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Fenofibrate


General


Pronunciation

(fen oh FYE brate)


Indications


Use: Labeled Indications

Adjunct to dietary therapy for the treatment of adults with elevations of serum triglyceride levels (Fredrickson types IV and V hyperlipidemia); adjunct to dietary therapy for the reduction of low density lipoprotein cholesterol (LDL-C), total cholesterol (total-C), triglycerides, and apolipoprotein B (apo B), and to increase high density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson types IIa and IIb hyperlipidemia)


Contraindications


Hypersensitivity to fenofibrate, fenofibric acid, or any component of the formulation; hepatic dysfunction including primary biliary cirrhosis and unexplained persistent liver function abnormalities; severe renal impairment (including patients on dialysis); pre-existing gallbladder disease; breast-feeding

Canadian labeling: Additional contraindications (not in U.S. labeling): Pregnancy; known photoallergy or phototoxic reaction during treatment with fibrates or ketoprofen

Lipidil EZ; Lipidil Micro; Lipidil Supra: Additional contraindications: Allergy to soya lecithin or peanut or arachis oil; chronic or acute pancreatitis; patients <18 years of age; coadministration with HMG-CoA reductase inhibitors in patients with a predisposition for myopathy.


Dosing and Administration


Dosing: Adult

Note: At least 2-3 months of therapy is required to determine efficacy.

Hypertriglyceridemia: Oral: Initial:

Antara (micronized): 43-130 mg once daily; maximum dose: 130 mg once daily

Fenoglide: 40-120 mg once daily; maximum dose: 120 mg once daily

Lipidil EZ (Canadian product): 145 mg once daily; maximum dose: 145 mg once daily

Lipidil Micro (Canadian product): 200 mg once daily; maximum dose: 200 mg once daily

Lipidil Supra (Canadian product): 160 mg once daily; maximum dose: 200 mg once daily

Lipofen: 50-150 mg once daily; maximum dose: 150 mg once daily

Lofibra (micronized): 67-200 mg once daily; maximum dose: 200 mg once daily

Lofibra (tablets): 54-160 mg once daily; maximum dose: 160 mg once daily

TriCor: 48-145 mg once daily; maximum dose: 145 mg once daily

Triglide: 50-160 mg once daily; maximum dose: 160 mg once daily

Hypercholesterolemia or mixed hyperlipidemia: Oral:

Antara (micronized): 130 mg once daily

Fenoglide: 120 mg once daily

Lipidil EZ (Canadian product): 145 mg once daily; maximum dose: 145 mg once daily

Lipidil Micro (Canadian product): 200 mg once daily; maximum dose: 200 mg once daily

Lipidil Supra (Canadian product): 160 mg once daily; maximum dose: 200 mg once daily

Lipofen: 150 mg once daily

Lofibra (micronized): 200 mg once daily

Lofibra (tablets): 160 mg once daily

TriCor: 145 mg once daily

Triglide: 160 mg once daily


Dosing: Geriatric

Oral: Initial:

Antara (micronized): Adjust dosage based on renal function.

Fenoglide: Adjust dosage based on renal function.

Lipidil EZ (Canadian product): 48 mg once daily

Lipidil Micro (Canadian product): Adjust dosage based on creatinine clearance

Lipidil Supra (Canadian product): Adjust dosage based on creatinine clearance

Lipofen: Adjust dosage based on renal function.

Lofibra (micronized): 67 mg once daily

Lofibra (tablets): 54 mg once daily

TriCor: Adjust dosage based on renal function.

Triglide: Adjust dosage based on renal function.


Dosing: Renal Impairment

Monitor renal function and lipid panel before adjusting. Note: Use in severe renal impairment (including patients on dialysis) is contraindicated (see specific product labeling):

Antara (micronized):

CrCl >80 mL/minute or eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.

CrCl >30-80 mL/minute or eGFR 30-59 mL/minute/1.73 m2: Initiate at 43 mg once daily

CrCl ≤30 mL/minute or eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

Fenoglide:

CrCl >80 mL/minute or eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.

CrCl >30-80 mL/minute or eGFR 30-59 mL/minute/1.73 m2: Initiate at 40 mg once daily

CrCl ≤30 mL/minute or eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

Lipidil EZ (Canadian product): Note: Interrupt treatment in patients with an increase in creatinine concentrations >50% the upper limit of normal (ULN).

CrCl >50 mL/minute: No dosage adjustment necessary.

CrCl 20-50 mL/minute: Initiate at 48 mg once daily

CrCl <20 mL/minute: Use is contraindicated.

Lipidil Micro (Canadian product): Note: Interrupt treatment in patients with an increase in creatinine concentrations >50% the upper limit of normal (ULN).

CrCl >85 mL/minute (women) or >95 mL/minute (men): No dosage adjustment necessary.

CrCl 20-85 mL/minute (women) or 20-95 mL/minute (men): Initiate therapy with Lipidil EZ formulation with a dose of 48 mg once daily.

CrCl <20 mL/minute: Use is contraindicated.

Lipidil Supra (Canadian product): Note: Interrupt treatment in patients with an increase in creatinine concentrations >50% the upper limit of normal (ULN).

CrCl >100 mL/minute: No dosage adjustment necessary.

CrCl 20-100 mL/minute: Initiate at 100 mg once daily

CrCl <20 mL/minute: Use is contraindicated.

Lipofen:

eGFR ≥90 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 30-89 mL/minute/1.73 m2: Initiate at 50 mg once daily

eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

Lofibra (micronized):

CrCl >80 mL/minute: No dosage adjustment necessary.

CrCl >30-80 mL/minute: Initiate at 67 mg once daily

CrCl ≤30 mL/minute: Use is contraindicated.

Lofibra (tablets):

eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 30-59 mL/minute/1.73 m2: Initiate at 54 mg once daily

eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

TriCor:

eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.

eGFR 30-59 mL/minute/1.73 m2: Initiate at 48 mg once daily

eGFR <30 mL/minute/1.73 m2: Use is contraindicated.

Triglide:

CrCl >80 mL/minute or eGFR ≥60 mL/minute/1.73 m2: No dosage adjustment necessary.

CrCl >30-80 mL/minute or eGFR 30-59 mL/minute/1.73 m2: Initiate at 50 mg once daily

CrCl ≤30 mL/minute or eGFR <30 mL/minute/1.73 m2: Use is contraindicated.


Dosing: Hepatic Impairment

Use is contraindicated.


Administration

Antara, TriCor, Triglide: May be administered with or without food. Swallow whole; do not crush, dissolve, or chew dosage form.

Fenoglide: Administer with meals. Swallow whole; do not crush, dissolve, or chew tablets.

Lipidil Micro (Canadian product), Lipofen, Lofibra: Administer with meals.

Lipidil Supra (Canadian product): Administer with meals. Swallow whole.

Lipidil EZ (Canadian product): May be administered with or without food. Swallow whole.


Dietary Considerations

Antara, Lipidil EZ (Canadian product), TriCor, Triglide: May be taken with or without food.

Fenoglide, Lipidil Micro (Canadian product), Lipidil Supra (Canadian product), Lipofen, Lofibra: Take with meals.


Storage

Store at 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F). Protect from light and moisture. Store tablets in moisture-protective container.


Dosage Forms/Strengths


Drug Interactions

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. Exceptions: Colesevelam. Consider therapy modification

Chenodiol: Fibric Acid Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any fibric acid derivative. Monitor therapy

Colchicine: Fibric Acid Derivatives may enhance the myopathic (rhabdomyolysis) effect of Colchicine. 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. Consider therapy modification

Ezetimibe: Fibric Acid Derivatives may increase the serum concentration of Ezetimibe. Monitor therapy

HMG-CoA Reductase Inhibitors: Fenofibrate may enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors. Monitor therapy

Sulfonylureas: Fibric Acid Derivatives may enhance the hypoglycemic effect of Sulfonylureas. Monitor therapy

Tacrolimus (Systemic): May enhance the nephrotoxic effect of Fenofibrate. Monitor therapy

Ursodiol: Fibric Acid Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy

Vitamin K Antagonists (eg, warfarin): Fibric Acid Derivatives may enhance the anticoagulant effect of Vitamin K Antagonists. Consider therapy modification

Warfarin: Fenofibrate may enhance the anticoagulant effect of Warfarin. Fenofibrate may increase the serum concentration of Warfarin. Consider therapy modification


Monitoring Parameters

Periodic blood counts during first year of therapy. Total cholesterol, LDL-C, triglycerides, and HDL-C should be measured periodically (6-8 weeks after initiation; if dose increased [or if combined with another agent], monitor again at 6-8 weeks until goal met, then every 4-6 months [NCEP, 2001); if only marginal changes are noted after 2-3 months of initiation, discontinue fenofibrate. Monitor LFTs regularly and discontinue therapy if levels remain >3 times normal limits. Monitor renal function in patients with renal impairment or in those at increased risk for developing renal impairment.


Adverse Reactions


>10%: Hepatic: Liver function tests increased (dose related; 3% to 13%; ALT/AST increased >3 x ULN: 5% to 13%)

1% to 10%:

Central nervous system: Headache (3%)

Dermatologic: Urticaria (1%)

Gastrointestinal: Abdominal pain (5%), constipation (2%), nausea (2%)

Neuromuscular & skeletal: Back pain (3%), CPK increased (3%)

Respiratory: Respiratory disorder (6%), rhinitis (2%)

<1% (Limited to important or life-threatening): Abnormal vision, acute renal failure, agranulocytosis, allergic reaction, alopecia, amblyopia, anemia, angina pectoris, anorexia, arrhythmia, arthralgia, arthritis, arthrosis, asthma, atrial fibrillation, bronchitis, bursitis, cataract, cholecystitis, cholelithiasis, cholestatic hepatitis, cirrhosis, colitis, conjunctivitis, contact dermatitis, cyst, cystitis, deep venous thrombosis, diabetes mellitus, diarrhea, duodenal ulcer, electrocardiogram abnormality, eosinophilia, esophagitis, extrasystoles, fatty liver deposits, gastritis, gastroenteritis, gout, gynecomastia, HDL-C decreased (paradoxical), hepatitis, hernia, herpes simplex, herpes zoster, homocysteine increased, hyper-/hypotension, hypersensitivity pneumonitis, hypersensitivity reaction, hypertonia, hyperuricemia, hypoglycemia, infection, leukopenia, lymphadenopathy, maculopapular rash, MI, migraine, myasthenia, myopathy, myositis, neuralgia, pancreatitis, peptic ulcer, photosensitivity reaction, pneumonia, pregnancy (unintended), prostate disorder, pulmonary embolus, rectal hemorrhage, refraction disorder, rhabdomyolysis, skin ulcer, Stevens-Johnson syndrome, tachycardia, tenosynovitis, thrombocytopenia, toxic epidermal necrolysis, urinary frequency, urolithiasis, vaginal moniliasis, vasodilatation, weight gain/loss


Warnings/Precautions


Special Populations: Renal Function Impairment

In patients with severe renal impairment (CrCl ≤30 mL/minute), clearance of fenofibrate is greatly reduced. Clearance is reduced to a lesser degree in patients with mild-to-moderate renal impairment (CrCl 30-80 mL/minute).


Warnings/Precautions

Concerns related to adverse effects:

- Cholelithiasis: May cause cholelithiasis; discontinue if gallstones are found upon gallbladder studies.

- HDL cholesterol (HDL-C): A paradoxical, severe, and reversible decrease in HDL-C (as low as 2 mg/dL) with a simultaneous decrease in apolipoprotein A1 has been reported within 2 weeks to years after initiation of fibrate therapy; clinical significance unknown. Monitor HDL-C within a few months of initiation of therapy and discontinue if HDL-C becomes severely depressed; do not restart therapy.

- Hemogloblin/hematocrit/WBC effects: May cause mild-to-moderate decreases in hemoglobin, hematocrit and WBC upon initiation of therapy which usually stabilizes with long-term therapy. Agranulocytosis and thrombocytopenia have been reported (rare). Periodic monitoring of blood counts is recommended during the first year of therapy.

- Hepatic effects: Hepatic transaminases can become significantly elevated (dose-related); hepatocellular, chronic active, and cholestatic hepatitis have been reported. Regular monitoring of liver function tests is required.

- Hypersensitivity reactions: Rarely hypersensitivity reactions (eg, severe skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis) may occur.

- Myopathy/rhabdomyolysis: Has been associated with rare myositis, myopathy, or rhabdomyolysis; patients should be monitored closely. Risk increased in the elderly, those receiving concomitant HMG-CoA reductase inhibitors or colchicine, and patients with diabetes mellitus, renal failure, or hypothyroidism. Patients should be instructed to report unexplained muscle pain, tenderness, weakness, or brown urine.

- Renal effects: Increases in serum creatinine (>2 mg/dL) have been observed with use; clinical significance unknown. Fenofibrate has been shown to increase creatinine production (unknown mechanism) resulting in an equal increase of creatinuria thereby demonstrating that the increase does not reflect a reduction in creatinine clearance (Hottelart, 2002). Monitor renal function in patients with renal impairment and consider monitoring patients with increased risk for developing renal impairment.

- Venous thromboembolism (VTE): Use has been associated with pulmonary embolism (PE) and deep vein thrombosis (DVT). Use with caution in patients with risk factors for VTE.

Disease-related concerns:

- Renal impairment: Use with caution in patients with mild-to-moderate renal impairment; dosage adjustment required. Contraindicated with severe renal impairment including those receiving dialysis.

Concurrent drug therapy issues:

- Anticoagulants: Use with caution in patient taking oral anticoagulants (eg, warfarin); adjustments in anticoagulation therapy may be required.

- HMG-CoA reductase inhibitors: Use caution with HMG-CoA reductase inhibitors; may lead to myopathy, rhabdomyolysis. No incremental benefit of combination therapy on cardiovascular morbidity and mortality over statin monotherapy has been established. In combination with HMG-CoA reductase inhibitors, fenofibrate is generally regarded as safer than gemfibrozil due to limited pharmacokinetic interaction with statins.

Special populations:

- Elderly: Due to a higher incidence of renal impairment, use with caution in the elderly; dosage adjustment may be required.

- Type 2 diabetes mellitus: In two large randomized controlled clinical trials, neither fenofibrate monotherapy (Keech, 2005) nor the addition of fenofibrate to simvastatin (ACCORD Study Group, 2010) compared to placebo has been shown to reduce cardiovascular disease morbidity and mortality in patients with type 2 diabetes.

Dosage form specific issues:

- Peanut or arachis oil: Some products may contain peanut or arachis oil; use is contraindicated in patients with a peanut or arachis allergy for applicable formulations.

- Soya lecithin: Some products may contain soya lecithin; use is contraindicated in patients with a soya lecithin allergy for applicable formulations.

Other warnings/precautions:

- Hyperlipidemia: Secondary causes of hyperlipidemia should be ruled out prior to therapy.

- Optimal response: Therapy should be withdrawn if an adequate response is not obtained after 2-3 months of therapy at the maximal daily dose. In patients with severe hypertriglyceridemia, the occurrence of pancreatitis may represent a failure of efficacy, a direct effect of the drug, or obstruction of the common bile duct due to biliary tract stone or sludge formation.


Pregnancy Risk Factor

C


Pregnancy Considerations

Maternal toxicity was observed in pregnant rats at doses approximately equivalent to the human dose; adverse events were not observed in reproduction studies done in rabbits. Reports of using fenofibrate during pregnancy are limited (Goldberg, 2012; Sunman, 2012; Whitten, 2011). Other agents are generally preferred if treatment for hypertriglyceridemia during pregnancy (Berglund, 2012) or treatment of lipid disorders in women of reproductive age (NCEP, 2001) is required. Use during pregnancy is specifically contraindicated in Canadian product labeling; some products recommend using effective birth control when treating women of reproductive age and discontinuing therapy several months prior to conception if planning a pregnancy.


Actions


Pharmacology

Fenofibric acid, an agonist for the nuclear transcription factor peroxisome proliferator-activated receptor-alpha (PPAR-alpha), downregulates apoprotein C-III (an inhibitor of lipoprotein lipase) and upregulates the synthesis of apolipoprotein A-I, fatty acid transport protein, and lipoprotein lipase resulting in an increase in VLDL catabolism, fatty acid oxidation, and elimination of triglyceride-rich particles; as a result of a decrease in VLDL levels, total plasma triglycerides are reduced by 30% to 60%; modest increase in HDL occurs in some hypertriglyceridemic patients.


Absorption

Increased when taken with meals


Distribution

Widely to most tissues


Metabolism

Tissue and plasma via esterases to active form, fenofibric acid; undergoes inactivation by glucuronidation hepatically or renally


Excretion

Urine (60% as metabolites); feces (25%); hemodialysis has no effect on removal of fenofibric acid from plasma


Time to Peak

2-8 hours


Half-Life Elimination

Half-life elimination: Fenofibric acid: Mean: 20 hours (range: 10-35 hours); half-life prolonged in patients with renal impairment


Protein Binding

>99%


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience headache, dyspepsia, pyrosis, or nausea. Have patient report immediately to prescriber severe asthenia, considerable fatigue, inability to eat, discolored urine, jaundice, or rash (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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