Class: Fibric Acid Derivatives
VA Class: CV350
Chemical Name: 2-[p-(p-chlorobenzoyl)phenoxy]-2-methylpropionate
Molecular Formula: C₂₀H₂₁ClO₄
CAS Number: 49562-28-9
Brands: Antara, Lofibra, TriCor, Triglide

Introduction

Antilipemic agent;^{1 2 4 7 16 17 18} fibric acid derivative.^{4 7}

Uses for Fenofibrate

Dyslipidemias

Adjunct 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.^{1 14 16 17 18} Additive antilipemic effects when used concomitantly with other antilipemic agents (e.g., colesevelam, ezetimibe).^{20 21}

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Adjunct to dietary therapy in the management of patients with hypertriglyceridemia.^{1 2 3 14 16 17 18}

Manufacturer states that fenofibrate is not indicated for use in patients with type I hyperlipoproteinemia who have elevated triglyceride and chylomicron concentrations but normal VLDL-cholesterol concentrations.^{1 14 16 17 18}

Fenofibrate Dosage and Administration

General

• Patients should be placed on a standard lipid-lowering diet before initiation of fenofibrate therapy and should remain on this diet during treatment with the drug.^{1 4 16 17 18}

Monitoring during Antilipemic Therapy

• Monitor lipoprotein concentrations periodically to ensure that target LDL-cholesterol goals are achieved and maintained at <100 mg/dL (optional goal: <70 mg/dL) for patients with CHD or CHD risk equivalents; <130 mg/dL (optional goal: <100 mg/dL) for patients with ≥2 risk factors and 10-year risk of 10–20%; <130 mg/dL for patients with ≥2 risk factors and 10-year risk <10%; or <160 mg/dL for patients with 0–1 risk factor.

Administration

Oral Administration

Administer orally once daily.^{1 2 14 16 17 18}

Administer micronized capsules and tablets (e.g., Lofibra) with meals to maximize bioavailability.^{14 16} Administer Antara micronized capsules, TriCor tablets, and Triglide tablets without regard to meals.^{1 17 18}

Dosage

Monitor lipoprotein concentrations periodically; consider reducing dosage in patients whose serum lipoprotein concentrations fall below the desired target range.^{1 14 16 17 18} Discontinue therapy in patients who fail to achieve an adequate response after 2 months of therapy with the maximum recommended dosage.^{1 2 10 14 16 17 18}

Adults

Dyslipidemias

Primary Hypercholesterolemia and Mixed Dyslipidemia

Oral

Antara micronized capsules: 130 mg daily.¹⁷

Lofibra micronized tablets (or generic equivalents): 160 mg daily.¹⁶

Lofibra micronized capsules (or generic equivalents): 200 mg daily.¹⁴

TriCor tablets: 145 mg daily.¹

Triglide tablets: 160 mg daily.¹⁸

Hypertriglyceridemia

Oral

Antara micronized capsules: 43–130 mg daily.¹⁷

Lofibra micronized tablets (or generic equivalents): 54–160 mg daily.¹⁶

Lofibra micronized capsules (or generic equivalents): 67–200 mg daily.¹⁴

TriCor tablets: 48–145 mg daily.¹

Triglide tablets: 50–160 mg daily.¹⁸

Adjust dosage at intervals of 4–8 weeks until the desired effect on lipoprotein concentrations is observed.^{1 4 14 16 17 18}

Prescribing Limits

Adults

Dyslipidemias

Hypertriglyceridemia

Oral

Antara micronized capsules: Maximum 130 mg daily.¹⁷

Lofibra micronized tablets (or generic equivalents): Maximum 160 mg daily.¹⁶

Lofibra micronized capsules (or generic equivalents): Maximum 200 mg daily.¹⁴

TriCor tablets: Maximum 145 mg daily.¹

Triglide tablets: Maximum 160 mg daily.¹⁸

Special Populations

Renal Impairment

Dyslipidemias

Oral

Antara micronized capsules: Initially, 43 mg daily in patients with renal impairment (Cl_cr <50 mL/minute).¹⁷

Lofibra micronized tablets (or generic equivalents): Initially, 54 mg daily in patients with renal impairment (Cl_cr <50 mL/minute).¹⁶

Lofibra micronized capsules (or generic equivalents): Initially, 67 mg daily in patients with renal impairment (Cl_cr <50 mL/minute).¹⁴

TriCor tablets: Initially, 48 mg daily in patients with renal impairment (Cl_cr <50 mL/minute).¹

Triglide tablets: Initially, 50 mg daily in patients with renal impairment (Cl_cr <50 mL/minute).¹⁸

Increase dosage only after evaluating therapeutic response and the effects of the drug on renal function.^{1 14 16 17 18}

Geriatric Patients

Antara micronized capsules: Initially, 43 mg daily.¹⁷

Lofibra micronized tablets (or generic equivalents): Initially, 54 mg daily.¹⁶

Lofibra micronized capsules (or generic equivalents): Initially, 67 mg daily.¹⁴

TriCor tablets: Initially, 48 mg daily.¹

Triglide tablets: Initially, 50 mg daily.¹⁸

Cautions for Fenofibrate

Contraindications

• Hepatic impairment, including primary biliary cirrhosis and unexplained and persistent liver function abnormality; severe renal impairment; or preexisting gallbladder disease.^{1 2 4 14}

• Known hypersensitivity to fenofibrate or any ingredient in the formulation.^{1 14}

Warnings/Precautions

Warnings

Hepatic Effects

Possible dose-related elevations in serum aminotransferase (transaminase) concentrations (i.e., AST, ALT >3 times the ULN) have been reported.^{1 14 16 17 18} Serum aminotransferase concentrations usually return slowly to pretreatment values during continued therapy or following discontinuance of fenofibrate.^{1 12}

Chronic active hepatitis and cholestatic hepatitis have occurred as early as several weeks and as late as several years after initiation of therapy;^{1 14} cirrhosis associated with chronic active hepatitis reported rarely.^{1 14}

Perform liver function tests periodically^{1 14} (i.e., every 3 months) during the first 12 months of therapy.^{2 10} If serum aminotransferase concentrations of ≥3 times the ULN persist, discontinue therapy.^{1 14}

Cholelithiasis

May increase cholesterol excretion in bile, resulting in cholelithiasis.^{1 2 4 14} Discontinue therapy if gallbladder studies indicate the presence of gallstones.^{1 14}

Musculoskeletal Effects

Myositis, myopathy, and/or rhabdomyolysis reported in patients (usually those with impaired renal function) receiving fenofibrate or other fibric acid derivatives.^{1 2 4 14}

Rhabdomyolysis and other complications also reported in patients receiving fenofibrate concomitantly with certain other antilipemic agents.¹

Monitor CK (CPK) concentrations periodically in patients reporting adverse musculoskeletal effects.^{1 14}

Discontinue therapy if serum CK concentrations become markedly elevated or if myositis/myopathy is suspected or diagnosed.^{1 14}

Sensitivity Reactions

Hypersensitivity Reactions

Severe rashes (e.g., Stevens-Johnson syndrome and toxic epidermal necrolysis) requiring hospitalization and corticosteroid therapy, reported rarely.^{1 14}

Major Toxicities

Pancreatitis

Possible pancreatitis with fenofibrate and other fibric acid derivatives.^{1 10 14}

Hematologic Effects

Mild to moderate decreases in hemoglobin, hematocrit, and leukocyte counts reported;^{1 3 14} these counts usually normalize during long-term therapy.^{1 14} Thrombocytopenia and agranulocytosis also reported rarely.^{1 14}

Monitor blood cell counts periodically during the first 12 months of therapy.¹

General Precautions

Effect on Morbidity and Mortality

Effect on cardiovascular or noncardiovascular morbidity and mortality has not been established.^{1 14} However, because fenofibrate is chemically, pharmacologically, and clinically similar to other fibric acid derivatives, some adverse effects of clofibrate (no longer commercially available in the US) and gemfibrozil such as increased incidence of cholelithiasis, cholecystitis requiring surgery, postcholecystectomy complications, malignancy, pancreatitis, appendectomy, gallbladder disease, and increased overall mortality may also apply to fenofibrate,^{1 4 10 14} and the usual precautions associated with fibrate therapy should be observed.⁴

Carcinogenicity

Carcinogenicity (e.g., hepatic, pancreatic, testicular tumors) demonstrated in animals.^{1 4 14 16 17 18}

Specific Populations

Pregnancy

Category C.^{1 16 17 18}

Lactation

Potential for serious effects in nursing infants;^{1 10 14 16 17 18} discontinue nursing or the drug.^{1 10 14 16 17 18}

Pediatric Use

Safety and efficacy not established in children <18 years of age.^{1 10 16 17 18}

Geriatric Use

Reduce dosage in patients ≥65 years of age because of potentially decreased renal function in these patients.^{1 14 16 17 18} (See Geriatric Patients under Dosage and Administration.)

Renal Impairment

Reduce dosage in patients with Cl_cr <50 mL/minute.^{1 10 14 16 17 18} (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Abnormal liver function tests (e.g., increased ALT, AST),^{1 2 14} respiratory disorder,^{1 14} abdominal pain,^{1 14} back pain,^{1 14} headache,^{1 14} increased CK concentrations,^{1 14} diarrhea,^{1 14} nausea,^{1 3 14} rhinitis,^{1 14} constipation,^{1 3 14} asthenia,^{1 14} flu syndrome.^{1 14}

Interactions for Fenofibrate

Drugs Metabolized by Hepatic Microsomal Enzymes

Fenofibrate and fenofibric acid are mild to moderate inhibitors of CYP2C9 and weak inhibitors of CYP2A6 and CYP2C19;^{1 10 14} do not inhibit CYP3A4, CYP2D6, CYP2E1, or CYP1A2 in vitro.^{1 14}

Specific Drugs

Drug	Interaction	Comments
Anticoagulants, oral (e.g., warfarin)	Prolongation of PT/INR1 2 7 14	Reduce anticoagulant dosage (e.g., by approximately one-third initially with subsequent dosage adjustment as necessary)2 10 14 and monitor PT/INR periodically until stabilized1 2 14
Bile acid sequestrants (i.e., cholestyramine, colestipol)	Decreased absorption of fenofibrate1 14	Administer fenofibrate 1 hour before or 4–6 hours after the resin1 4 7 14
Cyclosporine	Increased risk of cyclosporine-induced nephrotoxicity (i.e., deterioration in renal function)1 4 7 10 14	Use with caution1 14
HMG-CoA reductase inhibitors (statins)	Increased risk of adverse musculoskeletal effects (i.e., increased CK, myoglobinuria, rhabdomyolysis)1 7 14 Possible decreased AUC of atorvastatin and increased peak plasma concentration and AUC of pravastatin1	Avoid concomitant use unless potential benefit outweighs risk1 14

Fenofibrate Pharmacokinetics

Absorption

Bioavailability

Well absorbed from the GI tract.^{1 14}

Plasma concentrations of fenofibric acid achieved following administration of the 54-mg micronized tablets (e.g., Lofibra) are equivalent under fed conditions to those achieved with the 67-mg micronized capsules.¹⁶

Plasma concentrations of fenofibric acid achieved following administration of one 130-mg Antara micronized capsule,¹⁷ one 160-mg micronized tablet (e.g., Lofibra),¹⁶ three 48-mg or one 145-mg TriCor tablet(s),^{1 10} or one 160-mg Triglide tablet¹⁸ are equivalent under fed conditions to those achieved with the 200-mg micronized capsule.^{1 10 16 17 18}

Peak plasma concentrations of fenofibric acid attained within 3–8 hours; steady-state plasma levels attained within 5–7 days.^{1 14 16 17 18}

Food

AUC of fenofibric acid was not substantially altered following administration of TriCor or Triglide tablets with food.^{1 18}

Extent of absorption of fenofibric acid was not altered following administration of Antara micronized capsules with a low-fat meal; however, administration with a high-fat meal resulted in substantial increases in peak plasma concentration and AUC of fenofibric acid compared with administration under fasting conditions.¹⁷

Absorption was increased by approximately 35% following administration of micronized capsules or tablets (e.g., Lofibra) with food.^{14 16}

Distribution

Plasma Protein Binding

Approximately 99%.^{1 14 16 17 18}

Elimination

Metabolism

Rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid, which is principally conjugated with glucuronic acid.^{1 14 16 17 18}

Neither fenofibrate nor fenofibric acid undergoes oxidative metabolism (e.g., CYP450).^{1 14 16 18}

Elimination Route

Excreted in the urine (60%) as metabolites; and feces (approximately 25%).^{1 14 16 17 18}

Half-life

Approximately 16–23 hours (fenofibric acid).^{1 16 17 18}

Special Populations

Severe renal impairment (Cl_cr <50 mL/minute) may reduce the rate of clearance of fenofibric acid.^{1 14 16 17 18}

Stability

Storage

Oral

Capsules

Antara: Tight containers at 25°C (may be exposed to 15–30°C).¹⁷

Lofibra: 20–25°C.¹⁴ Protect from moisture.¹⁴

Tablets

Lofibra: Tight, light-resistant containers at20–25°C.¹⁶ Protect from moisture.¹⁶

Tricor: 25°C (may be exposed to 15–30°C).¹ Protect from moisture.¹

Triglide: 20–25°C (may be exposed to 15–30°C).¹⁸ Protect from light and moisture.¹⁸

Actions

• Prodrug² requiring hydrolysis in vivo for activity.^{1 2 10 14}

• Decreases serum concentrations of total cholesterol, LDL-cholesterol, apo B, VLDL-cholesterol, and triglycerides.^{1 2 7 14} Also increases serum concentrations of HDL-cholesterol, apolipoprotein A-I (apo A-I), and apolipoprotein A-II (apo A-II).^{1 2}

• 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.^{1 2 4 7 14} 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.^{1 2 4 14} 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.^{1 2 4 14}

Advice to Patients

• Importance of patients informing clinicians of any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.^{1 7 14}

• Importance of adhering to nondrug therapies and measures, including dietary management, weight control, physical activity, and management of potentially contributory disease (e.g., diabetes mellitus).^{10 11}

• Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.^{7 10}

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as concomitant illnesses.^{7 10}

• Importance of informing patients of other important precautionary information.¹ (See Cautions.)

Preparations

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

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

Fenofibrate

Routes	Dosage Forms	Strengths	Brand Names	Manufacturer
Oral	Tablets	48 mg	TriCor	Abbott
		50 mg	Triglide	Sciele
		54 mg*	Fenofibrate Tablets	Ranbaxy, Teva
		145 mg	TriCor	Abbott
		160 mg*	Fenofibrate Tablets	Ranbaxy, Teva
			Triglide	Sciele
	Tablets, film-coated	54 mg	Lofibra (with povidone)	Gate
		160 mg	Lofibra (with povidone)	Gate

* 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	43 mg	Antara	Reliant
		67 mg*	Fenofibrate Micronized Capsules	Global
			Lofibra (with povidone)	Gate
		130 mg	Antara	Reliant
		134 mg*	Fenofibrate Micronized Capsules	Global
			Lofibra (with povidone)	Gate
		200 mg*	Fenofibrate Micronized Capsules	Global
			Lofibra (with povidone)	Gate

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2013. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Antara 130MG Capsules (LUPIN PHARMACEUTICALS): 30/$182.00 or 90/$505.97

Fenofibrate 160MG Tablets (MYLAN): 30/$67.99 or 60/$135.98

Fenofibrate 54MG Tablets (MYLAN): 90/$69.99 or 270/$195.97

Fenofibrate Micronized 134MG Capsules (GLOBAL PHARMACEUTICAL CORP): 100/$155.99 or 200/$297.69

Fenofibrate Micronized 200MG Capsules (GLOBAL PHARMACEUTICAL CORP): 30/$72.54 or 90/$193.43

Fenofibrate Micronized 67MG Capsules (GLOBAL PHARMACEUTICAL CORP): 30/$29.99 or 90/$79.97

Fenoglide 120MG Tablets (SHORE THERAPEUTICS): 30/$215.99 or 90/$635.94

Lipofen 150MG Capsules (KOWA PHARMACEUTICALS AMERICA): 90/$351.00 or 270/$1,000.94

Lofibra 134MG Capsules (GATE): 30/$72.59 or 90/$193.56

Lofibra 160MG Tablets (GATE): 30/$105.59 or 90/$296.97

Lofibra 200MG Capsules (GATE): 30/$105.59 or 90/$292.56

Lofibra 67MG Capsules (GATE): 30/$43.99 or 90/$109.97

Tricor 145MG Tablets (ABBOTT): 30/$176.98 or 90/$484.99

Tricor 48MG Tablets (ABBOTT): 30/$62.99 or 90/$164.97

Triglide 160MG Tablets (SHIONOGI PHARMA): 30/$195.99 or 90/$539.97

Trilipix 135MG Delayed-release Capsules (ABBOTT): 90/$476.98 or 270/$1,343.02

Trilipix 45MG Delayed-release Capsules (ABBOTT): 90/$156.99 or 270/$451.97