Bezafibrate

Bezafibrate

Clinical data
Dependence liability	N/A
Routes of administration	oral
ATC code	C10AB02 (WHO)
Legal status
Legal status	RX/POM
Identifiers
IUPAC name 2-[4-[2-[(4-chlorobenzoyl)amino] ethyl]phenoxy]-2-methyl-propanoic acid
CAS Number	41859-67-0
PubChem CID	39042
E number	{{#property:P628}}
ECHA InfoCard	{{#property:P2566}}
Chemical and physical data
Formula	C19H20ClNO4
Molar mass	361.819

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2]

Overview

Bezafibrate (Bezalip® and various other brand names) is a fibrate drug used for the treatment of hyperlipidaemia. It helps to lower LDL cholesterol and triglyceride in the blood, and increase HDL.

History

Bezafibrate was first introduced by Boehringer Mannheim in 1977.

Use

Adjunct to diet and other therapeutic measures for treatment of type IIa and IIb mixed [[hyperlipidemia, to regulate lipid and apoprotein levels; treatment of adult patients with high to very high triglyceride levels (Fredrickson classification type IV and V hyperlipidemias), who are at high risk of sequelae and complications from their dyslipidemia.

Bezafibrate improves markers of combined hyperlipidemia, effectively reducing LDL and triglycerides and improving HDL levels. The main effect on cardiovascular morbidity is in patients with the metabolic syndrome, the features of which are attenuated by bezafibrate. Studies show that in patients with impaired glucose tolerance, bezafibrate may delay progress to diabetes, and in those with insulin resistance it slowed progress in the HOMA severity marker.

Administration

Immediate release: Do not crush or chew; tablet should be swallowed whole and with sufficient fluid, with or after meals

Sustained release: Do not crush or chew; tablet should be swallowed whole with sufficient fluid. Take in morning or evening with or after meals

Pregnancy Risk Factor

Not available; not recommended (per manufacturer)

Pregnancy Implications

Embryotoxicity has occurred in animals at toxic doses. Women planning pregnancy should discontinue bezafibrate several months before conception; strict birth control procedures must be exercised.

Lactation

Excretion in breast milk unknown/contraindicated

Contraindications

Hypersensitivity to bezafibrate, fibrates, or any component of the formulation; hepatic or renal dysfunction; primary biliary cirrhosis; preexisting gallbladder disease; concurrent use of MAO inhibitors; pregnancy or breast-feeding; not indicated for the treatment of type I hyperlipoproteinemia

Warnings/Precautions

Has been shown to be hepatotoxic and possibly tumorigenic (animal models); discontinue if response is not obtained in 3 months. Use caution in patients with history of jaundice or hepatic disorder; abnormal liver function tests have been observed (reversible when discontinued). Bezafibrate has been associated with rare myositis or rhabdomyolysis; risk may be increased by concurrent therapy with HMG CoA reductase inhibitors or cyclosporine. Use caution in renal impairment (dosage reduction required). Use with caution in patients with hypoalbuminemia or nephrotic syndrome. Limited experience is available in children; therefore, caution should be used when treating children.

Adverse Reactions

1% to 10%

Central nervous system: Dizziness (2%), insomnia (1%), migraine (1%), pain (1%)

Dermatologic: Pruritus (3%), eczema (1%), rash

Gastrointestinal: Gastritis (6%), flatulence (5%), dyspepsia (3%), nausea, diarrhea, constipation

Hematologic: Anemia (1%)

Hepatic: Transaminases increased

Miscellaneous: Allergic reaction (1%)

Neuromuscular and skeletal: CPK increased

Renal: Creatinine increased

<1%: Alkaline phosphatase increased, alopecia, asthenia, cholelithiasis, epigastric distress, erythema, headache, impotence, muscle pain, muscle cramps, myopathy, rhabdomyolysis, urticaria

Overdosage/Toxicology

Limited information. Symptomatic and supportive measures should be taken; hemodialysis should not be considered. In patients with existing renal dysfunction (if dosage recommendations are not followed), over dosage may occur and severe rhabdomyolysis may develop.

Drug Interactions

• Substrate of CYP3A4 (minor)
• Cholestyramine and colestipol: May impair bezafibrate absorption (separate doses by at least 2 hours).
• Cyclosporine: Severe myositis and rhabdomyolysis have been reported with concurrent use.
• Furosemide: Blood levels of furosemide and fibric acid derivatives (i.e., clofibrate and fenofibrate) may be increased during concurrent dosing (particularly in hypoalbuminemia). Limited documentation; monitor for increased effect/toxicity.
• HMG-CoA reductase inhibitors: Severe myositis and rhabdomyolysis have been reported with concurrent use; use extreme caution.
• MAO inhibitors: May increase the risk of hepatotoxicity.
• Warfarin (oral anticoagulants): May increase prothrombin time; dosage of oral anticoagulant should be reduced by 50%.

Stability

Store at room temperature of 15°C to 30°C (59°F to 86°F); protect from high humidity.

Mechanism of Action

Mechanism not definitely established; may increase VLDL catabolism by increasing lipoprotein and hepatic triglyceride lipase activities; attenuation of triglyceride biosynthesis by inhibition of acetyl-CoA carboxylase; decreased cholesterol biosynthesis by inhibition of 3-hydroxy-3-methyglutaryl-coenzyme A reductase

Pharmacodynamics/Kinetics

Absorption: Immediate release: Almost completely; Sustained release: 70%

Distribution: 17 L

Protein binding: 94% to 96%

Half-life elimination: 1-2 hours

Time to peak, serum: Immediate release: 1-2 hours; Sustained release: 3-4 hours

Excretion: Urine (95%); feces (3%)

Like the other fibrates, bezafibrate is an agonist of PPARα; some studies suggest it may have some activity on PPARγ and PPARδ as well.

Dosage

Oral: Adults:

Immediate release: 200 mg 2-3 times/day; may reduce to 200 mg twice daily in patients with good response

Sustained release: 400 mg once daily

Dosing interval in renal impairment:

Clcr >60 mL/minute: 200 mg 3 times/day

Clcr 60-40 mL/minute: 200 mg 2 times/day

Clcr 40-15 mL/minute: 200 mg every 1-2 days

Clcr<15 mL/minute: 200 mg every 3 days

Hemodialysis: 200 mg every 3 days

Monitoring Parameters

Periodic evaluation of serum lipids, cholesterol, and triglycerides (especially in the first few months of therapy). LFTs after 3-6 months; then annually. CBC (periodically during the first 12 months). Fasting glucose, creatinine, and CPK periodically.

Test Interactions

Glucose, creatinine, ALT, CGT, and CPK

Dietary Considerations

Should be taken with or after meals. Before initiation of therapy, patients should be placed on a standard lipid-lowering diet for 6 weeks and the diet should be continued during drug therapy.

Patient Education

Comply exactly to the terms of the prescription; do not change the dose or stop prescription without your prescriber's advice. Medication is meant to supplement an appropriate diet. Inform prescriber if you suffer from liver or kidney disease or are taking other medications (especially warfarin or cyclosporine). Swallow tablets without chewing and with sufficient fluid, with or after meals. If you are also taking cholestyramine or a bile acid resin, separate doses by at least 2 hours. Call prescriber if you experience abdominal pain, constipation, diarrhea, nausea, headache, dizziness, skin reactions, muscular pain or cramps, and fatigue. You will need regular check-ups and laboratory monitoring as recommended by your prescriber. 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

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

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

Mental Health: Effects on Mental Status

May cause dizziness or insomnia

Mental Health: Effects on Psychiatric Treatment Contraindicated with MAO inhibitors

Available Dosage Forms

Tablet, immediate release: 200 mg

Tablet, sustained release: 400 mg

Side-effects

The main toxicity is hepatic (abnormal liver enzymes), and myopathy and rarely rhabdomyolysis have been reported.

Other uses

The Australian biotech company Giaconda combines bezafibrate with chenodeoxycholic acid in an anti-hepatitis C drug combination called Hepaconda.

International Brand Names

Azufibrat® (DE); Befibrat® (DE); Béfizal® (FR); Beza 1A Pharma® (DE); Beza AbZ® (DE); Bezabeta® (DE); Bezacur® (AR, DE, LU); Bezacur® Retard (CL); Bezadoc® (DE); Bezafibrat 1A Pharma® (AT); Bezafibrat AL® (DE); Bezafibrat Arcana® (AT); Bezafibrate® (GB, ID, IL); Bezafibrat Genericon® (AT); Bezafibrat Heumann® (DE); Bezafibrat Lannacher® (AT); Bezafibrato Genfar® (EC); Bezafibrat PB® (DE); Bezafibrat Ratiopharm® (AT); Bezafibrat-ratiopharm® (DE); Bezafibrat Sandoz® (DE); Bezafibrat Stada® (DE); Bezafibrat Stada Retard® (SG); bezafibrat von ct® (DE); Bezafisal® (MX); Bezagamma® (DE); Bezagen® (GB); Bezalip® (AT, BE, BR, CA, CH, CO, CR, CZ, DE, DO, EC, ES, FI, FR, GB, GT, HK, HU, ID, IN, IT, JO, JP, LU, MX, NL, NZ, PA, PH, SE, SG, SV, TH, TW, ZA); Bezalip® Retard (AT, IL, PL, RO, SE, SG, TH); Bezamerck® (DE); Bezamidin® (PL); Bezamil® (TH); Bezapharm® (DE); Bezastad® (AT); Bezatol® (JP); Cedur® (BE, BR, CH, DE, LU); Cholestenorm® (RU); Decolest® (RO); Difaterol® (ES); Elpi Lip® (AR); Eulitop® (BE, ES); Fibalip® (NZ); Hadiel® (IT); Lacromid® (CY); Liparol® (GB); Lipox® (DE); Nebufurd Retard® (AR); Nimus® (CL); Norlip® (IL); Oralipin® (CL); Oralipin Retard® (CL); PMS-Bezafibrate (CA); Polyzalip® (TH); Raset® (TH); Reducterol® (ES); Regadrin B® (CZ, DE, RO); Rolab-Bezafibrate® (ZA); Sklerofibrat® (DE); Solibay® (MX); Verbital® (RO); Zafibral® (SG); Zimbacol® (GB)