Professional Information
Clofibrate (Systemic)
 |
VA CLASSIFICATION
Primary: CV359
Commonly used brand name(s): Abitrate; Atromid-S; Claripex; Novofibrate.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
Category:
Antihyperlipidemic—
antidiuretic (central diabetes insipidus)—
Indications
Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.
Accepted
Hyperlipidemia (treatment)—Clofibrate is indicated in the treatment of hyperlipidemia. Because of risks associated with its use (see Side/Adverse Effects ), clofibrate is recommended for use as an adjunct only in patients with severe primary hyperlipidemia (type III hyperlipidemia) and a significant risk of coronary artery disease who have not responded to diet or other measures alone. Clofibrate reduces plasma triglyceride concentrations to a greater extent than plasma cholesterol concentrations, and so is not useful in patients with elevated cholesterol concentrations alone. Its use is limited in type II hyperlipidemia because of its variable effect on cholesterol concentrations. Clofibrate is not recommended for community-wide prevention of ischemic heart disease. {01}
—Studies have suggested that control of elevated cholesterol and triglycerides may not lessen the danger of cardiovascular disease and mortality, although incidence of nonfatal myocardial infarctions may be decreased.
—For additional information on initial therapeutic guidelines related to the treatment of hyperlipidemia, see Appendix III.
[Diabetes insipidus, central (treatment) ]1—Clofibrate has been used in the treatment of partial central diabetes insipidus in patients with some residual posterior pituitary function; {08} however, it generally has been replaced by other agents. {09}
Unaccepted
Although clofibrate alters platelet function (decreases platelet adhesiveness), it has not shown significant efficacy as an antiplatelet drug.
1 Not included in Canadian product labeling.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Molecular weight—
242.70
pKa—
2.95 {02}
Mechanism of action/Effect:
Antihyperlipidemic—Not completely understood, but may involve inhibition of biosynthesis of cholesterol before mevalonate formation, increased secretion and fecal excretion of neutral sterols, {01} enhanced catabolism of very low–density lipoproteins (VLDL) due to increased lipoprotein lipase activity in extrahepatic tissues, and/or increased clearance of triglycerides (VLDL) from the circulation. {02}
Antidiuretic—May stimulate release of antidiuretic hormone (ADH) from the posterior pituitary. {02}
Absorption:
Completely but slowly absorbed from the intestine.
Protein binding:
Very high (96%).
Biotransformation:
Hepatic and gastrointestinal; rapid de-esterification occurs in the gastrointestinal tract and/or on first-pass metabolism to produce the active form, clofibric acid (chlorophenoxy isobutyric acid [CPIB]). {02}
Half-life:
Single dose:
Normal: 6 to 25 hours.
Anuria: 113 hours.
Steady state:
Normal: 54 hours.
Onset of action:
Plasma VLDL concentrations are reduced within 2 to 5 days.
Time to peak plasma concentration
2 to 6 hours after a dose.
Time to peak effect:
3 weeks (with continued use).
Duration of action:
Return to pretreatment VLDL concentrations occurs within 3 weeks after clofibrate is withdrawn.
Elimination:
Renal; 10 to 20% of clofibric acid excreted unchanged; also as glucuronide conjugate (60%).
Precautions to Consider
Carcinogenicity
Clofibrate, in doses 5 to 8 times the human dose, has been found to increase the incidence of malignant hepatic tumors in rodents. {01}
Pregnancy/Reproduction
Pregnancy—
Studies have not been done in humans. However, clofibrate may cross the placenta, and the fetus may not have developed the enzyme system required to excrete it; use is not recommended during pregnancy. If a pregnancy is planned, clofibrate therapy should be withdrawn several months before conception. {01}
Studies in rabbits indicate that fetal serum concentrations of clofibrate may be higher than maternal serum concentrations.
FDA Pregnancy Category C.
Breast-feeding
Clofibrate is distributed into breast milk. {01} Use of clofibrate during breast-feeding is not recommended because of potentially serious adverse effects on nursing infants. {01}
Pediatrics
Appropriate studies on the relationship of age to the effects of clofibrate have not been performed in the pediatric population. However, use in children under 2 years of age is not recommended since cholesterol is required for normal development. {06}
Geriatrics
Although appropriate studies on the relationship of age to the effects of clofibrate have not been performed in the geriatric population, geriatrics-specific problems that would limit the usefulness of this medication in the elderly are not expected. However, elderly patients are more likely to have age-related renal function impairment, which may require dosage adjustment in patients receiving clofibrate.
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):
Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
» Anticoagulants, coumarin- or indandione-derivative (concurrent use with clofibrate may significantly increase the anticoagulant effect; adjustment of anticoagulant dosage based on frequent prothrombin-time determinations is recommended; some clinicians recommend reduction of the anticoagulant dosage by one-half {01} {03} {04})
Antidiabetic agents, oral, especially tolbutamide{01} (concurrent use of clofibrate with oral antidiabetic agents may enhance the hypoglycemic effect through displacement from serum proteins; dosage adjustments may be necessary. Glipizide and glyburide, due to their non-ionic binding characteristics, may not be affected as much as the other oral agents; however, caution with concurrent use is recommended {04})
Chenodiol or{10}
Ursodiol{11} (effect may be decreased when chenodiol or ursodiol is used concurrently with clofibrate since clofibrate tends to increase cholesterol saturation of bile)
HMG-CoA reductase inhibitors (concurrent use with clofibrate may increase the risk of rhabdomyolysis; cases of rhabdomyolysis have not been reported with concurrent use of clofibrate and HMG-CoA reductase inhibitors; however, there have been reported cases of rhadomyolysis with concurrent use of another fibrate, gemfibrozil, and lovastatin {17})
Oral contraceptives (concurrent use may alter the effectiveness of clofibrate {04} {07} {14})
Probenecid (concurrent use of probenecid may decrease renal and metabolic clearances and alter the protein binding of clofibrate, increasing the therapeutic and toxic effects of clofibrate {12} {13})
Rifampin (concurrent use with clofibrate may enhance the metabolism of clofibrate by induction of hepatic microsomal enzymes, resulting in significantly lower serum clofibrate concentrations {15} {16})
Laboratory value alterations
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With physiology/laboratory test values
Alanine aminotransferase (ALT [SGPT]) and
Aspartate aminotransferase (AST [SGOT]) (serum concentrations may be increased, indicating hepatotoxicity)
Amylase (serum concentrations may be increased)
Beta-lipoprotein, plasma (low-density lipoprotein [LDL] or cholesterol concentrations may be increased as a paradoxical response to a large decrease in very low–density lipoprotein [VLDL] concentrations)
Creatine kinase (CK) (concentrations may be increased, especially in patients with renal failure or hypoalbuminemia)
Fibrinogen (plasma concentrations may be decreased)
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:
» Primary biliary cirrhosis{01} (use of clofibrate may further raise the cholesterol)
Risk-benefit should be considered when the following medical problems exist
Cardiovascular disease{01} (condition may be exacerbated)
Gallstones (increased risk of biliary complications {01})
» Hepatic function impairment (protein binding of clofibrate is reduced but half-life is not altered. It is recommended that patients with impaired hepatic function receive a reduced dose of clofibrate; some clinicians recommend reduction of dosage by one-half in patients with cirrhosis {01})
Hypothyroidism (may predispose to clofibrate-induced myopathy {05})
Peptic ulcer (reactivation has been reported {01})
» Renal function impairment (reduced protein binding and clearance of clofibrate leads to increased incidence of side effects, especially myopathy and rhabdomyolysis. It is recommended that clofibrate be administered in reduced dosage to patients with impaired renal function. However, dosage reduction is not necessary in nephrotic syndrome when renal function is not impaired, since steady-state concentration of unbound drug is unchanged in spite of markedly reduced protein binding and half-life {01})
Sensitivity to clofibrate
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):
» Cholesterol, serum concentrations and
» Triglyceride, serum concentrations (determinations recommended prior to initiation of therapy, at 2-week intervals during the first few months of therapy, at monthly intervals thereafter to detect a paradoxical rise in serum cholesterol or triglyceride concentrations as well as to confirm efficacy, then every few months when concentrations stabilize {01} {09})
Complete blood counts (recommended prior to initiation of therapy and at periodic intervals during therapy if signs of anemia or leukopenia occur {01})
Creatine kinase (CK) concentrations (recommended at periodic intervals in uremic patients receiving clofibrate {01})
Liver function tests, including serum transaminase concentrations (determinations recommended prior to initiation of therapy, every month for the first 2 months, then every 2 months until an effect is observed, and every 4 months thereafter {01})
Side/Adverse Effects
Note: The suggestion that long-term use of clofibrate may increase the risk of death from noncardiovascular causes (malignancy, postcholecystectomy complications, pancreatitis) was made after results first published in 1978 of a large prospective study (the WHO study). This suggestion has been controversial, in part because other studies (for example, the Coronary Drug Project report published in 1975) have not reached a similar conclusion, although both major studies agree that the risk of cholelithiasis and cholecystitis requiring surgery is greatly increased in clofibrate users. Clofibrate has been found to increase the risk of development of peripheral vascular disease, pulmonary embolism, thrombophlebitis, angina pectoris, arrhythmias, and intermittent claudication. Clofibrate, in doses 5 to 8 times the human dose, has been found to increase the incidence of malignant hepatic tumors in rodents. {01}
Rhabdomyolysis and severe hyperkalemia have been reported in patients with pre-existing renal function impairment. {17}
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 rare
Anemia or leukopenia (fever or chills; cough or hoarseness; lower back or side pain; painful or difficult urination){01}
angina (chest pain; shortness of breath){01}
cardiac arrhythmias (irregular heartbeat)
gallstones or pancreatitis (severe stomach pain with nausea and vomiting)
renal toxicity (blood in urine; decrease in urination; painful urination; swelling of feet and lower legs){01}
Note: Increased creatine kinase (CK) and serum transaminase concentrations may be caused by clofibrate rather than myocardial infarction.
Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
Diarrhea{01}
nausea{01}
Incidence less frequent or rare
Decreased sexual ability{01}
flu-like syndrome or myositis (muscle aches or cramps; unusual tiredness or weakness)
headache{01}
increased appetite or weight gain, slight{01}
stomach pain, gas, or heartburn{01}
stomatitis (sores in mouth and on lips){01}
vomiting{01}
Note: Flu-like syndrome or myositis occurs more frequently in patients with existing renal disease, and usually is accompanied by increased CK and serum transaminases. {01}
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Clofibrate (Systemic).
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Before using this medication
Potential serious toxicity; WHO study controversy
Diet as preferred therapy
» Conditions affecting use, especially:
Sensitivity to clofibrate
Pregnancy—May cross placenta; enzyme system required for excretion may not be developed in fetus; withdrawal of clofibrate therapy several months before conception is recommended if pregnancy is planned {01}
Breast-feeding—Use not recommended while nursing because of potentially serious adverse effects on nursing infants
Use in children—Not recommended in children less than 2 years of age since cholesterol is required for normal development
Other medications, especially anticoagulants
Other medical problems, especially primary biliary cirrhosis, hepatic function impairment, or renal function impairment
Proper use of this medication
» Importance of not taking more or less medication than the amount prescribed
» Compliance with prescribed diet
Taking with meals to prevent possible gastric irritation
» Proper dosing
Missed dose: Taking as soon as possible; not taking if almost time for next dose; not doubling doses
» Proper storage
Precautions while using this medication
» Importance of close monitoring by the physician
» Checking with physician before discontinuing medication; blood lipid concentrations may increase significantly
Side/adverse effects
Signs of potential side effects, especially angina, cardiac arrhythmias, leukopenia, anemia, pancreatitis, gallstones, and renal toxicity
General Dosing Information
If response is inadequate after 3 months of treatment, clofibrate therapy should be withdrawn, except in the case of xanthoma tuberosum, which may require up to 1 year of treatment as long as reduction in size and/or number of xanthomata occurs. {01}
If results of hepatic function tests rise significantly or show significant abnormalities, it is recommended that clofibrate therapy be withdrawn and not resumed; laboratory abnormalities are usually reversible. {01}
If an increase in serum amylase concentrations or a paradoxical increase in plasma cholesterol or plasma LDL concentrations occurs, it is recommended that clofibrate therapy be withdrawn.
When clofibrate is discontinued, an appropriate hypolipidemic diet and monitoring of serum lipids are recommended until the patient stabilizes, since a rise in serum cholesterol and triglyceride concentrations to or above the original base may occur. {01}
Diet/Nutrition
It is recommended that clofibrate be taken with food to minimize gastrointestinal upset.
Oral Dosage Forms
CLOFIBRATE CAPSULES USP
Usual adult dose
Antihyperlipidemic
Oral, 1.5 to 2 grams per day in two to four divided doses.
Note: Clofibrate has been used in the treatment of diabetes insipidus at an oral dose of 6 to 8 grams per day in two or four divided doses.
Usual adult prescribing limits
Antihyperlipidemic
2 grams daily.
Usual pediatric dose
Dosage has not been established.
Strength(s) usually available
U.S.—
500 mg (Rx) [Abitrate] [Atromid-S][Generic]
Canada—
500 mg (Rx) [Atromid-S] [Claripex] [Novofibrate]
1 gram (Rx) [Atromid-S]
Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), unless otherwise specified by manufacturer. Store in a well-closed, light-resistant container.
Auxiliary labeling:
• Take with meals.
Developed: 04/14/1994
Revised: 08/12/1998
References
Note: All references used in the development and earlier revisions of this monograph have not yet been incorporated into the computer database and, therefore, are not listed below. Citations for information not yet referenced in the monograph will be provided upon request.
- Atromid-S product information (Ayerst—US), Rec 1/90.
- Hospital Formulary Service, 1989: 859-62.
- Perry R. Contemporary recommendations for evaluating and treating hyperlipidemia. Clin Pharmacy 1986; 5: 113-27.
- Hansten's drug interactions. 5th ed. 1985: 152-3.
- Lehotay D, et al. Influence of clofibrate on thyroid hormone and muscle protein turnover. Metabolism 1984; 33(11): 1048-51.
- Panel comment, 1991.
- D'Arcy P. Drug interactions with oral contraceptives. DICP 1986; 20: 353-62.
- Avery's drug treatment. 2nd ed. 1980.
- Reviewers" consensus on monograph revision of 1991.
- Chenix product information (Reid-Rowell—US), Rec 10/88.
- Actigall product information (Ciba—US), Rev 6/88, Rec 1989.
- Drug information facts, 1990 Edition.
- Veenendaal J, Brooks P, Meffin P. Probenecid-clofibrate interaction. Clin Pharmacol Ther 1981; 29(3): 351-8.
- Miners J, Robson R, Burkett D. Gender and oral contraceptive steroid as determinants of drug glucuronidation: effects on clofibrate elimination. Br J Clin Pharmacol 1984; 18: 240-3.
- Hansten's drug interactions. 6th ed. 1989.
- Houin G, Tillement J. Clofibrate and enzymatic induction in man. Int J Clin Pharmacol 1978; 16: 150-4.
- Atromid-S package insert (Wyeth-Ayerst), Rev 4/91, Rec 6/92.
- The Expert Panel. Report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults. Arch Intern Med 1988 Jan; 148: 36-69.
- NIH Consensus Conference. Lowering blood cholesterol to prevent heart disease. JAMA 1985 Apr 12; 253: 2080-6.
- Knodel LC, Talbert RL. Adverse effects of hypolipidaemic drugs. Med Toxicol 1987; 2: 10-32.
 |
Link to Page |  |
Print Page |  |
Email Page |
