The format of this leaflet was determined by the Ministry of Healthand its content was 1. NAME OF THE MEDICINAL PRODUCT COLESTID 2. QUALITATIVE AND QUANTITATIVE COMPOSITION One dose (1 packet or 1 level teaspoon) of COLESTID Granules contains 5 grams of colestipol hydrochloride For excipients, see section 6.1 3. PHARMACEUTICAL FORM Light yellow, tasteless and odorless granules 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Adjunctive therapy to diet in the management of elevated cholesterol levels. 4.2 Posology and method of administration Treatment for elevated serum cholesterol levels should begin with dietary therapy. A minimum of six months of dietary therapy and counseling should usually be undertaken before initiating drug therapy; shorter periods can be considered in patients with severe elevations of LDL- cholesterol (>225 mg/dl or 5.8 mmol/L) or definite Coronary Heart Disease. Drug therapy should be added to dietary therapy, and not substituted for it.
Colestipol hydrochloride granules should never be taken in dry form. Esophageal spasm or respiratory distress can result from attempting to swallow the granules dry.
The recommended daily adult dose is one to six sachets or level scoopfuls (5-30 grams) taken once or in divided doses (each sachet or level scoopful contains approximately 5 grams of colestipol hydrochloride). Treatment should be started with 5 grams colestipol hydrochloride taken once or twice daily; increments of 5 grams colestipol hydrochloride/day are recommended no more frequently than at one month intervals, as needed. Appropriate use of lipid profiles including LDL-cholesterol and triglycerides is advised so that optimal, but not excessive doses are used to obtain the desired therapeutic effect. If the desired therapeutic effect is not obtained at 5-30 grams colestipol hydrochloride/day with good compliance and acceptable side effects, combined therapy or alternate treatment should be considered.
Colestipol hydrochloride should always be taken with fluids. Each sachet (or scoopful) of colestipol hydrochloride should be added to 100-150 ml of any appropriate fluid (e.g. fruit juices, milk, carbonated beverage or water), based on patient preference. Stir the mixture until the medication is completely suspended (cholestipol hydrochloride will not dissolve in the liquid). Colestipol hydrochloride may also be mixed with cereals, soups, or other foods provided that sufficient fluid is also ingested. (Each subsidiary may recommend local recipes or foodstuffs as vehicles.)
4.3 Contraindications Colestipol hydrochloride is contraindicated in those individuals who have shown hypersensitivity to colestipol hydrochloride or any of its components. 4.4 Special warnings and special precautions for use Before instituting therapy with colestipol hydrochloride, diseases contributing to increased blood cholesterol such as hypothyroidism, poorly controlled diabetes mellitus, nephrotic syndrome, dysproteinemias, other drug therapy, alcoholism and obstructive liver disease should be looked for and specifically treated. The patient's current medications should be reviewed for their potential to increase serum LDL-cholesterol or total cholesterol.
When used as sole therapy, colestipol hydrochloride will not improve hypertriglyceridemia and may elevate serum triglycerides. This elevation is generally transient, but may persist in some individuals. A significant rise in triglyceride level should be considered as an indication for dose reduction, drug discontinuation, or combined or alternate therapy.
Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat absorption and thus may reduce absorption of folic acid and fat soluble vitamins such as A, D, and K.
Information on the use of colestipol hydrochloride granules in children is limited; therefore, dosage and long-term safety have not been established. However, clinical trials conducted with colestipol hydrochloride granules in children have usually employed doses of 5 to 20 grams per day. The NCEP Report of the Expert Panel on Blood Cholesterol Levels in Children and Adolescents recommends a titration approach in children ages 10 and older, based on cholesterol levels and therapeutic response as an adjunct to dietary measures. Because bile acid sequestrants may interfere with the absorption of fat-soluble vitamins, appropriate monitoring of growth and development is essential.
4.5 Interaction with other medicinal products and other forms of interaction Since colestipol hydrochloride is an anion exchange resin, it may have a strong affinity for anions other than the bile acids. In vitro studies have indicated that colestipol hydrochloride binds a number of drugs. Therefore, colestipol hydrochloride may delay or reduce the absorption of concomitant oral medication. The interval between the administration of colestipol hydrochloride and other medication should be as long as possible. Patients should take other drugs at least one hour before or four hours after colestipol hydrochloride to avoid impeding their absorption.
Repeated doses of colestipol hydrochloride given prior to a single dose of propranolol in human trials have been reported to decrease propranolol absorption. However, in a follow-up study in normal subjects, single dose administration of colestipol hydrochloride and propranolol or multiple dose administration of both agents did not affect the extent of propranolol absorption. Effects on the absorption of other beta-blockers have not been determined. Patients on propranolol should be observed when colestipol hydrochloride is either added or deleted from a therapeutic regimen.
Studies in humans show that absorption of chlorothiazide is markedly decreased even when administered one hour before or after administration of colestipol hydrochloride.
The absorption of tetracycline, furosemide, penicillin G, hydrochlorothiazide and gemfibrozil was significantly decreased when given simultaneously with colestipol hydrochloride; however, colestipol hydrochloride and gemfibrozil can be used in the same patient when administered two hours apart.
Concurrent administration of colestipol hydrochloride with phenytoin, aspirin, tolbutamide, clofibrate, methyldopa, nicotinic acid (niacin), clindamycin, phenprocoumon or warfarin does not affect the respective drugs bioavailability.
Particular caution should be observed with digitalis preparations since there are conflicting results for the effect of colestipol hydrochloride on the availability of digoxin and digitoxin. The potential for binding of these drugs if given concomitantly is present. The serum digoxin and digitoxin levels should be monitored during periods of administration or discontinuation of colestipol hydrochloride.
Bile acid binding resins may also interfere with the absorption of oral phosphate supplements.
4.6 Pregnancy and lactation
Due to its known interference with absorption of fat-soluble vitamins, the use of colestipol hydrochloride in pregnancy or lactation or by women of childbearing age requires that the potential benefits of drug therapy be weighed against the possible hazards to the mother and child. The safe use of colestipol hydrochloride resin by pregnant women has not been established.
4.7 Effects on ability to drive and use machines Based on the pharmacodynamic and general safety profiles of colestipol hydrochloride, it is not expected to affect the ability to drive or use machines. 4.8 Undesirable effects Metabolism and Nutrition Disorders: Decreased appetite
Nervous System Disorders: Headache, Migraine, Sinus headache, and Dizziness
Cardiac Disorders: Angina pectoris, Chest pain, and Tachycardia
Respiratory, Thoracic and Mediastinal Disorders: Dyspnoea
Gastrointestinal Disorders: Peptic ulcer, Haematochezia, Constipation, Haemorrhoidal haemorrhage, Diarrhoea, Vomiting, Haemorrhoids aggravated, Abdominal pain, Abdominal discomfort, Nausea, Abdominal distention, Flatulence, and Dyspepsia.
Hepatobiliary Disorders: Cholecystitis and Cholelithiasis
Skin and Subcutaneous Tissue Disorders: Urticaria, Rash, and Dermatitis.
Musculoskeletal, Connective Tissue and Bone Disorders: Arthritis, Musculoskeletal pain, Pain in extremity, Arthralgia, and Back pain
General Disorders and Administration Site Conditions: Fatigue, Asthenia, and Oedema peripheral
Investigations: Alanine aminotransferase increased, Aspartate aminotransferase increased, and Alkaline phosphatase increased.
4.9 Overdose Overdose with colestipol hydrochloride has not been reported. Should overdosage occur, however, the chief harm would be obstruction of the gastrointestinal tract. Treatment would be determined by the location and degree of obstruction. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties In a large, placebo-controlled, multiclinic study, the LRC-CPPT, hypercholesterolemic subjects treated with cholestyramine, a bile acid sequestrant with a mechanism of action and effect on serum cholesterol similar to that of colestipol hydrochloride, had reductions in total and low- density lipoprotein cholesterol (LDL-C). Over the seven-year study period, the cholestyramine group experienced a 19% reduction in the combined rate of coronary heart disease death plus non-fatal myocardial infarction (cumulative incidences of 7% cholestyramine and 8.6% placebo). The subjects included in the study were middle-aged men (age 35–59) with elevated serum cholesterol and no known coronary heart disease. It is not clear to what extent these findings can be extrapolated to other segments of the hypercholesterolemic population not studied.
Treatment with colestipol hydrochloride results in a significant increase in lipoprotein LpAI. Lipoprotein LpAI is one of the two major lipoprotein particles within the high-density lipoprotein (HDL) density range, and has been shown in cell culture to promote cholesterol efflux or removal from cells. Although the significance of this finding has not been established in clinical studies, the elevation of the lipoprotein LpAI particle within the HDL fraction is consistent with an antiatherogenic effect of colestipol hydrochloride, even though little change is observed in HDL cholesterol.
When compared to conventional measures, intensive lipid-lowering combination therapy, which included colestipol hydrochloride plus either niacin or lovastatin, significantly reduced the frequency of progression and increased the frequency of regression of coronary atherosclerotic lesions in patients with or at risk for symptomatic coronary artery disease.
5.2 Pharmacokinetic properties Colestipol hydrochloride is hydrophilic, but it is virtually water insoluble (99.75%) and it is not hydrolyzed by digestive enzymes. The high molecular weight polymer in colestipol hydrochloride apparently is not absorbed in the gastrointestinal tract; colestipol hydrochloride action is limited to the lumen of the gastrointestinal tract and it is passed in the feces. It binds bile acids in the intestinal lumen and causes them to be excreted in the feces together with the polymer. In humans, less than 0.17% of a single 14C-labeled colestipol hydrochloride dose is excreted in the urine when given following 60 days of dosing of 20 grams of colestipol hydrochloride per day. For the treatment of hypercholesterolemia, initial response occurs at 24-48 hours while the peak occurs at 1 month after the oral administration of colestipol 5.3 Preclinical safety data Carcinogenesis, mutagenesis and impairment of fertility:
In studies conducted in rats in which cholestyramine resin (a bile acid sequestering agent similar to colestipol hydrochloride) was used as a tool to investigate the role of various intestinal factors, such as fat, bile salts and microbial flora, in the development of intestinal tumors induced by potent carcinogens, the incidence of such tumors was observed to be greater in cholestyramine resin treated rats than in control rats.
The relevance of this laboratory observation from studies in rats with cholestyramine resin to the clinical use of colestipol hydrochloride is not known. In the LRC-CPPT study referred to section 5.1 Pharmacodynamic properties, the total incidence of fatal and non-fatal neoplasms was similar in both treatment groups. When the many different categories of tumors are examined, various alimentary system cancers were somewhat more prevalent in the cholestyramine group. The small numbers and the multiple categories prevent conclusions from being drawn. Further follow-up of the LRC-CPPT participants by the sponsors of that study is planned for cause-specific mortality and cancer morbidity.
When colestipol hydrochloride was administered in the diet to rats for 18 months, there was no evidence of any drug related intestinal tumor formation. In the Ames assay, colestipol hydrochloride was not mutagenic
6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients 1 sachet 5 g: Anhydrous colloidal silica 10 mg. 6.2 Incompatibilities None. 6.3 Special precautions for storage
Store at room temperature, below 25°C. 6.4 Nature and contents of container Sachet consisting of paper/aluminium/polyethylene laminate.
6.6 Manufacturer: Farmea, France For: Pfizer Pharmaceuticals Israel Ltd., 9 Shenkar St. Herzliya Pituach 46725
INSTRUÇÃO NORMATIVA Nº 003/2004. REGULAMENTA O REEMBOLSO DE MEDICAMENTOS A Diretora Presidente da Caixa de Assistência da FIPECq Vida, no uso das atribuições, que lhe foram conferidas pela Resolução nº 007/2004, e em conformidade com o disposto na Ata da Reunião do Acordo Coletivo realizada no dia 12 de março de 2004, RESOLVE: Conceder aos empregados efetivos d
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