Lipocol-Merz

1) QUESTRAN (Cholestyramine for Oral Suspension USP), is indicated as adjunctive therapy to diet for the reduction of elevated serum cholesterol in patients with primary hypercholesterolemia (elevated low density lipoprotein [LDL] cholesterol) who do not respond adequately to diet. QUESTRAN may be useful to lower LDL cholesterol in patients who also have hypertriglyceridemia, but it is not indicated where hypertriglyceridemia is the abnormality of most concern.

Therapy with lipid-altering agents should be a component of multiple risk factor intervention in those individuals at significantly increased risk for atherosclerotic vascular disease due to hypercholesterolemia. Treatment should begin and continue with dietary therapy specific for the type of hyperlipoproteinemia determined prior to initiation of drug therapy. Excess body weight may be an important factor and caloric restriction for weight normalization should be addressed prior to drug therapy in the overweight.

Prior to initiating therapy with QUESTRAN, 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). For individuals with TG less than 400 mg/dL (<4.5 mmol/L), LDL-C can be estimated using the following equation:

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

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

Serum cholesterol and triglyceride levels should be determined periodically based on NCEP guidelines to confirm initial and adequate long-term response. A favorable trend in cholesterol reduction should occur during the first month of QUESTRAN therapy. The therapy should be continued to sustain cholesterol reduction. If adequate cholesterol reduction is not attained, increasing the dosage of QUESTRAN or adding other lipid-lowering agents in combination with QUESTRAN should be considered.

Since the goal of treatment is to lower LDL-C, the NCEP⁴ recommends that LDL-C levels be used to initiate and assess treatment response. If LDL-C levels are not available then Total-C alone may be used to monitor long-term therapy. A lipoprotein analysis (including LDL-C determination) should be carried out once a year. The NCEP treatment guidelines are summarized below.

1) QUESTRAN monotherapy has been demonstrated to retard the rate of progression^2,3 and increase the rate of regression³ of coronary atherosclerosis.

2) QUESTRAN is indicated for the relief of pruritus associated with partial biliary obstruction. QUESTRAN for oral suspension has been shown to have a variable effect on serum cholesterol in these patients. Patients with primary biliary cirrhosis may exhibit an elevated cholesterol as part of their disease.

The recommended starting adult dose for all QUESTRAN powdered products (QUESTRAN Powder and QUESTRAN Light) is one packet or one level scoopful once or twice a day. The recommended maintenance dose for all QUESTRAN powdered products is 2 to 4 packets or scoopfuls daily (8-16 grams anhydrous cholestyramine resin) divided into two doses. Four grams of anhydrous cholestyramine resin is contained in each measured dose of QUESTRAN as follows:

It is recommended that increases in dose be gradual with periodic assessment of lipid/lipoprotein levels at intervals of not less than 4 weeks. The maximum recommended daily dose is six packets or scoopfuls of QUESTRAN (24 grams of anhydrous cholestyramine resin). The suggested time of administration is at mealtime but may be modified to avoid interference with absorption of other medications. Although the recommended dosing schedule is twice daily, QUESTRAN may be administered in 1–6 doses per day.

QUESTRAN should not be taken in its dry form. Always mix QUESTRAN with water or other fluids before ingesting. See Preparation Instructions.

Concomitant Therapy

Preliminary evidence suggests that the lipid-lowering effects of QUESTRAN on total and LDLcholesterol are enhanced when combined with a HMG-CoA reductase inhibitor, e.g., pravastatin, lovastatin, simvastatin, and fluvastatin. Additive effects on LDL-cholesterol are also seen with combined nicotinic acid/QUESTRAN therapy. See the Drug Interactions subsection of the PRECAUTIONS section for recommendations on administering concomitant therapy.

Preparation

The color of QUESTRAN may vary somewhat from batch to batch but this variation does not affect the performance of the product. Place the contents of one single-dose packet or one level scoopful of QUESTRAN in a glass or cup. Add an amount of water or other noncarbonated beverage of your choice depending on the product being used:

Stir to a uniform consistency and drink.

QUESTRAN may also be mixed with highly fluid soups or pulpy fruits with a high moisture content such as applesauce or crushed pineapple.

QUESTRAN is contraindicated in patients with complete biliary obstruction where bile is not secreted into the intestine and in those individuals who have shown hypersensitivity to any of its components.

WARNINGS

PHENYLKETONURICS: CHOLESTYRAMINE for ORAL SUSPENSION USP, LIGHT CONTAINS 14.0 mg PHENYLALANINE PER 5 GRAM DOSE.

PRECAUTIONS

General

Chronic use of QUESTRAN may be associated with increased bleeding tendency due to hypoprothrombinemia associated with Vitamin K deficiency. This will usually respond promptly to parenteral Vitamin K1 and recurrences can be prevented by oral administration of Vitamin K1. Reduction of serum or red cell folate has been reported over long term administration of QUESTRAN. Supplementation with folic acid should be considered in these cases.

There is a possibility that prolonged use of QUESTRAN, since it is a chloride form of anion exchange resin, may produce hyperchloremic acidosis. This would especially be true in younger and smaller patients where the relative dosage may be higher. Caution should also be exercised in patients with renal insufficiency or volume depletion, and in patients receiving concomitant spironolactone.

QUESTRAN may produce or worsen pre-existing constipation. The dosage should be increased gradually in patients to minimize the risk of developing fecal impaction. In patients with pre-existing constipation, the starting dose should be 1 packet or 1 scoop once daily for 5–7 days, increasing to twice daily with monitoring of constipation and of serum lipoproteins, at least twice, 4–6 weeks apart. Increased fluid intake and fiber intake should be encouraged to alleviate constipation and a stool softener may occasionally be indicated. If the initial dose is well tolerated, the dose may be increased as needed by one dose/day (at monthly intervals) with periodic monitoring of serum lipoproteins. If constipation worsens or the desired therapeutic response is not achieved at one to six doses/day, combination therapy or alternate therapy should be considered. Particular effort should be made to avoid constipation in patients with symptomatic coronary artery disease. Constipation associated with QUESTRAN may aggravate hemorrhoids.

Laboratory Tests

Serum cholesterol levels should be determined frequently during the first few months of therapy and periodically thereafter. Serum triglyceride levels should be measured periodically to detect whether significant changes have occurred.

The LRC-CPPT showed a dose-related increase in serum triglycerides of 10.7%–17.1% in the cholestyramine-treated group, compared with an increase of 7.9%–11.7% in the placebo group. Based on the mean values and adjusting for the placebo group, the cholestyramine-treated group showed an increase of 5% over pre-entry levels the first year of the study and an increase of 4.3% the seventh year.

Carcinogenesis And Mutagenesis And Impairment Of Fertility

In studies conducted in rats in which cholestyramine resin 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 to the clinical use of QUESTRAN is not known. In the LRC-CPPT study referred to above, the total incidence of fatal and nonfatal 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. However, in view of the fact that cholestyramine resin is confined to the GI tract and not absorbed, and in light of the animal experiments referred to above, a six-year post-trial follow-up of the LRC-CPPT⁵ patient population has been completed (a total of 13.4 years of in-trial plus post-trial follow-up) and revealed no significant difference in the incidence of cause-specific mortality or cancer morbidity between cholestyramine and placebo treated patients.

Pregnancy

Pregnancy Category C

There are no adequate and well controlled studies in pregnant women. The use of QUESTRAN 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. QUESTRAN is not absorbed systemically, however, it is known to interfere with absorption of fat-soluble vitamins; accordingly, regular prenatal supplementation may not be adequate (see DRUG INTERACTIONS).

Nursing Mothers

Caution should be exercised when QUESTRAN is administered to a nursing mother. The possible lack of proper vitamin absorption described in the “Pregnancy” section

Pediatric Use

Although an optimal dosage schedule has not been established, standard texts^(6,7) list a usual pediatric dose of 240 mg/kg/day of anhydrous cholestyramine resin in two to three divided doses, normally not to exceed 8 gm/day with dose titration based on response and tolerance.

In calculating pediatric dosages, 44.4 mg of anhydrous choleystramine resin are contained in 100 mg of QUESTRAN powder and 80 mg of anhydrous cholestyramine resin are contained in 100 mg of QUESTRAN LIGHT.

The effects of long-term administration, as well as its effect in maintaining lowered cholesterol levels in pediatric patients, are unknown. (Also see ADVERSE REACTIONS.)

REFERENCES

The Lipid Research Clinics Investigators. The Lipid Research Clinics Coronary Primary Prevention Trial: Results of 6 Years of Post-Trial Follow-up. Arch Intern Med 1992; 152:1399- 1410.

Behrman RE et al (eds): Nelson, Textbook of Pediatrics, ed 15. Philadelphia, PA, WB Saunders Company, 1996.

Takemoto CK et al (eds): Pediatric Dosage Handbook, ed 3. Cleveland/Akron, OH, Lexi-Comp, Inc., 1996-1997.

The most common adverse reaction is constipation. When used as a cholesterol-lowering agent predisposing factors for most complaints of constipation are high dose and increased age (more than 60 years old). Most instances of constipation are mild, transient, and controlled with conventional therapy. Some patients require a temporary decrease in dosage or discontinuation of therapy.

Less Frequent Adverse Reactions: Abdominal discomfort and/or pain, flatulence, nausea, vomiting, diarrhea, eructation, anorexia, and steatorrhea, bleeding tendencies due to hypoprothrombinemia (Vitamin K deficiency) as well as Vitamin A (one case of night blindness reported) and D deficiencies, hyperchloremic acidosis in children, osteoporosis, rash and irritation of the skin, tongue and perianal area. Rare reports of intestinal obstruction, including two deaths, have been reported in pediatric patients.

Occasional calcified material has been observed in the biliary tree, including calcification of the gallbladder, in patients to whom QUESTRAN has been given. However, this may be a manifestation of the liver disease and not drug related.

One patient experienced biliary colic on each of three occasions on which he took QUESTRAN. One patient diagnosed as acute abdominal symptom complex was found to have a “pasty mass” in the transverse colon on x-ray.

Other events (not necessarily drug related) reported in patients taking QUESTRAN include:

Gastrointestinal - GI-rectal bleeding, black stools, hemorrhoidal bleeding, bleeding from known duodenal ulcer, dysphagia, hiccups, ulcer attack, sour taste, pancreatitis, rectal pain, diverticulitis.

Laboratory test changes - Liver function abnormalities.

Hematologic - Prolonged prothrombin time, ecchymosis, anemia

Hypersensitivity - Urticaria, asthma, wheezing, shortness of breath.

Musculoskeletal - Backache, muscle and joint pains, arthritis.

Neurologic - Headache, anxiety, vertigo, dizziness, fatigue, tinnitus, syncope, drowsiness, femoral nerve pain, paresthesia.

Eye - Uveitis.

Renal - Hematuria, dysuria, burnt odor to urine, diuresis.

Miscellaneous - Weight loss, weight gain, increased libido, swollen glands, edema, dental bleeding, dental caries, erosion of tooth enamel, tooth discoloration.

Overdosage with QUESTRAN has been reported in a patient taking 150% of the maximum recommended daily dosage for a period of several weeks. No ill effects were reported. Should an overdosage occur, the chief potential harm would be obstruction of the gastrointestinal tract. The location of such potential obstruction, the degree of obstruction, and the presence or absence of normal gut motility would determine treatment.