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Fenofibric Acid/Fenofibrate

Class: Fibric Acid Derivatives
VA Class: CV350
Chemical Name: 2-[p-(p-chlorobenzoyl)phenoxy]-2-methylpropionate
Molecular Formula: C20H21ClO4
CAS Number: 42017-89-0
Brands: Antara, Fenoglide, Lipofen, Lofibra, TriCor, Triglide, Trilipix

Medically reviewed by Drugs.com on Nov 11, 2020. Written by ASHP.

Introduction

Fenofibric acid (active moiety) and fenofibrate are antilipemic agents; fibric acid derivatives.

Uses for Fenofibric Acid/Fenofibrate

Dyslipidemias

Adjuncts to dietary therapy to decrease elevated serum total and LDL-cholesterol, triglyceride, and apolipoprotein B (apo B) concentrations, and to increase HDL-cholesterol concentrations in the management of primary hypercholesterolemia and mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia. Additive antilipemic effects when used concomitantly with other antilipemic agents (e.g., colesevelam, ezetimibe).

Potential benefit unlikely to outweigh potential risks in patients with type IIa hyperlipoproteinemia and elevations of LDL-cholesterol only (because of toxicity, including malignancy, gallbladder disease, abdominal pain leading to appendectomy and other abdominal surgeries, and increased incidence of noncardiovascular and all-cause mortality, associated with the chemically and pharmacologically similar drug clofibrate [no longer commercially available in US]).

Fenofibric acid: Used in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin) to decrease triglyceride concentrations and increase HDL-cholesterol concentrations in patients with mixed dyslipidemia and CHD (or CHD risk equivalents) who are receiving optimal statin therapy; however, no incremental benefit on cardiovascular morbidity and mortality beyond that already established with statin monotherapy.

Adjuncts to dietary therapy in the management of severe hypertriglyceridemia. Efficacy in reducing risk of pancreatitis in patients with marked elevations in triglyceride concentrations (i.e., >2000 mg/dL) not established.

Effects on cardiovascular morbidity and mortality or noncardiovascular mortality not established. (See Effects on Morbidity and Mortality under Cautions.)

ACC/AHA cholesterol management guideline states that nonstatin drugs (e.g., fibric acid derivatives) do not provide acceptable atherosclerotic cardiovascular disease (ASCVD) risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. May be useful as adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, patients with LDL-cholesterol concentrations ≥190 mg/dL, patients 40–75 years of age with diabetes mellitus) who have a less-than-anticipated response to statins, are unable to tolerate even a less-than-recommended intensity of a statin, or are completely intolerant to statin therapy. However, because the addition of fenofibrate to simvastatin therapy has not been shown to provide an incremental benefit on cardiovascular morbidity and mortality beyond that already established with statin monotherapy, ACC/AHA cholesterol management guideline states that combination of fenofibrate and low- or moderate-intensity statin therapy may be considered only if benefits from ASCVD risk reduction or triglyceride lowering (when triglyceride concentrations >500 mg/dL) outweigh potential risks of adverse effects and drug interactions.

Current ACC/AHA recommendations regarding prevention of ASCVD and lifestyle modifications to reduce cardiovascular risk are available at or [Web]).

Fenofibric Acid/Fenofibrate Dosage and Administration

General

  • Patients should be placed on a standard lipid-lowering diet before initiation of fenofibrate or fenofibric acid therapy and should remain on this diet during treatment with the drug.

  • Determine serum lipoprotein concentrations prior to initiating therapy (to confirm an abnormality) and monitor periodically thereafter.

Administration

Oral Administration

Administer orally once daily.

When fenofibric acid is used in combination with a statin, may administer daily dose at the same time as the statin, in accordance with recommended dosing schedules for each drug.

Fenofibrate is commercially available as nonmicronized drug in capsules (e.g., Lipofen), nonmicronized drug in tablets (e.g., Fenoglide, Lofibra), micronized drug in capsules (e.g., Antara, Lofibra ), “nanocrystal” drug in tablets (i.e., TriCor) , or “insoluble drug delivery-microparticle (IDD-P)” drug in tablets (i.e., Triglide ). Fenofibric acid is commercially available as delayed-release capsules (e.g., Trilipix). These formulations are not bioequivalent and vary substantially in potency and food effects.

Administer Fenoglide tablets, Lipofen capsules, and Lofibra micronized capsules with food. May administer Antara micronized capsules, Lofibra tablets, TriCor tablets, Triglide tablets, and Trilipix delayed-release capsules without regard to meals.

Swallow Antara capsules, Fenoglide tablets, Lipofen capsules, and Trilipix delayed-release capsules intact; do not open, crush, dissolve, or chew.

Dosage

Monitor lipoprotein concentrations periodically; consider reducing dosage in patients whose serum lipoprotein concentrations fall below the desired target range. Discontinue therapy in patients who fail to achieve an adequate response after 2 months of therapy with the maximum recommended dosage.

Adults

Dyslipidemias
Primary Hypercholesterolemia and Mixed Dyslipidemia
Oral

Antara (fenofibrate) micronized capsules: 90 mg daily.

Fenoglide (fenofibrate) tablets: 120 mg daily.

Lipofen (fenofibrate) capsules: 150 mg daily.

Lofibra(fenofibrate) tablets: 160 mg daily.

Lofibra (fenofibrate) micronized capsules or generic equivalents: 200 mg daily.

TriCor (fenofibrate) tablets or generic equivalents: 145 mg daily.

Triglide (fenofibrate) tablets: 160 mg daily.

Trilipix (fenofibric acid) delayed-release capsules or generic equivalents: 135 mg once daily.

Combination Therapy with a Statin for Mixed Dyslipidemia
Oral

Trilipix (fenofibric acid) delayed-release capsules or generic equivalents: 135 mg once daily. Avoid concomitant use with maximum dosages of statins unless benefits expected to outweigh risks.

Hypertriglyceridemia
Oral

Antara (fenofibrate) micronized capsules: 30–90 mg daily.

Fenoglide (fenofibrate) tablets: 40–120 mg daily.

Lipofen (fenofibrate) capsules: 50–150 mg daily.

Lofibra (fenofibrate) tablets: 54–160 mg daily.

Lofibra (fenofibrate) micronized capsules or generic equivalents: 67–200 mg daily.

TriCor (fenofibrate) tablets or generic equivalents: 48–145 mg daily.

Triglide (fenofibrate) tablets: 50–160 mg daily.

Trilipix (fenofibric acid) delayed-release capsules or generic equivalents: 45–135 mg once daily.

Adjust dosage at intervals of 4–8 weeks until the desired effect on lipoprotein concentrations is observed or maximum recommended dosages are reached.

Prescribing Limits

Adults

Dyslipidemias
Hypertriglyceridemia
Oral

Antara (fenofibrate) micronized capsules: Maximum 90 mg daily.

Fenoglide (fenofibrate) tablets: Maximum 120 mg daily.

Lipofen (fenofibrate) capsules: Maximum 150 mg daily.

Lofibra (fenofibrate) tablets: Maximum 160 mg daily.

Lofibra (fenofibrate) micronized capsules or generic equivalents: Maximum 200 mg daily.

TriCor (fenofibrate) tablets or generic equivalents: Maximum 145 mg daily.

Triglide (fenofibrate) tablets: Maximum 160 mg daily.

Trilipix (fenofibric acid) delayed-release capsules or generic equivalents: Maximum 135 mg once daily.

Special Populations

Renal Impairment

Dyslipidemias
Oral

Reduce initial dosage in patients with mild to moderate renal impairment (estimated GFR 30–59 mL/minute per 1.73 m2); increase only after effects of the drug on renal function and lipid concentrations have been evaluated. Avoid use in patients with severe renal impairment (estimated GFR <30 mL/minute per 1.73 m2).

The following dosage adjustments are recommended in patients with mild to moderate renal impairment:

Antara (fenofibrate) micronized capsules: Initially, 30 mg daily.

Fenoglide (fenofibrate) tablets: Initially, 40 mg daily.

Lipofen (fenofibrate) capsules: Initially, 50 mg daily.

Lofibra (fenofibrate) tablets: Initially, 54 mg daily.

Lofibra (fenofibrate) micronized capsules or generic equivalents: Initially, 67 mg daily.

TriCor (fenofibrate) tablets or generic equivalents: Initially, 48 mg daily.

Triglide (fenofibrate) tablets: Initially, 50 mg daily.

Trilipix (fenofibric acid) delayed-release capsules: Initially, 45 mg once daily.

Geriatric Patients

Select dosage based on renal function. (See Renal Impairment under Dosage and Administration and also under Cautions.) No dosage adjustment is required in geriatric patients with normal renal function.

Cautions for Fenofibric Acid/Fenofibrate

Contraindications

  • Patients with severe renal impairment, including those undergoing dialysis.

  • Active liver disease, including primary biliary cirrhosis and unexplained and persistent liver function abnormality.

  • Preexisting gallbladder disease.

  • Nursing women.

  • Known hypersensitivity to fenofibrate or fenofibric acid.

Warnings/Precautions

Sensitivity Reactions

Hypersensitivity Reactions

Severe rashes (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) requiring hospitalization and corticosteroid therapy, reported rarely.

Effects on Morbidity and Mortality

Effects on cardiovascular morbidity and mortality and noncardiovascular mortality not established.

In several randomized, placebo-controlled studies in patients with type 2 diabetes mellitus, fenofibrate did not substantially reduce the risk of cardiovascular events (e.g., nonfatal MI, nonfatal stroke, cardiovascular death) despite favorable effects on plasma lipid concentrations. Combination therapy with fenofibrate and a statin (simvastatin) did not substantially reduce rate of major adverse cardiovascular events (i.e., nonfatal MI, nonfatal stroke, fatal cardiovascular events) compared with statin monotherapy.

Because fenofibrate and fenofibric acid are chemically, pharmacologically, and clinically similar to other fibric acid derivatives (e.g., gemfibrozil, clofibrate [no longer commercially available in US]), adverse findings with these other drugs (i.e., increased incidence of cholelithiasis, cholecystitis requiring surgery, postcholecystectomy complications, malignancy, pancreatitis, and gallbladder disease, and increased overall mortality) also may apply to fenofibrate and fenofibric acid.

Musculoskeletal Effects

Serious muscle toxicity, including myopathy and rhabdomyolysis, reported in patients receiving fibric acid derivatives. Risk appears to be increased in geriatric patients and in patients with diabetes mellitus, renal impairment, or hypothyroidism. Concomitant use with statins or other drugs (e.g., colchicine) also may increase risk. (See Interactions.)

Monitor CK (CPK) concentrations periodically in patients reporting adverse musculoskeletal effects. Consider myopathy in any patient who develops diffuse myalgias, muscle tenderness or weakness, and/or marked increases in CK concentrations. (See Advice to Patients.)

Discontinue therapy if serum CK concentrations become markedly elevated or if myositis/myopathy is suspected or diagnosed.

Hepatic Effects

Dose-related elevations in serum aminotransferase (i.e., AST, ALT) concentrations >3 times the ULN reported. Concentrations usually return to pretreatment values during continued therapy or following drug discontinuance.

Chronic active hepatitis and cholestatic hepatitis have occurred as early as several weeks and as late as several years after initiation of therapy; cirrhosis associated with chronic active hepatitis reported rarely.

Perform liver function tests prior to initiating therapy and periodically thereafter. If serum aminotransferase concentrations of ≥3 times the ULN persist, discontinue therapy.

Renal Effects

Transient elevations of Scr reported. Elevations generally stable over time, with no evidence of continued increases following long-term therapy; elevations usually returned to baseline following discontinuance of therapy. Clinical importance not known.

ACC/AHA cholesterol management guideline recommends evaluating renal status before initiation of fenofibrate or fenofibric acid, within 3 months after initiation of therapy, and every 6 months thereafter.

Cholelithiasis

May increase cholesterol excretion in bile, resulting in cholelithiasis. Discontinue therapy if gallbladder studies indicate presence of gallstones.

Pancreatitis

Pancreatitis reported with fenofibrate, fenofibric acid, and other fibric acid derivatives; may be due to progression of hypertriglyceridemia (i.e., resulting from failure of response to therapy in patients with severe hypertriglyceridemia), a direct effect of the drug, or a secondary effect (e.g., biliary tract stone or sludge formation leading to obstruction of the common bile duct).

Hematologic Effects

Mild to moderate decreases in hemoglobin, hematocrit, and WBC counts reported; generally stabilize during long-term therapy.

Thrombocytopenia and agranulocytosis also reported.

Monitor blood cell counts periodically during first 12 months of therapy.

Thromboembolism

Increased incidence of venous thromboembolic events (e.g., DVT, PE, thrombophlebitis) observed with fibric acid derivatives.

Decreased HDL-cholesterol Concentrations

Paradoxical decrease in HDL-cholesterol concentrations (e.g., to as low as 2 mg/dL), accompanied by a decrease in apolipoprotein A1 concentrations, reported. Occurred as early as 2 weeks to as late as several years after initiation of therapy. HDL-cholesterol concentrations rapidly returned to baseline and remained at normal levels following discontinuance of therapy. Clinical importance not known.

Determine HDL-cholesterol concentrations within the first few months after initiating therapy. If concentrations are severely depressed, permanently discontinue drug and monitor until HDL-cholesterol concentrations return to normal.

Specific Populations

Pregnancy

Category C.

Lactation

Potential for serious adverse effects in nursing infants. Contraindicated in nursing women; discontinue nursing or the drug.

Pediatric Use

Safety and efficacy not established in children <18 years of age.

Geriatric Use

Risk of adverse effects may be increased in patients ≥65 years of age because of potentially decreased renal function in these patients. Select dosage based on renal function. (See Geriatric Patients and also Renal Impairment under Dosage and Administration.) Consider monitoring renal function.

Hepatic Impairment

Not evaluated in patients with hepatic impairment.

Renal Impairment

Reduce dosage in patients with mild to moderate renal impairment; avoid use in patients with severe renal impairment. (See Renal Impairment under Dosage and Administration.)

Monitor renal function in patients with preexisting renal impairment; consider monitoring renal function in patients at risk for developing renal impairment (e.g., geriatric patients, those with diabetes mellitus).

Common Adverse Effects

Fenofibrate: Abnormal liver function tests (e.g., increased ALT and/or AST), respiratory disorder, abdominal pain, back pain, headache, increased CK concentrations, diarrhea, nausea, rhinitis, constipation, asthenia, flu syndrome.

Fenofibric acid (alone or in combination with a statin): Headache, back pain, nasopharyngitis, nausea, myalgia, diarrhea, upper respiratory tract infection.

Interactions for Fenofibric Acid/Fenofibrate

Drugs Metabolized by Hepatic Microsomal Enzymes

Fenofibrate and fenofibric acid are mild to moderate inhibitors of CYP2C9 and weak inhibitors of CYP isoenzymes 2C8, 2A6 and 2C19; do not inhibit CYP isoenzymes 3A4, 2D6, 2E1, or 1A2 in vitro.

Specific Drugs

Drug

Interaction

Comments

Anticoagulants, oral (e.g., warfarin)

Prolongation of PT/INR and potential increased risk of bleeding

Use concomitantly with caution

Monitor PT/INR frequently until stable and adjust anticoagulant dosage as necessary

Antidiabetic agents (i.e., glimepiride, metformin, rosiglitazone)

Glimepiride: Increased systemic exposure and peak plasma concentrations of glimepiride; glucose concentrations substantially reduced; pharmacokinetics of fenofibrate not altered

Metformin, rosiglitazone: Slight alterations in pharmacokinetics of each drug

Bile acid sequestrants (i.e., cholestyramine, colestipol)

Possible decreased absorption of fenofibrate or fenofibric acid

Administer fenofibrate or fenofibric acid 1 hour before or 4–6 hours after the bile acid sequestrant

Colchicine

Increased risk of myopathy, including rhabdomyolysis

Use concomitantly with caution

Ezetimibe

Ezetimibe with atorvastatin: Increased peak plasma concentrations and systemic exposure of ezetimibe; pharmacokinetics of atorvastatin and fenofibric acid not substantially altered

HMG-CoA reductase inhibitors (statins)

Increased risk of adverse musculoskeletal effects (i.e., increased CK, myoglobinuria, rhabdomyolysis)

Atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin: Slight alterations in pharmacokinetics of fenofibric acid; more pronounced effects on pharmacokinetics of the statin

Possible decreased AUC of atorvastatin; increased peak plasma concentrations and AUC of fluvastatin, pravastatin (and active metabolite), and rosuvastatin; and decreased peak plasma concentrations and AUC of simvastatin (and active metabolite)

Avoid concomitant use unless potential benefit outweighs risk

Immunosuppressive agents (i.e., cyclosporine, tacrolimus)

Increased risk of cyclosporine- or tacrolimus-induced nephrotoxicity

Carefully consider risks versus benefits of concomitant therapy; use lowest effective dosages and monitor renal function

Omeprazole

Increased peak plasma concentrations of fenofibric acid observed under fasting conditions, but not when fenofibric acid was administered with food; systemic exposure to fenofibric acid not substantially altered

Fenofibric Acid/Fenofibrate Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract.

Plasma concentrations of fenofibric acid achieved following administration of three 48-mg or one 145-mg TriCor tablet(s), one 160-mg Triglide tablet, or one 135-mg Trilipix delayed-release tablet are equivalent under fed conditions to those achieved with one 200-mg micronized fenofibrate capsule. Plasma concentrations of fenofibric acid following administration of a single 120-mg Fenoglide tablet are equivalent to those achieved with fenofibrate 130 mg capsules under fed (high-fat) conditions. Plasma concentrations of fenofibric acid following administration of 150-mg Lipofen capsules are equivalent to those achieved with Tricor 160-mg tablets.

Peak plasma concentrations of fenofibric acid attained within 2–8 hours depending on the formulation; steady-state plasma levels attained within 5–9 days.

Food

Administration of Lofibra, TriCor or Triglide tablets with food did not substantially alter AUC of fenofibric acid.

Administration of Fenoglide tablets with a high-fat meal increased peak plasma concentrations of the drug by 44% but had no effect on systemic exposure.

Administration of Antara micronized capsules with a high-fat meal substantially increased peak plasma concentrations and AUC of fenofibric acid compared with administration under fasting conditions.

Administration of Lipofen micronized capsules with food increased extent of absorption by approximately 58 or 25% under high-fat or low-fat conditions, respectively, compared with the fasting state.

Distribution

Plasma Protein Binding

Fenofibric acid: Approximately 99%.

Elimination

Metabolism

Following oral administration, fenofibrate (prodrug) is rapidly hydrolyzed by esterases to fenofibric acid (active metabolite); fenofibric acid is principally conjugated with glucuronic acid.

Neither fenofibrate nor fenofibric acid undergoes oxidative metabolism (e.g., CYP450).

Elimination Route

Fenofibric acid: Excreted in urine (60%) as metabolites and in feces (approximately 25%).

Half-life

Fenofibric acid: Approximately 16–23 hours.

Special Populations

Mild to moderate renal impairment: Half-life of fenofibric acid prolonged, but systemic exposure similar to that observed in individuals with normal renal function.

Severe renal impairment: Systemic exposure substantially increased (by 2.7-fold); increased drug accumulation also observed.

Stability

Storage

Oral

Fenofibrate Capsules

Antara: Tight containers at 25°C (may be exposed to 15–30°C).

Lipofen: 15–30°C. Protect from moisture and light.

Lofibra: 20–25°C. Protect from moisture.

Fenofibrate Tablets

Fenoglide: 25° (may be exposed to 15–30°C). Protect from moisture and light.

Lofibra: Tight, light-resistant containers at 20–25°C. Protect from moisture.

Tricor: 25°C (may be exposed to 15–30°C). Protect from moisture.

Triglide: 20–25°C (may be exposed to 15–30°C). Protect from light and moisture.

Fenofibric Acid Delayed-release Capsules

Trilipix: 25°C (may be exposed to 15–30°C). Protect from moisture.

Actions

  • Fenofibrate (prodrug) has no pharmacologic activity until hydrolyzed by esterases in vivo to fenofibric acid (active metabolite).

  • Decreases serum concentrations of total cholesterol, LDL-cholesterol, apo B, VLDL-cholesterol, and triglycerides. Also increases serum concentrations of HDL-cholesterol, apolipoprotein A-I (apo A-I), and apolipoprotein A-II (apo A-II).

  • Activates lipoprotein lipase and reduces production of apolipoprotein C-III (apo C-III), an inhibitor of lipoprotein lipase activity, thereby increasing lipolysis and clearance of triglyceride-rich particles. The reduction in triglyceride concentrations via this mechanism alters the size and composition of LDL-cholesterol from small, dense particles to larger, more buoyant particles that are less atherogenic and more rapidly catabolized. Also appears to activate a receptor (peroxisome proliferator activated receptor α) that induces the synthesis of HDL-cholesterol, apo A-I, and apo A-II.

Advice to Patients

  • Importance of advising patients of the potential risks and benefits of fenofibrate or fenofibric acid.

  • Importance of advising patients who are taking fenofibric acid to read the manufacturer's patient information (medication guide) prior to initiating therapy and each time the prescription is refilled.

  • Importance of advising patients to take fenofibrate or fenofibric acid as prescribed.

  • Importance of patients not taking fenofibrate if they have known hypersensitivity to fenofibrate or fenofibric acid.

  • Importance of advising patients to avoid certain drugs during therapy with fenofibrate or fenofibric acid. In particular, advise patients that concomitant use with coumarin anticoagulants (e.g., warfarin) may increase anticoagulant effects and risk of bleeding and may necessitate increased monitoring.

  • Importance of following an appropriate lipid-modifying diet.

  • Importance of patients promptly informing clinicians of any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.

  • Importance of routine monitoring.

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.

  • Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fenofibrate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

50 mg

Lipofen

Kowa

150 mg

Lipofen

Kowa

Tablets

40 mg

Fenoglide

Santarus

48 mg

Fenofibrate Tablets

TriCor

AbbVie

50 mg

Triglide

Shionogi

54 mg*

Fenofibrate Tablets

120 mg

Fenoglide

Santarus

145 mg

Fenofibrate Tablets

TriCor

AbbVie

160 mg*

Fenofibrate Tablets

Triglide

Shionogi

Tablets, film-coated

54 mg

Lofibra

Teva

160 mg

Lofibra

Teva

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fenofibrate (micronized)

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

30 mg

Antara

Lupin

67 mg*

Fenofibrate Micronized Capsules

Lofibra

Teva

90 mg

Antara

Lupin

134 mg*

Fenofibrate Micronized Capsules

Lofibra

Teva

200 mg*

Fenofibrate Micronized Capsules

Lofibra

Teva

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Fenofibric Acid

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules, delayed-release

45 mg*

Fenofibric Acid Delayed-release Capsules

Trilipix

Abbvie

135 mg*

Fenofibric Acid Delayed-release Capsules

Trilipix

Abbvie

AHFS DI Essentials™. © Copyright 2021, Selected Revisions November 21, 2014. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

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