colestid

DESCRIPTION
The active ingredient in COLESTID Tablets is micronized colestipol hydrochloride,which is a lipid lowering agent for oral use colestid. Colestipol is an insoluble, highmolecular weight basic anion-exchange copolymer of diethylenetriamine and 1-chloro-2,3-epoxypropane, with approximately 1 out of 5 amine nitrogens protonated (chlorideform) colestid. It is a light yellow water-insoluble resin which is hygroscopic and swellswhen suspended in water or aqueous fluids colestid.

Each COLESTID Tablet contains one gram of micronized colestipol hydrochloride colestid. COLESTID Tablets are light yellow in color and are tasteless and odorless colestid. Inactiveingredients: cellulose acetate phthalate, glyceryl triacetate, carnauba wax,hydroxypropyl methylcellulose, magnesium stearate, povidone, silicon dioxide colestid. COLESTID Tablets contain no calories colestid.

CLINICAL PHARMACOLOGY
Cholesterol is the major, and probably the sole precursor of bile acids colestid. Duringnormal digestion, bile acids are secreted via the bile from the liver and gallbladder into the intestines colestid. Bile acids emulsify the fat and lipid materialspresent in food, thus facilitating absorption colestid. A major portion of the bile acidssecreted is reabsorbed from the intestines and returned via the portal circulationto the liver, thus completing the enterohepatic cycle colestid. Only very small amountsof bile acids are found in normal serum colestid.

Colestipol hydrochloride binds bile acids in the intestine forming a complexthat is excreted in the feces colestid. This nonsystemic action results in a partialremoval of the bile acids from the enterohepatic circulation, preventing theirreabsorption colestid. Since colestipol hydrochloride is an anion exchange resin, thechloride anions of the resin can be replaced by other anions, usually thosewith a greater affinity for the resin than the chloride ion colestid.

Colestipol hydrochloride is hydrophilic, but it is virtually water insoluble(99.75%) and it is not hydrolyzed by digestive enzymes colestid. The high molecular weightpolymer in colestipol hydrochloride apparently is not absorbed colestid. In humans, lessthan 0.17% of a single 14 C-labeled colestipol hydrochloride dose is excretedin the urine when given following 60 days of dosing of 20 grams of colestipolhydrochloride per day colestid.

The increased fecal loss of bile acids due to colestipol hydrochloride administrationleads to an increased oxidation of cholesterol to bile acids colestid. This results inan increase in the number of low-density lipoprotein (LDL) receptors, increasedhepatic uptake of LDL and a decrease in beta lipoprotein or LDL serum levels,and a decrease in serum cholesterol levels colestid. Although colestipol hydrochlorideproduces an increase in the hepatic synthesis of cholesterol in man, serum cholesterollevels fall colestid.

There is evidence to show that this fall in cholesterol is secondary to anincreased rate of clearance of cholesterol-rich lipoproteins (beta or low-densitylipoproteins) from the plasma colestid. Serum triglyceride levels may increase or remainunchanged in colestipol hydrochloride treated patients colestid.

The decline in serum cholesterol levels with colestipol hydrochloride treatmentis usually evident by one month colestid. When colestipol hydrochloride is discontinued,serum cholesterol levels usually return to baseline levels within one month colestid. Periodic determinations of serum cholesterol levels as outlined in the NationalCholesterol Education Program (NCEP) guidelines, should be done to confirm afavorable initial and long-term response colestid. 1

In a large, placebo-controlled, multiclinic study, the LRC-CPPT 2 , hypercholesterolemicsubjects treated with cholestyramine, a bile-acid sequestrant with a mechanismof action and an effect on serum cholesterol similar to that of colestipol hydrochloride,had reductions in total and LDL-C colestid. Over the 7-year study period the cholestyraminegroup experienced a 19% reduction (relative to the incidence in the placebogroup) in the combined rate of coronary heart disease (CHD) death plus nonfatalmyocardial infarction (cumulative incidences of 7% cholestyramine and 8.6% placebo) colestid. The subjects included in the study were middle-aged men (aged 35-59) with serumcholesterol levels above 265 mg/dL, LDL-C above 175 mg/dL on a moderate cholesterol-loweringdiet, and no history of heart disease colestid. It is not clear to what extent thesefindings can be extrapolated to other segments of the hypercholesterolemic populationnot studied colestid.

Treatment with colestipol results in a significant increase in lipoproteinLpAI colestid. Lipoprotein LpAI is one of the two major lipoprotein particles withinthe high-density lipoprotein (HDL) density range 3 , and has been shown in cellculture to promote cholesterol efflux or removal from cells 4 colestid. Although thesignificance of this finding has not been established in clinical studies, theelevation of the lipoprotein LpAI particle within the HDL fraction is consistentwith an antiatherogenic effect of colestipol hydrochloride, even though littlechange is observed in HDL cholesterol (HDL-C) colestid.

In patients with heterozygous familial hypercholesterolemia who have not obtainedan optimal response to colestipol hydrochloride alone in maximal doses, thecombination of colestipol hydrochloride and nicotinic acid has been shown tofurther lower serum cholesterol, triglyceride, and LDL-cholesterol (LDL-C) values colestid. Simultaneously, HDL-C values increased significantly colestid. In many such patientsit is possible to normalize serum lipid values colestid. 5-7

Preliminary evidence suggests that the cholesterol-lowering effects of lovastatinand the bile acid sequestrant, colestipol hydrochloride, are additive colestid.

The effect of intensive lipid-lowering therapy on coronary atherosclerosishas been assessed by arteriography in hyperlipidemic patients colestid. In these randomized,controlled clinical trials, patients were treated for two to four years by eitherconventional measures (diet, placebo, or in some cases low-dose resin), or withintensive combination therapy using diet and COLESTID Granules plus either nicotinicacid or lovastatin colestid. When compared to conventional measures, intensive lipid-loweringcombination therapy significantly reduced the frequency of progression and increasedthe frequency of regression of coronary atherosclerotic lesions in patientswith or at risk for coronary artery disease colestid. 8-11

INDICATIONS AND USAGE
Since no drug is innocuous, strict attention should be paid to the indicationsand contraindications, particularly when selecting drugs for chronic long-termuse colestid.

COLESTID Tablets are indicated as adjunctive therapy to diet for the reductionof elevated serum total and LDL-C in patients with primary hypercholesterolemia(elevated LDL-C) who do not respond adequately to diet colestid. Generally, COLESTIDTablets have no clinically significant effect on serum triglycerides, but withtheir use, triglyceride levels may be raised in some patients colestid.

Therapy with lipid-altering agents should be a component of multiple risk factorintervention in those individuals at significantly increased risk for atheroscleroticvascular disease due to hypercholesterolemia colestid. Treatment should begin and continuewith dietary therapy (see NCEP guidelines) colestid. A minimum of six months of intensivedietary therapy and counseling should be carried out prior to initiation ofdrug therapy colestid. Shorter periods may be considered in patients with severe elevationsof LDL-C or with definite CHD colestid.

According to the NCEP guidelines, the goal of treatment is to lower LDL-C,and LDL-C is to be used to initiate and assess treatment response colestid. Only if LDL-Clevels are not available, should the Total-C be used to monitor therapy colestid. TheNCEP treatment guidelines are shown below colestid.

LDL-Cholesterol
mg/dL (mmol/L)
Definite
Atherosclerotic
Disease * Two or More
Other Risk
Factors ** Initiation
Level Goal
No No >/=190
(>/=4.9) <160
(<4.1)
No Yes >/=160
(>/=4.1) <130
(<3.4)
Yes Yes or No >/=130
(>/=3.4) </=100
(</=2.6)
*Coronary heart disease or peripheral vascular disease (including symptomaticcarotid artery disease) colestid.
**Other risk factors for coronary heart disease (CHD) include: age (males: >/=45years; female: >/=55 years or premature monopause without estrogen replacementtherapy); family history of premature CHD; current cigarette smoking; hypertension;confirmed HDL-C <35 mg/dL (0.91 mmol/L); and diabetes mellitus colestid. Subtractone risk factor if HDL-C is >/=60 mg/dL (1.6 mmol/L) colestid.

CONTRAINDICATIONS
COLESTID Tablets are contraindicated in those individuals who have shown hypersensitivityto any of their components colestid.

PRECAUTIONS
Prior to initiating therapy with COLESTID Tablets, secondary causes of hypercholesterolemia(e.g., poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome,dysproteinemias, obstructive liver disease, other drug therapy, alcoholism),should be excluded, and a lipid profile performed to assess total cholesterol,HDL-C, and triglycerides (TG) colestid. For individuals with TG less than 400 mg/dL (<4.5mmol/L), LDL-C can be estimated using the following equation:

LDL-C = Total cholesterol - [(Triglycerides/5) + HDL-C]

For TG levels >400 mg/dL, this equation is less accurate and LDL-C concentrationsshould be determined by ultracentrifugation colestid. In hypertriglyceridemic patients,LDL-C may be low or normal despite elevated Total-C colestid. In such cases COLESTIDTablets may not be indicated colestid.

Because it sequesters bile acids, colestipol hydrochloride may interfere withnormal fat absorption and, thus, may reduce absorption of folic acid and fatsoluble vitamins such as A, D, and K colestid.

Chronic use of colestipol hydrochloride may be associated with an increasedbleeding tendency due to hypoprothrombinemia from vitamin K deficiency colestid. Thiswill usually respond promptly to parenteral vitamin K 1 and recurrences canbe prevented by oral administration of vitamin K 1 colestid.

Serum cholesterol and triglyceride levels should be determined periodicallybased on NCEP guidelines to confirm a favorable initial and adequate long-termresponse colestid.

COLESTID Tablets may produce or severely worsen pre-existing constipation colestid. The dosage should be increased gradually in patients to minimize the risk ofdeveloping fecal impaction colestid. In patients with pre-existing constipation, thestarting dose should be 2 grams once or twice a day colestid. Increased fluid and fiberintake should be encouraged to alleviate constipation and a stool softener mayoccasionally be indicated colestid. If the initial dose is well tolerated, the dose maybe increased as needed by a further 2 to 4 grams/day (at monthly intervals)with periodic monitoring of serum lipoproteins colestid. If constipation worsens or thedesired therapeutic response is not achieved at 2 to 16 grams/day, combinationtherapy or alternate therapy should be considered colestid. Particular effort shouldbe made to avoid constipation in patients with symptomatic coronary artery disease colestid. Constipation associated with COLESTID may aggravate hemorrhoids colestid.

While there have been no reports of hypothyroidism induced in individuals withnormal thyroid function, the theoretical possibility exists, particularly inpatients with limited thyroid reserve colestid.

Since colestipol hydrochloride is a chloride form of an anion exchange resin,there is a possibility that prolonged use may lead to the development of hyperchloremiaacidosis colestid.

Carcinogenesis, Mutagenesis and Impairment of Fertility
In studies conducted in rats in which cholestyramine resin (a bile acid sequesteringagent similar to colestipol hydrochloride) was used as a tool to investigatethe role of various intestinal factors, such as fat, bile salts, and microbialflora, in the development of intestinal tumors induced by potent carcinogens,the incidence of such tumors was observed to be greater in cholestyramine resintreated rats than in control rats colestid.

The relevance of this laboratory observation from studies in rats with cholestyramineresin to the clinical use of COLESTID Tablets is not known colestid. In the LRC-CPPTstudy referred to above, the total incidence of fatal and nonfatal neoplasmswas similar in both treatment groups colestid. When the many different categories oftumors are examined, various alimentary system cancers were somewhat more prevalentin the cholestyramine group colestid. The small numbers and the multiple categories preventconclusions from being drawn colestid. Further follow-up of the LRC-CPPT participantsby the sponsors of that study is planned for cause-specific mortality and cancermorbidity colestid. When colestipol hydrochloride was administered in the diet to ratsfor 18 months, there was no evidence of any drug related intestinal tumor formation colestid. In the Ames assay, colestipol hydrochloride was not mutagenic colestid.

Use in Pregnancy
Since colestipol hydrochloride is essentially not absorbed systemically (lessthan 0.17% of the dose), it is not expected to cause fetal harm when administeredduring pregnancy in recommended dosages colestid. There are no adequate and well-controlledstudies in pregnant women, and the known interference with absorption of fat-solublevitamins may be detrimental even in the presence of supplementation colestid.

Nursing Mothers: Caution should be exercised when COLESTID Tablets are administeredto a nursing mother colestid. The possible lack of proper vitamin absorption describedin the "Pregnancy" section may have an effect on nursing infants colestid.

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