect from moisture. {03}

Auxiliary labeling:
   • Take with meals.
   • Swallow capsules whole. Do not break or chew.



Developed: 06/08/1999
Revised: 01/16/2001



References
  1. Renagel package insert (Genzyme—US), Rev 10/98, Rec 12/2/98 (printed off Internet site http://www.geltex.com/PressReleases/RenagelPackage.html).
  1. Manufacturer comment, 2/10/99.
  1. Product Information: Renagel®, sevelamer hydrochloride. Genzyme Corporation, Waltham, MA (PI revised 07/2000) PI Reviewed 12/2000.
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