Professional Drug Information > Welchol

Colesevelam (Oral-Local)

VA CLASSIFICATION
Primary: CV359

Another commonly used name is:
GT31-104 GT31-104HB Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

^†Not commercially available in Canada.

Category:


Antihyperlipidemic—

Indications

Accepted

Hyperlipidemia (treatment)—Colesevelam is indicated as an adjunct to diet and exercise for reducing elevated low-density-lipoprotein cholesterol (LDL-C) in patients with primary hypercholesterolemia (Fredrickson Type IIa)^{01}. Colesevelam may be used alone or in combination with a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.^{01}
—For additional information on initial therapeutic guidelines related to the treatment of hyperlipidemia, see Appendix III.


Pharmacology/Pharmacokinetics

Physicochemical characteristics:

Solubility
    Colesevelam is insoluble in water.^{01}

Mechanism of action/Effect:

Colesevelam is a high capacity bile-acid binding molecule.^{01}

Colesevelam binds to bile acids in the intestine which reduces the amount of bile acids that are returned to the liver via enterohepatic circulation.^{01} Reduction of the bile acid pool results in upregulation of the hepatic enzyme, cholesterol 7–-hydroxylase, which increases conversion of cholesterol to bile acids.^{01}As more bile acids are formed, the demand for cholesterol by the liver cells increases.^{01} This results in the dual effect of increasing transcription and activity of the cholesterol biosynthetic enzyme, hydroxymethyl-glutaryl-coenzyme A (HMG-CoA) reductase.^{01} The end result is increased clearance of LDL-cholesterol from the blood with decreased serum LDL-cholesterol.^{01}

Absorption:

Colesevelam is a hydrophilic, water-insoluble polymer that is not hydrolyzed by digestive enzymes and is not absorbed.^{01}

Elimination:
    After administering colesevelam 1.9 grams twice daily for 28 days, an average of 0.05% of a single ¹⁴C-labeled colesevelam dose was excreted in the urine.^{01}


Precautions to Consider

Carcinogenicity

A 2–year carcinogenicity study was conducted in CD-1 mice at an oral dose up to 3 grams (g) per kilogram (kg) of body weight (approximately 50 times the maximum recommended human dose of 4.5 g per day, based on body weight).^{01}. In this study, no significant drug-induced tumors were found in male or female mice.^{01}

In another 2–year study involving Harlan Sprague-Dawley rats, a statistically significant increase in pancreatic acinar cell adenoma was observed in male rats treated with a dose greater than 1.2 g/kg/day (approximately 20 times the maximum human dose based on body weight, mg/kg) (trend test only).^{01}A statistically significant increase in thyroid C-cell adenoma was seen in female rats at 2.4 g/kg/day (approximately 40 times the maximum human dose, based on body weight, mg/kg).^{01}

Mutagenicity

Colesevelam and four degradants present in the drug have been evaluated for mutagenicity in the Ames test and a mammalian chromosomal aberration test. ^{01} The four degradants and an extract of the parent compound did not exhibit genetic toxicity in an in vitro bacterial mutagenesis assay in S typhimurium and E coli (Ames assay) with or without rat liver metabolic activation.^{01} An extract of the parent compound was positive in the Chinese Hamster Ovary (CHO) cell chromosomal aberration assay in the presence of metabolic activation and negative in the absence of metabolic activation. ^{01}The results of the CHO cell chromosomal aberration assay with two of the four degradants, decylamine HCl and aminohexyltrimethyl ammonium chloride HCl, were equivocal in the absence of metabolic activation and negative in the presence of metabolic activation.^{01} The other two degradants, didecylamine HCl and 6–decylamino-hexyltrimethyl ammonium chloride HCl, were negative in the presence and absence of metabolic activation.^{01}

Pregnancy/Reproduction
Fertility—
Colesevelam did not impair fertility in rats at doses of up to 3 g/kg/day (approximately 50 times the maximum human dose, based on body weight, mg/kg).^{01}

Pregnancy—
Studies have not been done in humans.^{01}

No evidence of harm to the fetus due to colesevelam was detected in reproduction studies performed in rats and rabbits at doses up to 3 g/kg/day and 1 g/kg/day, respectively (approximately 50 and 17 times the maximum human dose, based on body weight, mg/kg). ^{01} Because animal reproductive studies do not always predict human response, colesevelam should be used only if it is clearly needed.^{01}

The requirements for vitamins and other nutrients increase during pregnancy. ^{01} The effect of colesevelam on the absorption of vitamins has not been studied in pregnant women.^{01}

FDA Pregnancy Category B.^{01}

Breast-feeding

It not known whether colesevelam is distributed into breast milk.^{01}

Pediatrics

The safety and effectiveness of colesevelam have not been established in pediatric patients.^{01}


Geriatrics


Appropriate studies on the relationship of age to the effects of colesevelam have not been performed in the geriatric population. However, no geriatrics-specific problems have been documented to date.^{01}

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):

Verapamil    (colesevelam decreased the area under the curve and maximum concentration of sustained-release verapamil by 11% and 31%, respectively; however, since there is a high degree of variability in the bioavailability of verapamil, the clinical significance of this finding is unclear^{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).


Except under special circumstances, this medication should not be used when the following medical problem exists:
» Bowel obstruction^{01}    (this condition may be exacerbated ^{01})


Risk-benefit should be considered when the following medical problems exist
Dysphagia^{01} and
Major gastrointestinal surgery ^{01}and
Severe gastrointestinal motility disorders    (although colesevelam was not used in patients with these conditions, it may worsen these conditions ^{01})


Hypersensitivity
Vitamin deficiencies such as A, D, E, or K ^{01}    (although colesevelam did not reduce absorption of fat soluble vitamins during clinical trials, reduced absorption of fat soluble vitamins is possible^{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):

» High-density-lipoprotein cholesterol^{01}    (monitor before beginning therapy and periodically, thereafter; increase expected^{01})


» Low-density-lipoprotein cholesterol^{01}and
Total cholesterol ^{01}    (monitor before beginning therapy and periodically, thereafter; reduction in both expected^{01})


» Triglycerides ^{01}    (monitor before beginning therapy and periodically, thereafter; increase expected^{01})




Side/Adverse Effects
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
Incidence less frequent
    
Myalgia^{01} (muscle aches or pain)
    
pharyngitis^{01} (congestion; cough ; dryness or soreness of throat; hoarseness; trouble in swallowing)



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Constipation^{01}
    
dyspepsia^{01} (acid or sour stomach; belching; indigestion; stomach discomfort, upset, or pain)





Overdose
For more information on the management of overdose or unintentional ingestion, contact a poison control center (see Poison Control Center Listing).

Note: Colesevelam is not absorbed; therefore, the risk of systemic toxicity is low. Doses above 4.5 grams were not tested. ^{01}



Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Colesevelam (Oral).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Hypersensitivity to colesevelam
Other medical problems, especially bowel obstruction

Proper use of this medication
» Importance of adherence to recommended regimens for diet and exercise

» Take this medicine with meals and a liquid

» Proper dosing
Missed dose: If you miss a dose of this medicine, skip the missed dose and go back to your regular dosing schedule. Do not double doses

Proper storage

Precautions while using this medication
» Regular visits to physician to check progress


Side/adverse effects
Signs of potential side effects, especially myalgia or pharyngitis


General Dosing Information
Colesevelam should be used as an adjunct to diet and exercise for reducing total and low-density-lipoprotein cholesterol.^{01}

The maximum therapeutic effect was achieved within 2 weeks and persisted during long-term treatment.^{01}


Oral Dosage Forms

COLESEVELAM TABLETS

Usual Adult Dose
Hyperlipidemia (treatment)
Oral, 3 tablets twice daily with meals or 6 tablets once daily with a meal.^{01} The dose may be increased to 7 tablets depending upon desired therapeutic effect.^{01}

Note: Colesevelam may be used as monotherapy or in combination with an HMG-CoA reductase inhibitor. If used with an HMG-CoA reductase inhibitor, the two medications may be administered at the same time or different times.^{01}
Colesevelam should be taken with a liquid.^{01}



Usual adult prescribing limits
Up to 7 tablets per day. ^{01}

Usual Pediatric Dose
Safety and efficacy have not been established.^{01}

Usual Geriatric Dose
See Usual adult dose.

Usual geriatric prescribing limits
See Usual adult prescribing limits.

Strength(s) usually available
U.S.—


625 mg of colesevelam per tablet (Rx) [Welchol™ (magnesium stearate) (microcrystalline cellulose) (silicon dioxide)]

Packaging and storage:
Store at 25 °C. ^{01} Brief exposure to 40 °C does not adversely affect this product.^{01} Protect from moisture. ^{01}

Auxiliary labeling:
   • Take with meals.
   • Protect from moisture.
   • Take with a liquid.

Developed: 08/14/2000

References

1. Product Information: Welchol(TM), colesevelam hydrochloride. Sankyo Parke Davis, Parsippany, NJ, (PI revised 07/2000) reviewed 07/2000.
   

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