Clofibrate

Clofibrate

Clinical data
Pregnancy category	AU: B1 US: C (Risk not ruled out)
Routes of administration	Oral
ATC code	C10AB01 (WHO)
Legal status
Legal status	US: ℞-only
Pharmacokinetic data
Protein binding	Variable, 92–97% at therapeutic concentrations
Metabolism	Hydrolyzed to clofibric acid; hepatic glucuronidation
Elimination half-life	Highly variable; average 18–22 hours. Prolonged in renal failure
Excretion	Renal, 95 to 99%
Identifiers
IUPAC name ethyl 2-(4-chlorophenoxy)-2-methylpropanoate
CAS Number	637-07-0
PubChem CID	2796
DrugBank	APRD00879
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C12H15ClO3
Molar mass	242.698 g/mol

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Associate Editor: Cafer Zorkun, M.D., Ph.D. [2]

Overview

Clofibrate is a fibrate. It is used in the treatment of cardiovascular disease.

Generic Available

Yes

Use

Adjunct to dietary therapy in the management of hyperlipidemias associated with high triglyceride levels (types III, IV, V); primarily lowers triglycerides and very low density lipoprotein

Pregnancy Risk Factor

C

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to clofibrate or any component of the formulation; significant hepatic or renal dysfunction; primary biliary cirrhosis

Warnings/Precautions

Possible increased risk of malignancy and cholelithiasis. No evidence of cardiovascular mortality benefit. Anemia and leukopenia have been reported. Elevations in serum transaminases can be seen. Discontinue if lipid response is not seen. Use with caution in peptic ulcer disease. Flu-like symptoms may occur. Be careful in patient selection; this is not a first- or second-line choice. Other agents may be more suitable.

Adverse Reactions

Frequency not defined

Common: Gastrointestinal: Nausea, diarrhea

Less common:

Central nervous system: Headache, dizziness, fatigue

Gastrointestinal: Vomiting, loose stools, heartburn, flatulence, abdominal distress, epigastric pain

Neuromuscular & skeletal: Muscle cramping, aching, weakness, myalgia

Frequency unknown

Central nervous system: Fever

Cardiovascular: Chest pain, cardiac arrhythmia

Dermatologic: Rash, urticaria, pruritus, alopecia, toxic epidermal necrolysis, erythema multiforme, Stevens-Johnson syndrome; dry, brittle hair

Endocrine & metabolic: Polyphagia, gynecomastia, hyperkalemia

Gastrointestinal: Stomatitis, gallstones, pancreatitis, gastritis, peptic ulcer, weight gain

Genitourinary: Impotence, decreased libido

Hematologic: Leukopenia, anemia, eosinophilia, agranulocytosis, thrombocytopenic purpura

Hepatic: Hepatomegaly, jaundice, liver function tests increased

Local: Thrombophlebitis

Neuromuscular & skeletal: Myalgia, myopathy, myositis, arthralgia, rhabdomyolysis, increased creatinine phosphokinase (CPK), rheumatoid arthritis, tremor

Ocular: Photophobic

Renal: Dysuria, hematuria, proteinuria, renal toxicity (allergic), rhabdomyolysis-induced renal failure

Miscellaneous: Diaphoresis increased, flu-like syndrome, systemic lupus erythematosus

Overdosage/Toxicology Symptoms of overdose include nausea, vomiting, diarrhea, and GI distress. Treatment is supportive.

Drug Interactions

Substrate of CYP3A4 (minor); Inhibits CYP2A6 (weak); Induces CYP2B6 (weak), 2E1 (weak), 3A4 (weak)

Chlorpropamide: May increase risk of hypoglycemia.

Furosemide: Blood levels of furosemide and fibric acid derivatives (ie, clofibrate and fenofibrate) may be increased during concurrent dosing (particularly in hypoalbuminemia). Limited documentation; monitor for increased effect/toxicity.

HMG-CoA reductase inhibitors (atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, simvastatin) may increase the risk of myopathy and rhabdomyolysis. The manufacturer warns against the concomitant use. However, combination therapy with statins has been used in some patients with resistant hyperlipidemias (with great caution).

Insulin: Hypoglycemic effects may be potentiated by an unknown mechanism.

Probenecid may decrease the clearance of clofibrate.

Rifampin: Decreased clofibrate blood levels.

Sulfonylureas (including glyburide, glipizide): Hypoglycemic effects may be potentiated by an unknown mechanism.

Warfarin: Increased hypoprothrombinemic response; monitor INRs closely when clofibrate is initiated or discontinued.

Mechanism of Action

Mechanism is unclear but thought to reduce cholesterol synthesis and triglyceride hepatic-vascular transference

Pharmacodynamics/Kinetics

Absorption: Complete

Distribution: Vd: 5.5 L/kg; crosses placenta

Protein binding: 95%

Metabolism: Hepatic to an inactive glucuronide ester; intestinal transformation required to activate drug

Half-life elimination: 6-24 hours, significantly prolonged with renal impairment; Anuria: 110 hours

Time to peak, serum: 3-6 hours

Excretion: Urine (40% to 70%)

Dosage

Adults: Oral: 500 mg 4 times/day; some patients may respond to lower doses

Dosing interval in renal impairment:

Clcr >50 mL/minute: Administer every 6-12 hours

Clcr 10-50 mL/minute: Administer every 12-18 hours

Clcr<10 mL/minute: Avoid use

Hemodialysis: Elimination is not enhanced via hemodialysis; supplemental dose is not necessary

Administration

Administer with meals or milk if GI upset occurs.

Monitoring Parameters

Serum lipids, cholesterol and triglycerides, LFTs, CBC

Test Interactions

Increased creatine phosphokinase [CPK] (S); decreased alkaline phosphatase (S), cholesterol (S), glucose, uric acid (S)

Patient Education

Inform prescriber of all prescriptions, OTC medications, or herbal products you are taking, and any allergies you have. Do not take any new medication during therapy unless approved by prescriber. Take as directed. May take with food or milk to reduce stomach upset.

This drug may have to be taken long-term; ongoing follow-up is essential. May cause nausea, vomiting, or stomach upset (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); headache, dizziness, fatigue (use care when driving or engaging in potentially hazardous tasks until response to drug is known); or muscle cramping or pain (if persistent, consult prescriber for analgesic).

Report chest pain, shortness of breath, irregular heartbeat, palpitations, severe stomach pain with persistent nausea and vomiting, persistent fever, sore throat, or unusual bleeding or bruising. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.

Nursing Implications

Monitor serum lipids, LFTs, CBC

Cardiovascular Considerations

Fibric acids decrease triglycerides (TGs) by 20% to 50%, and increase HDL-cholesterol (HDL-C) by 10% to 35%. They decrease LDL-cholesterol (LDL-C) by 5% to 20%, however, LDL-C actually may increase by 10% to 30% when fibrates are initiated in patients with high TGs (>400 mg/dL).

Dental Health: Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Stomatitis.

Dental Health: Vasoconstrictor/Local Anesthetic Precautions No information available to require special precautions

Mental Health: Effects on Mental Status

May cause sedation or dizziness

Mental Health: Effects on Psychiatric Treatment Rare reports of agranulocytosis; use caution with clozapine and carbamazepine

Dosage Forms

Capsule: 500 mg

References

"Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III)," JAMA , 2001, 285(19):2486-97.

Mahley RW and Bersot TP, "Drug Therapy for Hypercholesterolemia and Dyslipidemia," Goodman and Gilman's The Pharmacological Basis of Therapeutics , 10th ed, Hardman JE and Limbird LE, eds, New York, NY: McGraw-Hill, 2001, 993-5.

"WHO Cooperative Trial on Primary Prevention of Ischaemic Heart Disease With Clofibrate to Lower Serum Cholesterol: Final Mortality Follow-up. Report of the Committee of Principal Investigators," Lancet , 1984, 2(8403):600-4.

International Brand Names

Arterioflexin® (AT) Atromid® (HK) Atromidin® (LU) Claripex (CA) Clof® (CH) Clofibrat Tripharma® (CH) Elpi® (AR) Levatrom® (IL) Lipilim® (HK) Novo-Fibrate (CA)

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