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Rx only
Atromid-S Capsules (clofibrate capsules) is ethyl 2-(p-chlorophenoxy)-2-methyl-propionate, an antilipidemic agent.
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Its molecular formula is C 12 H 15 O 3 Cl, molecular weight 242.7, and boiling point 148-150°C at 25 mm Hg. It is a stable, colorless to pale-yellow liquid with a faint odor and characteristic taste, soluble in common solvents but not in water. Each Atromid-S Capsule contains 500 mg clofibrate for oral administration.
Atromid-S Capsules contain the following inactive ingredients: D&C Red No. 28, D&C Red No. 30, D&C Yellow No. 10, FD&C Blue No. 1, FD&C Red No. 28, FD&C Red No. 40, FD&C Yellow No. 6, gelatin.
Atromid-S is an antilipidemic agent. It acts to lower elevated serum lipids by reducing the very low-density lipoprotein fraction (S f 20-400) rich in triglycerides. Serum cholesterol may be decreased, particularly in those patients whose cholesterol elevation is due to the presence of IDL as a result of Type III hyperlipoproteinemia.
The mechanism of action has not been established definitively. Clofibrate may inhibit the hepatic release of lipoproteins (particularly VLDL), potentiate the action of lipoprotein lipase, and increase the fecal excretion of neutral sterols.
Between 95% and 99% of an oral dose of clofibrate is excreted in the urine as free and conjugated clofibric acid; thus, the absorption of clofibrate is virtually complete. The half-life of clofibric acid in normal volunteers averages 18 to 22 hours (range 14 to 35 hours) but can vary by up to 7 hours in the same subject at different times. Clofibric acid is highly protein-bound (95% to 97%). In subjects undergoing continuous clofibrate treatment, 1 g q12h, plasma concentrations of clofibric acid range from 120 to 125 mcg/mL to an approximate peak of 200 mcg/mL.
Several investigators have observed in their studies that clofibrate may produce a decrease in cholesterol linoleate but an increase in palmitoleate and oleate, the latter being considered atherogenic in experimental animals. The significance of this finding is unknown at this time.
Reduction of triglycerides in some patients treated with clofibrate or certain of its chemically and clinically similar analogs may be associated with an increase in LDL cholesterol. Increase in LDL cholesterol has been observed in patients whose cholesterol is initially normal.
Animal studies suggest that clofibrate interrupts cholesterol biosynthesis prior to mevalonate formation.
The initial treatment of choice for hyperlipidemia is dietary therapy specific for the type of hyperlipidemia. 1
Excess body weight and alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Estrogen therapy, some beta-blockers, and thiazide diuretics may also be associated with increases in plasma triglycerides. Discontinuation of such products may obviate the need for specific antilipidemic therapy. Contributory diseases such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with nondrug methods. If the decision ultimately is to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet.
Because Atromid-S is associated with certain serious adverse findings reported in two large clinical trials (see " "), agents other than clofibrate may be more suitable for a particular patient.
Atromid-S is indicated for Primary Dysbetalipoproteinemia (Type III hyperlipidemia) that does not respond adequately to diet.
Atromid-S may be considered for the treatment of adult patients with very high serum-triglyceride levels (Type IV and V hyperlipidemia) who present a risk of abdominal pain and pancreatitis and who do not respond adequately to a determined dietary effort to control them. Patients who present such risk typically have serum triglycerides over 2000 mg/dl and have elevations of VLDL-cholesterol as well as fasting chylomicrons (Type V hyperlipidemia). Subjects who consistently have total serum or plasma triglycerides below 1000 mg/dl are unlikely to present a risk of pancreatitis. Atromid-S therapy may be considered for those subjects with triglyceride elevations between 1000 and 2000 mg/dl who have a history of pancreatitis or of recurrent abdominal pain typical of pancreatitis. It is recognized that some Type IV patients with triglycerides under 1000 mg/dl may, through dietary or alcoholic indiscretion, convert to a Type V pattern with massive triglyceride elevations accompanying fasting chylomicronemia, but the influence of Atromid-S therapy on the risk of pancreatitis in such situations has not been adequately studied.
Atromid-S is not useful for the hypertriglyceridemia of Type I hyperlipidemia, where elevations of chylomicrons and plasma triglycerides are accompanied by normal levels of very low-density lipoprotein (VLDL). Inspection of plasma refrigerated for 12 to 14 hours is helpful in distinguishing Types I, IV, and V hyperlipoproteinemia. 2
Atromid-S has not been shown to be effective for prevention of coronary heart disease.
The biochemical response to Atromid-S is variable, and it is not always possible to predict from the lipoprotein type or other factors which patients will obtain favorable results. LDL cholesterol, as well as triglycerides, should be rechecked during the first several months of therapy in order to detect rises in LDL cholesterol that often accompany fibric-acid-type drug-induced reductions in elevated triglycerides. It is essential that lipid levels be reassessed periodically and that the drug be discontinued in any patient in whom lipids do not show significant improvement.
Clofibrate is contraindicated in pregnant women. While teratogenic studies have not demonstrated any effect attributable to clofibrate, it is known that serum of the rabbit fetus accumulates a higher concentration of clofibrate than that found in maternal serum, and it is possible that the fetus may not have developed the enzyme system required for the excretion of clofibrate.
It is contraindicated in patients with clinically significant hepatic or renal dysfunction. Rhabdomyolysis and severe hyperkalemia have been reported in association with pre-existing renal insufficiency.
It is contraindicated in patients with primary biliary cirrhosis, since it may raise the already elevated cholesterol in these cases.
It is contraindicated in patients with a known hypersensitivity to clofibrate.
It is contraindicated in nursing women (see " PRECAUTIONS ").
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In a large study involving 5,000 patients in a clofibrate-treated group and 5,000 in a placebo-treated group followed for an average of five years on drug or placebo and one year beyond (the WHO study), there was a statistically significant 44% higher age-adjusted total mortality in the clofibrate-treated group than in a comparable placebo group. The excess deaths were due to noncardiovascular causes; half of this difference was due to malignancy; other causes of death included postcholecystectomy complications and pancreatitis. 3 In another prospective study involving 1,000 clofibrate- and 3,000 placebo-treated patients followed for an average of six years on drug or placebo (the Coronary Drug Project study), the noncardiovascular mortality rate, including that of malignancy, was not significantly different in the clofibrate- and placebo-treated groups. 4 This should not be interpreted to mean that clofibrate is not associated with an increased risk of noncardiovascular death, because the patients in the Coronary Drug Project were much older than those in the WHO study and they all had had a previous myocardial infarction, so that the deaths in the Coronary Drug Project were overwhelmingly due to cardiovascular causes, and it would have been very difficult to discern a clofibrate-associated risk of death due to noncardiovascular causes if it existed. Both studies demonstrated that clofibrate users have twice the risk of developing cholelithiasis and cholecystitis requiring surgery as do nonusers. A potential benefit of clofibrate was, however, reported in the WHO study which involved patients with hypercholesterolemia and no history of myocardial infarction or angina pectoris. In this study, there was a statistically significant 25% decrease in subsequent nonfatal myocardial infarctions in the clofibrate-treated group when compared with the placebo group. There was no difference in incidence of fatal myocardial infarction in the two groups. In the Coronary Drug Project study, which involved patients with or without hypercholesterolemia and/or hypertriglyceridemia and with a history of previous myocardial infarction, there was no significant difference in incidence of either nonfatal or fatal myocardial infarction between the clofibrate- and placebo-treated groups. 3 As a result of these and other studies, the following can be stated:
BECAUSE OF THE TUMORIGENICITY OF CLOFIBRATE IN RODENTS AND THE POSSIBLE INCREASED RISK OF MALIGNANCY ASSOCIATED WITH CLOFIBRATE IN THE HUMAN, AS WELL AS THE INCREASED RISK OF CHOLELITHIASIS, AND BECAUSE THERE IS NOT, TO DATE, SUBSTANTIAL EVIDENCE OF A BENEFICIAL EFFECT ON CARDIOVASCULAR MORTALITY FROM CLOFIBRATE, THIS DRUG SHOULD BE UTILIZED ONLY FOR THOSE PATIENTS DESCRIBED IN THE " " SECTION, AND SHOULD BE DISCONTINUED IF SIGNIFICANT LIPID RESPONSE IS NOT OBTAINED. |
Concomitant Anticoagulants
CAUTION SHOULD BE EXERCISED WHEN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH ATROMID-S®. THE DOSAGE OF THE ANTICOAGULANT SHOULD BE REDUCED USUALLY BY ONE-HALF (DEPENDING ON THE INDIVIDUAL CASE) TO MAINTAIN THE PROTHROMBIN TIME AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT PROTHROMBIN DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN LEVEL HAS BEEN STABILIZED.
Myalgia, myositis, myopathy, and rhabdomyolysis with or without elevation of CPK have been associated with Atromid-S therapy. Consideration should be given to withholding or discontinuing drug therapy in any patient with a risk factor predisposing to the development of renal failure secondary to rhabdomyolysis, including: severe acute infection; hypotension; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; and uncontrolled seizures.
Atromid-S therapy should be discontinued if markedly elevated CPK levels occur or myositis is diagnosed.
Avoidance of Pregnancy
Strict birth-control procedures must be exercised by women of child-bearing potential. In patients who plan to become pregnant, clofibrate should be withdrawn several months before conception. Because of the possibility of pregnancy occurring despite birth-control precautions in patients taking clofibrate, the possible benefits of the drug to the patient must be weighed against possible hazards to the fetus. (See Pregnancy section
General
Before instituting therapy with clofibrate, attempts should be made to control serum lipids with appropriate dietary regimens, weight loss in obese patients, control of diabetes mellitus, etc.
Because of the long-term administration of a drug of this nature, adequate baseline studies should be performed to determine that the patient has significantly elevated serum lipid levels. Frequent determinations of serum lipids should be obtained during the first few months of Atromid-S administration, and periodic determinations made thereafter. The drug should be withdrawn after three months if response is inadequate. However, in the case of xanthoma tuberosum, the drug should be employed for longer periods (even up to one year) provided that there is a reduction in the size and/or number of the xanthomata.
Since cholelithiasis is a possible side effect of clofibrate therapy, appropriate diagnostic procedures should be performed if signs and symptoms related to disease of the biliary system should occur.
Clofibrate may produce "flu-like" symptoms (muscular aching, soreness, cramping) associated with increased creatine kinase levels indicative of drug-induced myopathy. The physician should differentiate this from actual viral and/or bacterial disease.
Use with caution in patients with peptic ulcer, since reactivation has been reported. Whether this is drug related is unknown.
Various cardiac arrhythmias have been reported with the use of clofibrate.
Laboratory Tests
Subsequent serum lipid determinations should be done to detect a paradoxical rise in serum cholesterol or triglyceride levels. Clofibrate will not alter the seasonal variations of serum cholesterol: peak elevations in midwinter and late summer and decreases in fall and spring. If the drug is discontinued, the patient should be continued on an appropriate hypolipidemic diet, and serum lipids should be monitored until stabilized, as a rise in these values to or above the original baseline may occur.
During clofibrate therapy, frequent serum-transaminase determinations and other liver-function tests should be performed, since the drug may produce abnormalities in these parameters. These effects are usually reversible when the drug is discontinued. Hepatic biopsies are usually within normal limits. If the hepatic-function tests steadily rise or show excessive abnormalities, the drug should be withdrawn. Therefore, use with caution in those patients with a past history of jaundice or hepatic disease.
Complete blood counts should be done periodically since anemia, and more frequently, leukopenia have been reported in patients who have been taking clofibrate.
Caution should be exercised when anticoagulants are given in conjunction with Atromid-S. Usually, the dosage of the anticoagulant should be reduced by one-half (depending on the individual case) to maintain the prothrombin time at the desired level to prevent bleeding complications. Frequent prothrombin determinations are advisable until it has been determined definitely that the prothrombin level has been stabilized.
Atromid-S may displace acidic drugs such as phenytoin or tolbutamide from their binding sites. Caution should be exercised when treating patients with either of these drugs or other highly protein-bound drugs and Atromid-S. The hypoglycemic effect of tolbutamide has been reported to increase when Atromid-S is given concurrently.
Fulminant rhabdomyolysis has been seen as early as three weeks after initiation of combined therapy with another fibrate and lovastatin but may be seen after several months. For these reasons, it is felt that, in most subjects who have had an unsatisfactory lipid response to either drug alone, the possible benefits of combined therapy with lovastatin and a fibrate do not outweigh the risks of severe myopathy, rhabdomyolysis, and acute renal failure. While it is not known whether this interaction occurs with fibrates other than gemfibrozil, myopathy and rhabdomyolysis have occasionally been associated with the use of fibrates alone, including clofibrate. Therefore, the combined use of lovastatin with fibrates should generally be avoided.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See " " section for information on carcinogenesis and mutagenesis.
Arrest of spermatogenesis has been seen in both dogs and monkeys at doses approximately 2 times the maximum recommended human dose (based on surface area).
Electron microscopy studies have demonstrated peroxisomal proliferation following clofibrate administration to the rat. Changes in peroxisome morphology and numbers have been observed in humans after treatment with several members of the fibrate class, including clofibrate, when liver biopsies were compared before and after treatment in the same individual.
Pregnancy Category C. Animal reproduction studies have not been conducted with Atromid-S. It is also not known whether Atromid-S can cause fetal harm when administered to a pregnant woman or can affect reproductive capacity. However, animal reproduction studies with clofibrate plus androsterone showed increases in neonatal deaths and pup mortality during lactation.
Nursing Mothers
Atromid-S is contraindicated in lactating women, since an active metabolite (CPIB) has been measured in breast milk.
Pediatric Use
Safety and efficacy in pediatric patients have not been established.
The most common is nausea. Less frequently encountered gastrointestinal reactions are vomiting, loose stools, dyspepsia, flatulence, and abdominal distress. Reactions reported less often than gastrointestinal ones are headache, dizziness, and fatigue; muscle cramping, aching, and weakness; skin rash, urticaria, and pruritus; dry brittle hair, and alopecia.
The following reported adverse reactions are listed alphabetically by systems:
Increased or decreased angina.
Cardiac arrhythmias.
Dermatologic
Allergic reactions including urticaria.
Pruritus.
Dry skin and dry, brittle hair.
Alopecia.
Erythema multiforme.
Gastrointestinal
Gallstones.
Nausea.
Diarrhea.
Gastrointestinal upset (bloating, flatulence, abdominal distress).
Hepatomegaly (not associated with hepatotoxicity).
Stomatitis and gastritis.
Genitourinary
Findings consistent with renal dysfunction as evidenced by dysuria, hematuria, proteinuria, decreased urine output. One patient' renal biopsy suggested "allergic reaction."
Hematologic
Potentiation of anticoagulant effect.
Anemia.
Agranulocytosis.
Myalgia (muscle cramping, aching, weakness).
"Flu-like" symptoms.
Myopathy.
Rhabdomyolysis in the setting of preexisting renal insufficiency.
Arthralgia.
Neurologic
Fatigue, weakness, drowsiness.
Dizziness.
Miscellaneous
Polyphagia.
Laboratory Findings
Abnormal liver-function tests as evidenced by increased transaminase (SGOT and SGPT), BSP retention, and increased thymol turbidity.
Proteinuria.
Increased creatine phosphokinase.
Hyperkalemia in association with renal insufficiency and continuous ambulatory peritoneal dialysis treatment.
Reported adverse reactions whose direct relationship with the drug has not been established: peptic ulcer, gastrointestinal hemorrhage, rheumatoid arthritis, tremors, increased perspiration, systemic lupus erythematosus, blurred vision, gynecomastia, thrombocytopenic purpura.
While there has been no reported case of overdosage, should it occur, symptomatic supportive measures should be taken.
Initial: The recommended dosage for adults is 2 g daily in divided doses. Some patients may respond to a lower dosage.
Maintenance: Same as for initial dosage.
Atromid-S Capsules (clofibrate capsules)--Each orange, oblong, soft-gelatin capsule contains 500 mg clofibrate, in bottles of 100 (NDC 0046-0243-81).
The appearance of these orange, oblong, soft-gelatin capsules is a trademark of Wyeth-Ayerst Laboratories.
Dispense in a well-closed, light-resistant container as defined in the USP.
Avoid freezing and excessive heat.
Manufactured for
Ayerst Laboratories Inc.
A Wyeth-Ayerst Company
Philadelphia, PA 19101
CI 3770-7 Revised June 19, 1996
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