Hyperlipidemia, mixed: Oral: Sustained release: 400 mg once daily.
Hypertriglyceridemia (alternative agent) (adjunctive agent):
Note: For patients requiring fibrate therapy, fenofibrate is generally preferred. All patients should receive general measures (ie, address modifiable causes, manage atherosclerotic cardiovascular disease [ASCVD] risk, implement lifestyle modification [eg, dietary changes, reduction of alcohol consumption]) and optimal low-density lipoprotein lowering therapy for 4 to 12 weeks before considering triglyceride lowering therapy. For patients whose triglycerides remain ≥500 mg/dL and who do not warrant icosapent ethyl for additional ASCVD risk reduction, either a fibrate or any prescription strength omega-3 fatty acid (including icosapent ethyl) is reasonable (ACC [Virani 2021]).
Oral: Sustained release: 400 mg once daily.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
CrCl ≥60 mL/minute: No dosage adjustment required
CrCl <60 mL/minute or Scr >1.5 mg/dL [>135 micromol/L]: Use is contraindicated
Dialysis: Use is contraindicated.
Use is contraindicated.
Dyslipidemia: Children and Adolescents: Oral: 10 to 20 mg/kg/day (maximum: 400 mg daily). Note: Limited experience available; use caution. Based on child’s weight, dosing may not be possible as the manufacturer recommends administering the sustained release tablet whole.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Patients ≤70 years of age: Refer to adult dosing.
Patients >70 years of age: Avoid use in patients >70 years of age due to declining renal function and the likelihood of CrCl <60 mL/minute in this population.
Yes
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release, Oral:
Bezalip SR: 400 mg
Generic: 400 mg
Not available in the US
Do not crush or chew tablet; should be swallowed whole with sufficient fluid. Administer in morning or evening with or after meals.
Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Cannot be cut or crushed. Switch to fenofibrate tablet.
Oral: Sustained release: Do not crush or chew; tablet should be swallowed whole with sufficient fluid. Take in morning or evening with or after meals. Take a missed dose as soon as remembered unless it is almost time for the next dose, then skip the missed dose and continue your regular dosing schedule. Do not take 2 doses at the same time.
Note: Not approved in the United States.
Hyperlipidemia, mixed or hypertriglyceridemia: Adjunct to diet and other therapeutic measures for treatment of type IIa and IIb mixed hyperlipidemia, to regulate lipid and apoprotein levels (reduce serum TG, LDL-cholesterol, and apolipoprotein B, increase HDL-cholesterol and apolipoprotein A); 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.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Adverse reactions are for immediate release formulation.
>10%:
Hepatic: Increased serum aspartate aminotransferase
Neuromuscular & skeletal: Increased creatine phosphokinase in blood specimen
1% to 10%:
Dermatologic: Eczema (1%), pruritus (3%)
Gastrointestinal: Decreased appetite, diarrhea, dyspepsia (3%), flatulence (5%), gastritis (6%)
Hematologic & oncologic: Anemia (1%)
Hypersensitivity: Hypersensitivity reaction (1%)
Nervous system: Dizziness (2%), headache, insomnia (1%), migraine (1%), pain (1%)
Respiratory: Bronchitis, pharyngitis
<1%:
Dermatologic: Alopecia, erythema multiforme, skin photosensitivity, skin rash, toxic epidermal necrolysis, urticaria
Gastrointestinal: Abdominal distention, abdominal pain, cholelithiasis, cholestasis, constipation, nausea
Genitourinary: Erectile dysfunction
Hematologic & oncologic: Decreased white blood cell count, immune thrombocytopenia, pancytopenia, thrombocytopenia
Hepatic: Abnormal hepatic function tests (including decreased serum alkaline phosphatase, increased serum alkaline phosphatase, and increased serum transaminases), decreased gamma-glutamyl transferase, increased gamma-glutamyl transferase
Nervous system: Depression, myasthenia, paresthesia
Neuromuscular & skeletal: Muscle cramps, myalgia, myositis
Renal: Acute kidney injury, increased serum creatinine
Respiratory: Interstitial pulmonary disease
Postmarketing:
Dermatologic: Purpuric rash (pigmented purpuric dermatosis) (Yung 2005), Stevens-Johnson syndrome (Sawamura 2000)
Gastrointestinal: Pancreatitis (Gang 1999)
Hypersensitivity: Anaphylaxis (Frendo 2007), angioedema (Frendo 2007)
Nervous system: Peripheral neuropathy (Ellis 1994)
Neuromuscular & skeletal: Rhabdomyolysis (Panuccio 1996)
Hypersensitivity to bezafibrate, fibrates, or any component of the formulation; photoallergic or phototoxic reactions to fibrates; hepatic impairment; primary biliary cirrhosis; renal impairment (serum creatinine >1.5 mg/dL [>135 micromol/L], CrCl <60 mL/minute, or patients undergoing dialysis); pre-existing gallbladder disease; concomitant use with HMG CoA reductase inhibitors in patients predisposed to myopathy (eg, preexisting renal impairment, hormonal or electrolyte imbalance, severe infection, trauma, surgery); pregnancy or breast-feeding; not indicated for the treatment of type I hyperlipoproteinemia
Concerns related to adverse effects:
• Hematologic effects: Mild decreases in WBCs, platelets, and hemoglobin may occur following initiation of therapy; levels tend to stabilize with prolonged therapy.
• Hepatic effects: Has been shown to be hepatotoxic; discontinue therapy if significant response is not obtained in 3 months. Use with caution in patients with history of jaundice or hepatic disorder. Abnormal liver function tests have been observed; discontinue therapy if abnormalities persist (reversible when discontinued). May increase risk for cholelithiasis; discontinue therapy in patients diagnosed with cholelithiasis.
• Myopathy/rhabdomyolysis: Has been associated with rare myositis or rhabdomyolysis (usually with renal impairment); monitor closely. Instruct patients to report unexplained muscle pain, tenderness, weakness, or brown urine. Evaluate creatine phosphokinase (CPK) levels with signs/symptoms of myotoxicity; discontinue therapy with marked elevation of CPK (10 x ULN) or diagnosis of myopathy.
Special populations:
• Older adult: Due to the likelihood of renal impairment (CrCl <60 mL/minute) in patients >70 years of age, use is not recommended in this patient population.
• Pediatric: Limited experience is available in children; therefore, caution should be used when treating children. Accurate dosing may not be achievable as sustained release tablet should be administered whole and not cut.
Other warnings/precautions:
• Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy.
Substrate of CYP3A4 (minor); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Acipimox: May enhance the myopathic (rhabdomyolysis) effect of Fibric Acid Derivatives. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Fibric Acid Derivatives. Management: Separate doses by at least 2 hours to minimize this interaction; fenofibric acid labeling recommends administration one hour prior to or 4-6 hours after a bile acid sequestrant. Risk D: Consider therapy modification
Ciprofibrate: May enhance the adverse/toxic effect of Fibric Acid Derivatives. Risk X: Avoid combination
Colchicine: Fibric Acid Derivatives may enhance the myopathic (rhabdomyolysis) effect of Colchicine. Risk C: Monitor therapy
CycloSPORINE (Systemic): May enhance the nephrotoxic effect of Fibric Acid Derivatives. Fibric Acid Derivatives may decrease the serum concentration of CycloSPORINE (Systemic). Management: Careful consideration of the risks and benefits should be undertaken prior to use of this combination; extra monitoring of renal function and cyclosporine concentrations will likely be required. Adjustment of cyclosporine dose may be necessary. Risk D: Consider therapy modification
Ezetimibe: Fibric Acid Derivatives may enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Fibric Acid Derivatives may increase the serum concentration of Ezetimibe. Risk X: Avoid combination
HMG-CoA Reductase Inhibitors (Statins): Bezafibrate may enhance the myopathic (rhabdomyolysis) effect of HMG-CoA Reductase Inhibitors (Statins). Bezafibrate may increase the serum concentration of HMG-CoA Reductase Inhibitors (Statins). More specifically, bezafibrate may increase the serum concentration of fluvastatin Management: Avoid use of bezafibrate and HMG-CoA reductase inhibitors (statins) unless strictly indicated due to the increased of muscle toxicity (including rhabdomyolysis). In patients who may be predisposed to myopathy, concomitant use is contraindicated. Risk D: Consider therapy modification
Mizoribine: May enhance the adverse/toxic effect of Bezafibrate. Specifically, the risk for muscle toxicities may be increased. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the adverse/toxic effect of Bezafibrate. Risk X: Avoid combination
Raltegravir: May enhance the myopathic (rhabdomyolysis) effect of Fibric Acid Derivatives. Risk C: Monitor therapy
Sulfonylureas: Fibric Acid Derivatives may enhance the hypoglycemic effect of Sulfonylureas. Risk C: Monitor therapy
Vitamin K Antagonists (eg, warfarin): Fibric Acid Derivatives may enhance the anticoagulant effect of Vitamin K Antagonists. Management: Consider reducing the oral anticoagulant dose by 25% to 33% when initiating a fibric acid derivative. Monitor for toxic or reduced anticoagulant effects if a fibric acid derivative is initiated/dose increased, or discontinued/dose decreased, respectively. Risk D: Consider therapy modification
Effective contraception is recommended when used in females of reproductive potential. Women planning pregnancy should discontinue bezafibrate several months before conception.
Use is contraindicated in pregnant women. Therapy should be discontinued in women who become pregnant during therapy.
It is not known if bezafibrate is excreted in breast milk. Use in breastfeeding women is contraindicated.
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.
Periodic evaluation of serum lipids, cholesterol, and triglycerides (especially in the first few months of therapy). LFTs after 3-6 months; then at least annually. CBC (periodically during the first 12 months). Fasting glucose, creatinine, and CPK periodically.
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
Distribution: ~17 L
Protein binding: 94% to 96%
Half-life elimination: 1-2 hours
Time to peak, serum: 3-4 hours
Excretion: Urine (95%); feces (3%)
