Fenofibrate

Pharmacologic Category

Antilipemic Agent, Fibric Acid

Dosing: Adult

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

Hypertriglyceridemia: Oral: Initial:

Antara (micronized): 30 to 90 mg once daily; maximum dose: 90 mg/day

Fenofibrate (micronized): 43 to 130 mg once daily; maximum dose: 130 mg/day

Fenoglide: 40 to 120 mg once daily; maximum dose: 120 mg/day

Fibricor: 35 to 105 mg once daily; maximum dose: 105 mg/day

Lipidil EZ [Canadian product]: 145 mg once daily; maximum dose: 145 mg/day

Lipidil Supra [Canadian product]: 160 mg once daily; maximum dose: 200 mg/day

Lipofen: 50 to 150 mg once daily; maximum dose: 150 mg/day

Lofibra (micronized): 67 to 200 mg once daily; maximum dose: 200 mg/day

Lofibra (tablets): 54 to 160 mg once daily; maximum dose: 160 mg/day

TriCor: 48 to 145 mg once daily; maximum dose: 145 mg/day

Triglide: 160 mg once daily

Trilipix: 45 to 135 mg once daily; maximum dose: 135 mg/day

Hypercholesterolemia or mixed hyperlipidemia: Oral: Initial:

Antara (micronized): 90 mg once daily; maximum dose: 90 mg/day

Fenofibrate (micronized): 130 mg once daily; maximum dose: 130 mg/day

Fenoglide: 120 mg once daily

Fibricor: 105 mg once daily

Lipidil EZ [Canadian product]: 145 mg once daily; maximum dose: 145 mg/day

Lipidil Supra [Canadian product]: 160 mg once daily; maximum dose: 200 mg/day

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

Trilipix: 135 mg once daily

Primary biliary cholangitis (off-label use): Oral: Note: For use in patients with incomplete biochemical response to ursodiol monotherapy. Do not initiate in patients with decompensated liver disease (Child-Pugh B or C) (AASLD [Lindor 2019]; Cheung 2016).

145 to 160 mg once daily in combination with ursodiol (AASLD [Lindor 2019]; Cheung 2016; Levy 2011).

Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.

Dosing: Geriatric

Oral: Initial: Adjust dosage based on renal function; additional product-specific recommendations for initial dose:

Lipidil EZ [Canadian product]: 48 mg once daily

Lofibra (micronized): 67 mg once daily

Lofibra (tablets): 54 mg once daily

Dosing: Renal Impairment: Adult

The renal dosing recommendations are based upon the best available evidence and clinical expertise. Senior Editorial Team: Bruce Mueller, PharmD, FCCP, FASN, FNKF; Jason Roberts, PhD, BPharm (Hons), B App Sc, FSHP, FISAC; Michael Heung, MD, MS.

Note: Fenofibrate use has been associated with reversible elevations in serum creatinine, although the clinical significance is unknown. If creatinine levels are significantly elevated with fibrate therapy and no other clinically relevant cause is evident, then interruption of therapy may be warranted (Davidson 2007).

Altered kidney function:

Note: Multiple formulations available. The following recommendations are considered applicable to all formulations (Davidson 2007; expert opinion; manufacturer's labeling).

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

CrCl >30 to 80 mL/minute: Use lowest available tablet strength (if a formulation is not available in a strength that is ≤67 mg, then an alternate formulation should be used); do not titrate (expert opinion).

CrCl ≤30 mL/minute: Use contraindicated.

Hemodialysis, intermittent (thrice weekly): Not dialyzable (Desager 1982): Use is contraindicated.

Peritoneal dialysis: Not likely to be dialyzable: Avoid use (expert opinion).

CRRT: Not likely to be significantly removed; avoid use (expert opinion).

PIRRT (eg, sustained, low-efficiency diafiltration): Not likely to be significantly removed; avoid use (expert opinion).

Dosing: Hepatic Impairment: Adult

Use is contraindicated. Regular monitoring of liver function tests is required; discontinue therapy in patients whose enzyme levels persist above 3 times the upper limit of normal.

Dosing: Adjustment for Toxicity: Adult

Cholelithiasis: Discontinue if gallstones are found upon gallbladder studies.

CPK elevation, myopathy, and/or myositis: Discontinue therapy if the patient develops markedly elevated CPK concentrations or if myopathy/myositis is suspected or diagnosed.

HDL-C reductions: Permanently discontinue therapy if HDL-C becomes severely depressed; monitor HDL-C concentrations until returned to baseline.

Calculations

• Creatinine Clearance by Cockcroft-Gault
• Creatinine Clearance by Cockcroft-Gault (SI units)
• Creatinine Clearance by Cockcroft-Gault with IBW
• Creatinine Clearance by Cockcroft-Gault with IBW (SI units)
• Creatinine Clearance by Jelliffe
• Creatinine Clearance by Sanaka
• Glomerular Filtration Rate by Abbreviated MDRD
• Glomerular Filtration Rate by Abbreviated MDRD (SI units)
• Glomerular Filtration Rate by MDRD
• Glomerular Filtration Rate by MDRD (IDMS-Traceable SCr)
• Glomerular Filtration Rate by MDRD (SI units)
• Glomerular Filtration Rate Estimate in African Americans by AASK Equation

Use: Labeled Indications

Hypercholesterolemia or mixed dyslipidemia: Adjunctive therapy to diet 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 adults with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson types IIa and IIb). Use lipid-altering agents in addition to a diet restricted in saturated fat and cholesterol when response to diet and nonpharmacological interventions alone has been inadequate.

Note: While FDA-approved for hypercholesterolemia, fenofibrate is not a first- or second-line choice; other agents may be more suitable (ACC/AHA [Stone 2013]). In addition, use is not recommended to lower LDL-C or raise HDL-C in the absence of hypertriglyceridemia.

Hypertriglyceridemia: Adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia (Fredrickson types IV and V hyperlipidemia).

Use: Off-Label: Adult

​Primary biliary cholangitisLevel of Evidence [C, G]

Data from a single-center, retrospective cohort study support the use of fenofibrate (in combination with ursodiol) in patients with primary biliary cholangitis (PBC) who have had an incomplete biochemical response to ursodiol monotherapy and showed significant improvement in alkaline phosphatase, a reduction in hepatic decompensation, and transplant-free survival improvement Ref. Data from a small, open-label pilot study support the use of fenofibrate (in combination with ursodiol) in patients with PBC who have had an incomplete biochemical response to ursodiol monotherapy and showed improvement in liver biochemistries (ie, alkaline phosphatase) and IgM and lowered levels of proinflammatory cytokines Ref.

Based on the 2018 primary biliary cholangitis practice guidance from the American Association for the Study of Liver Disease (AASLD), fenofibrate may be considered an alternative to ursodiol in patients with PBC who have had an inadequate biochemical response to ursodiol monotherapy Ref.

Level of Evidence Definitions

​Level of Evidence Scale

Class and Related Monographs

Fibric Acid Derivatives

Clinical Practice Guidelines

Dyslipidemia:

AACE/ACE, “Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease,” April 2017

ACC, “2017 Focused Update of the 2016 ACC Expert Consensus Decision Pathway on the Role of Non-Statin Therapies for LDL-Cholesterol Lowering in the Management of Atherosclerotic Cardiovascular Disease Risk,” October 2017

ACC/AHA, “2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults,” November 2013

AHA/ACC, “Guideline on the Management of Blood Cholesterol,” November 2018

Canadian Cardiovascular Society, “2016 Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult,” November 2016

NLA, “National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia” Part 1: April 2015; Part 2: December 2015

Hypertriglyceridemia:

The Endocrine Society, “Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline,” September 2012

Primary Biliary Cirrhosis:

AASLD, “Primary Biliary Cirrhosis,” January 2019

Administration: Oral

Antara, fenofibrate (micronized), Fibricor, Lipidil EZ [Canadian product], Lofibra tablets, TriCor, Triglide, Trilipix: Administer with or without food. Swallow whole; do not open (capsules), crush, dissolve, or chew.

Lofibra (micronized) capsules: Administer with meals.

Fenoglide, Lipofen, Lipidil Supra [Canadian product]: Administer with meals. Swallow whole; do not open (capsules), crush, dissolve, or chew.

Bariatric surgery: Capsule, delayed release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. Delayed-release capsules should not be opened. Switch to a formulation that is not delayed release at the nearest possible dose in a tablet or capsule and either crush or open as appropriate.

Dietary Considerations

Antara, Fibricor, Lipidil EZ [Canadian product], Lofibra tablets, TriCor, Triglide, Trilipix: May be taken with or without food.

Fenoglide, Lipidil Supra [Canadian product], Lipofen, Lofibra (micronized capsules): Take with meals.

Storage/Stability

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect Fibricor, Lipofen, Lofibra, TriCor, Triglide, and Trilipix from moisture. Protect Fibricor, Lofibra tablets, Lipofen, and Triglide from light.

Lipidil EZ, Lipidil Supra [Canadian products]: Store at 15°C to 30°C (59°F to 86°F). Protect from light and moisture.

Medication Patient Education with HCAHPS Considerations

What is this drug used for?

• It is used to lower triglycerides.

• It is used to lower bad cholesterol and raise good cholesterol (HDL).

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Headache

• Back pain

• Abdominal pain

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Pancreatitis like severe abdominal pain, severe back pain, severe nausea, or vomiting.

• Gallstones like pain in the upper right abdominal area, right shoulder area, or between the shoulder blades; yellow skin; or fever with chills.

• Blood clots like numbness or weakness on one side of the body; pain, redness, tenderness, warmth, or swelling in the arms or legs; change in color of an arm or leg; chest pain; shortness of breath; fast heartbeat; or coughing up blood.

• Infection

• Muscle pain

• Muscle weakness

• Severe loss of strength and energy

• Severe joint pain

• Severe joint swelling

• Unable to pass urine

• Change in amount of urine passed

• Bruising

• Bleeding

• Stevens-Johnson syndrome/toxic epidermal necrolysis like red, swollen, blistered, or peeling skin (with or without fever); red or irritated eyes; or sores in mouth, throat, nose, or eyes.

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Medication Safety Issues

​Sound-alike/look-alike issues:

Contraindications

Hypersensitivity to fenofibrate or fenofibric acid or any component of the formulation; active liver disease, including primary biliary cirrhosis and unexplained, persistent liver function abnormality; severe renal impairment or end-stage renal disease, including those receiving dialysis; preexisting gallbladder disease; breastfeeding

Documentation of allergenic cross-reactivity for fibrates is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

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

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

Warnings/Precautions

Concerns related to adverse effects:

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

• HDL cholesterol: 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.

• Hematologic 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. 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 after weeks to several years of therapy. Baseline and regular monitoring of liver function tests is required; discontinue therapy in patients whose enzyme levels persist above 3 times the upper limit of normal.

• Hypersensitivity reactions: Acute hypersensitivity reactions, including anaphylaxis and angioedema, have been reported. Additionally, delayed hypersensitivity reactions, including severe cutaneous adverse reactions such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms (DRESS) have been reported, occurring days to weeks following fenofibrate initiation. Discontinue immediately for severe acute or delayed hypersensitivity reactions.

• Myopathy/Rhabdomyolysis: Has been associated with rare myositis, myopathy, or rhabdomyolysis; monitor patients closely. Risk increased in the elderly, those receiving concomitant HMG-CoA reductase inhibitors or colchicine, and patients with diabetes mellitus, renal insufficiency, or hypothyroidism. Instruct patients to report unexplained muscle pain, tenderness, weakness, especially if accompanied with malaise or fever; or brown urine. Discontinue therapy in patients who develop markedly elevated CPK concentrations or if myopathy/myositis is suspected or diagnosed.

• Pancreatitis: Pancreatitis has been reported with fenofibrate use; may be secondary to a failure of efficacy in patients with severe hypertriglyceridemia, medication side effect, or due to biliary tract stone or sludge formation from bile duct obstruction.

• Photosensitivity: Photosensitivity reactions have been reported, sometimes days to months after therapy was initiated; some patients reported previous photosensitivity to ketoprofen.

• Renal effects: Increases in serum creatinine (>2 mg/dL) have been observed with use; clinical significance unknown. These elevations tend to return to baseline following discontinuation of fenofibrate. 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; consider monitoring renal function in patients with increased risk for developing renal impairment (eg, elderly and patients with diabetes).

• Venous thromboembolism: Use has been associated with PE and DVT. Use with caution in patients with risk factors for VTE.

Disease-related concerns:

• Cardiovascular disease: Fibric acid derivatives have not demonstrated significant efficacy in altering cardiovascular disease mortality in major clinical studies. 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 were shown to reduce cardiovascular disease morbidity and mortality in patients with type 2 diabetes.

• Hepatic impairment: Contraindicated in patients with active liver disease, including primary biliary cirrhosis and unexplained persistent liver function abnormalities.

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

Concurrent drug therapy issues:

• 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. Fenofibrate may be considered in patients on low- or moderate-intensity statin therapy (ie, statin therapy intended to lower LDL-C by <30% or ~30% to 50%, respectively) only if the benefits from atherosclerotic cardiovascular disease (ASCVD) risk reduction or triglyceride lowering when triglycerides are >500 mg/dL, outweigh the potential risk for adverse effects (ACC/AHA [Stone 2013]).

Special populations:

• Elderly: Use with caution in the elderly; dosage adjustment may be required.

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:

• Appropriate use: Fenofibrate is not a first- or second-line choice in patients with hypercholesterolemia; other agents may be more suitable (ACC/AHA [Stone 2013]). 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 to 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.

Geriatric Considerations

Adjust dose based on renal function and product.

The definition of and, therefore, when to treat hyperlipidemia in the elderly is a controversial issue. According to the 2013 ACC/AHA Guidelines on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults, there are no supporting data for the routine use of nonstatin drugs in combination with a statin to further reduce atherosclerotic cardiovascular disease (ASCVD) events. Evidence for nonstatins in statin-intolerant patients is also lacking (Stone 2013). It is the authors' belief that pharmacologic treatment be reserved for those who are unable to obtain a desirable plasma cholesterol concentration by diet alone and for whom the benefits of treatment are believed to outweigh the potential adverse effects, drug interactions, and cost of treatment.

Pregnancy Considerations

Triglyceride and lipid concentrations increase during pregnancy as required for normal fetal development. When increases are greater than expected, supervised dietary intervention should be initiated. In women who develop very severe hypertriglyceridemia and are at risk for pancreatitis, use of fenofibrate beginning in the second trimester is one intervention that may be considered. Agents other than fenofibrate should be used for hypercholesterolemia (Avis 2009; Berglund 2012; Jacobson 2015; Wong 2015).

Breast-Feeding Considerations

It is not known if fenofibrate is present in breast milk.

Lipids are a normal component of breast milk and the fatty acid component is required for normal infant neurologic development. Maternal diet, as well as other factors, may influence the fatty acid composition (Innis 2014). When treatment for very severe hypertriglyceridemia in breastfeeding women at risk for pancreatitis is needed, therapy with fenofibrate may be considered (Jacobson 2015). When treatment is needed for other indications, agents other than fenofibrate are preferred (Jacobson 2015; NICE 2008). Due to the potential for serious adverse reactions in the breastfed infant (such as disrupting lipid metabolism), breastfeeding is contraindicated by the manufacturer; some products specifically do not recommend breastfeeding until 5 days after the last dose.

Briggs' Drugs in Pregnancy & Lactation

• Fenofibrate

Adverse Reactions

>10%: Hepatic: Increased serum transaminases (≥3 x ULN: 5% to 13%)

1% to 10%:

Cardiovascular: Pulmonary embolism (≤5%), thrombophlebitis (≤5%)

Central nervous system: Dizziness (≥3%), pain (≥3%)

Dermatologic: Skin rash (1%), urticaria (1%)

Gastrointestinal: Abdominal pain (5%), diarrhea (≥3%), dyspepsia (≥3%), constipation (2%)

Hepatic: Abnormal hepatic function tests (8%), increased serum alanine aminotransferase (3%), increased serum aspartate aminotransferase (3%)

Neuromuscular & skeletal: Arthralgia (≥3%), limb pain (≥3%), myalgia (≥3%), increased creatine phosphokinase in blood specimen (3%)

Respiratory: Nasopharyngitis (≥3%), sinusitis (≥3%), upper respiratory tract infection (≥3%), rhinitis (2%)

<1%, postmarketing, and/or case reports: Acute renal failure, agranulocytosis, anaphylaxis, anemia, angioedema, asthenia, cholestatic hepatitis, chronic active hepatitis, decreased HDL cholesterol (severe), decreased hematocrit, decreased hemoglobin, decreased white blood cell count, drug reaction with eosinophilia and systemic symptoms, headache, hepatic cirrhosis, hepatitis, hepatocellular hepatitis, hypersensitivity reaction, increased serum creatinine, interstitial pulmonary disease, muscle spasm, myopathy, pancreatitis, renal failure syndrome, rhabdomyolysis, severe dermatological reaction (severe cutaneous adverse reactions [SCAR]), skin photosensitivity, Stevens-Johnson syndrome, thrombocytopenia, toxic epidermal necrolysis

Allergy and Idiosyncratic Reactions

• Fibric Acid Derivative Allergy

Metabolism/Transport Effects

Inhibits CYP2C9 (weak)

Drug Interactions Open Interactions

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. Exceptions: Colesevelam. Risk D: 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. Risk C: Monitor therapy

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: Fenofibrate and Derivatives may enhance the adverse/toxic effect of Ezetimibe. Specifically, the risk of myopathy and cholelithiasis may be increased. Fenofibrate and Derivatives may increase the serum concentration of Ezetimibe. Risk C: Monitor therapy

Fosphenytoin-Phenytoin: CYP2C9 Inhibitors (Weak) may increase the serum concentration of Fosphenytoin-Phenytoin. Risk C: Monitor therapy

HMG-CoA Reductase Inhibitors (Statins): Fenofibrate and Derivatives may enhance the adverse/toxic effect of HMG-CoA Reductase Inhibitors (Statins). Risk C: Monitor therapy

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

Tacrolimus (Systemic): May enhance the nephrotoxic effect of Fenofibrate and Derivatives. Risk C: Monitor therapy

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

Warfarin: Fenofibrate and Derivatives may enhance the anticoagulant effect of Warfarin. Fenofibrate and Derivatives may increase the serum concentration of Warfarin. Management: Monitor for signs and symptoms of bleeding, and increase INR monitoring in patients taking warfarin who are initiated on fenofibrate derivatives. Warfarin dose reductions will likely be required. Risk D: Consider therapy modification

Food Interactions

Antara (micronized): When administered under fasted conditions or with a low-fat meal, the extent of absorption and the time to peak did not change; however peak concentrations were increased in the presence of a low-fat meal. When administered with a high fat meal, a 26% increase in the AUC and 108% increase in the peak concentration were seen in comparison to the fasted state. Management: Administer with or without food.

Fenoglide: When administered with a high-fat meal, the peak concentration was increased by 44% as compared to fasting conditions. Management: Administer with meals.

Fibricor: When administered with a high-fat meal, the peak concentration was decreased by ~35% while AUC remained unchanged as compared to fasting conditions. Management: Administer with or without food.

Lipidil EZ [Canadian product]: Bioavailability was not significantly different when administered under fasting and nonfasting conditions. Management: Administer with or without food.

Lipidil Supra [Canadian product]: In general, fenofibrate absorption is low and variable when administered under fasting conditions; absorption is increased when administered with food. Management: Administer with meals.

Lipofen: When administered with a low-fat and high-fat meal, the extent of absorption is increased by ~25% and ~58%, respectively, as compared to fasting conditions. Management: Administer with meals.

Lofibra (micronized) capsules: Absorption is increased by ~35% under fed as compared to fasting conditions. Management: Administer with meals.

Lofibra tablets: Peak concentrations and AUC were not significantly different when a single dose was administered under fasting and nonfasting conditions. Management: Administer with or without food.

TriCor: Peak concentrations and AUC were not significantly different when a single dose was administered under fasting and nonfasting conditions. Management: Administer with or without food.

Triglide: When administered with food, the rate of absorption was increased ~55% as compared to fasting conditions; the AUC remained unchanged. Management: Administer with or without food.

Trilipix: Peak concentrations and AUC were not significantly different when a single dose was administered under fasting and nonfasting conditions. Management: Administer with or without food.

Genes of Interest

• Angiotensin I Converting Enzyme 1
• Cholesteryl Ester Transfer Protein, Plasma

Monitoring Parameters

Periodic blood counts during first year of therapy. Monitor lipid profile periodically. 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.

2013 ACC/AHA Blood Cholesterol Guideline recommendations (ACC/AHA [Stone 2013]): Evaluate renal status at baseline, within 3 months after initiation, and every 6 months thereafter.

Advanced Practitioners Physical Assessment/Monitoring

Before initiating, check patient's profile against contraindications. Obtain baseline liver function tests and monitor throughout therapy. In patients with known renal impairment, monitor serum creatinine during therapy. Dose reduction in patients with mild to moderate renal impairment. Increased risk of cholelithiasis due to increased cholesterol excretion in the bile. May have a paradoxical affect on HDL.

Nursing Physical Assessment/Monitoring

Monitor for signs/symptoms of myopathy (muscular pain, weakness, fatigue). Obtain baseline liver function tests and monitor throughout therapy. Increased risk of cholelithiasis due to increased cholesterol excretion in the bile.

Dosage Forms Considerations

Micronized formulations: Antara, Lofibra capsules

Strength of choline fenofibrate products are expressed in terms of fenofibric acid.

Dosage Forms: US

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral, as fenofibrate:

Antara: 30 mg [contains fd&c blue #2 (indigotine), fd&c yellow #10 (quinoline yellow)]

Antara: 90 mg [contains brilliant blue fcf (fd&c blue #1), fd&c yellow #10 (quinoline yellow), fd&c yellow #6 (sunset yellow)]

Lipofen: 50 mg [contains brilliant blue fcf (fd&c blue #1), fd&c blue #2 (indigotine), fd&c red #40, fd&c yellow #10 (quinoline yellow)]

Lipofen: 150 mg

Lofibra: 67 mg [DSC], 134 mg [DSC], 200 mg [DSC]

Generic: 43 mg, 50 mg, 67 mg, 130 mg, 134 mg, 150 mg, 200 mg

Capsule Delayed Release, Oral, as choline fenofibrate:

Trilipix: 45 mg

Trilipix: 135 mg [contains fd&c blue #2 (indigotine)]

Generic: 45 mg, 135 mg

Tablet, Oral, as fenofibrate:

Fenoglide: 40 mg, 120 mg

Lofibra: 54 mg [DSC] [contains fd&c yellow #10 aluminum lake]

Lofibra: 160 mg [DSC]

Tricor: 48 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake, soybean lecithin]

Tricor: 145 mg [contains soybean lecithin]

Triglide: 160 mg [DSC]

Triglide: 160 mg [DSC] [contains egg phospholipids (egg lecithin)]

Generic: 40 mg, 48 mg, 54 mg, 120 mg, 145 mg, 160 mg

Tablet, Oral, as fenofibric acid:

Fibricor: 35 mg, 105 mg

Generic: 35 mg [DSC], 105 mg

Dosage Forms: Canada

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Capsule, Oral:

Fenomax: 100 mg, 160 mg

Generic: 100 mg

Capsule, Oral, as fenofibrate:

Lipidil Micro: 200 mg [DSC]

Generic: 67 mg, 200 mg

Tablet, Oral:

Generic: 100 mg

Tablet, Oral, as fenofibrate:

Lipidil EZ: 48 mg [contains fd&c blue #2 aluminum lake, fd&c yellow #10 aluminum lake, fd&c yellow #6 aluminum lake, soybean lecithin]

Lipidil EZ: 145 mg [contains soybean lecithin]

Lipidil Supra: 160 mg [contains soybean lecithin]

Generic: 48 mg, 145 mg, 160 mg

Anatomic Therapeutic Chemical (ATC) Classification

• C10AB05

Generic Available (US)

Yes

Pricing: US

Capsule, delayed release (Trilipix Oral)

45 mg (per each): $3.61

135 mg (per each): $10.83

Capsules (Antara Oral)

30 mg (per each): $6.90

90 mg (per each): $20.32

Capsules (Fenofibrate Micronized Oral)

43 mg (per each): $2.27 - $2.35

67 mg (per each): $0.27 - $1.06

130 mg (per each): $6.83 - $6.93

134 mg (per each): $0.45 - $1.96

200 mg (per each): $0.79 - $3.15

Capsules (Fenofibrate Oral)

50 mg (per each): $3.27

150 mg (per each): $7.16

Capsules (Lipofen Oral)

50 mg (per each): $4.35

150 mg (per each): $9.54

Tablets (Fenofibrate Oral)

40 mg (per each): $10.45

48 mg (per each): $0.61 - $1.91

54 mg (per each): $0.30 - $0.82

120 mg (per each): $31.34

145 mg (per each): $1.12 - $5.73

160 mg (per each): $0.61 - $2.88

Tablets (Fenofibric Acid Oral)

105 mg (per each): $46.60

Tablets (Fenoglide Oral)

40 mg (per each): $14.84

120 mg (per each): $44.53

Tablets (Fibricor Oral)

35 mg (per each): $19.73

105 mg (per each): $39.40

Tablets (Tricor Oral)

48 mg (per each): $0.68

145 mg (per each): $1.24

Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Absorption: Increased when taken with meals

Distribution: Widely to most tissues

Protein binding: ~99%

Metabolism: Fenofibrate is metabolized in the tissue and plasma via esterases to the active form, fenofibric acid; fenofibric acid then undergoes inactivation by glucuronidation hepatically or renally

Bioavailability: Fenofibric acid: ~81%

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

Time to peak: 2 to 8 hours

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

Pharmacodynamics/Kinetics: Additional Considerations

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 to 80 mL/minute).

Local Anesthetic/Vasoconstrictor Precautions

No information available to require special precautions

Effects on Dental Treatment

Key adverse event(s) related to dental treatment: Dry mouth

Effects on Bleeding

Thrombocytopenia has been reported through postmarketing surveillance.

Related Information

• Oral Medications That Should Not Be Crushed or Altered

Index Terms

ABT-335; Choline Fenofibrate; Fenofibric Acid; Procetofene; Proctofene

FDA Approval Date

December 31, 1993

References

ACCORD Study Group, Ginsberg HN, Elam MB, et al, “Effects of Combination Lipid Therapy in Type 2 Diabetes Mellitus,” N Engl J Med, 2010, 362(17):1563-74.[PubMed 20228404]

Antara (fenofibrate) [prescribing information]. Baltimore, MD: Lupin Pharma; November 2018.

Avis HJ, Hutten BA, Twickler MT, et al. Pregnancy in women suffering from familial hypercholesterolemia: a harmful period for both mother and newborn? Curr Opin Lipidol. 2009;20(6):484-490. doi: 10.1097/MOL.0b013e3283319127.[PubMed 19741526]

Berglund L, Brunzell JD, Goldberg AC, et al, “Evaluation and Treatment of Hypertriglyceridemia: An Endocrine Society Clinical Practice Guideline,” J Clin Endocrinol Metab, 2012, 97(9):2969-89.[PubMed 22962670]

Bonds DE, Craven TE, Buse J, et al, "Fenofibrate-Associated Changes in Renal Function and Relationship to Clinical Outcomes Among Individuals With Type 2 Diabetes: The Action to Control Cardiovascular Risk in Diabetes (ACCORD) Experience," Diabetologia, 2012, 55(6):1641-50.[PubMed 22450889]

Cheung AC, Lapointe-Shaw L, Kowgier M, et al. Combined ursodeoxycholic acid (UDCA) and fenofibrate in primary biliary cholangitis patients with incomplete UDCA response may improve outcomes. Aliment Pharmacol Ther. 2016;43(2):283-293. doi:10.1111/apt.13465[PubMed 26559762]

Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol. 2007;99(6A):3C-18C. doi:10.1016/j.amjcard.2006.11.016[PubMed 17368275]

Desager JP, Costermans J, Verberckmoes R, Harvengt C. Effect of hemodialysis on plasma kinetics of fenofibrate in chronic renal failure. Nephron. 1982;31(1):51-54. doi:10.1159/000182614[PubMed 7110477]

Farnier M, Bonnefous F, Debbas N, et al, “Comparative Efficacy and Safety of Micronized Fenofibrate and Simvastatin in Patients With Primary Type IIa or IIb Hyperlipidemia,” Arch Intern Med, 1994, 154(4):441-9.[PubMed 8117177]

Fenofibrate [prescribing information]. Bridgewater, NJ: Alembic Pharmaceuticals, Inc; November 2019.

Fenofibrate (fenofibric acid) [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals; November 2015.

Fenoglide (fenofibric acid) [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals; March 2019.

Fenoglide (fenofibric acid) [prescribing information]. Bridgewater, NJ: Valeant Pharmaceuticals; May 2018.

Fibricor (fenofibrate) tablets [prescribing information]. Princeton, NJ: Aralez Pharmaceuticals; May 2018.

Hottelart C, El Esper N, Rose F, et al, "Fenofibrate Increases Creatininemia by Increasing Metabolic Production of Creatinine," Nephron, 2002, 92(3):536-41.[PubMed 12372935]

Innis SM. Impact of maternal diet on human milk composition and neurological development of infants. Am J Clin Nutr. 2014;99(3):734S-741S. doi: 10.3945/ajcn.113.072595.[PubMed 24500153]

Jacobson TA, Maki KC, Orringer CE, et al; NLA Expert Panel. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2 [published correction appears in J Clin Lipidol. 2016;10(1):211]. J Clin Lipidol. 2015;9(6 suppl):S1-S122.e1. doi: 10.1016/j.jacl.2015.09.002.[PubMed 26699442]

Keech A, Simes RJ, Barter P, et al, “Effects of Long-term Fenofibrate Therapy on Cardiovascular Events in 9795 People With Type 2 Diabetes Mellitus (The FIELD Study): Randomised Controlled Trial,” Lancet, 2005, 366(9500):1849-61.[PubMed 16310551]

Levy C, Peter JA, Nelson DR, et al. Pilot study: fenofibrate for patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Aliment Pharmacol Ther. 2011;33(2):235-242. doi: 10.1111/j.1365-2036.2010.04512.x.[PubMed 21083674]

Lindor KD, Bowlus CL, Boyer J, Levy C, Mayo M. Primary biliary cholangitis: 2018 practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2019;69(1):394-419. doi: 10.1002/hep.30145.[PubMed 30070375]

Lipidil EZ (fenofibrate) tablets [product monograph]. Etobicoke, Ontario, Canada: BGP Pharma; January 2017.

Lipidil Supra (fenofibrate) tablets [product monograph]. Etobicoke, Ontario, Canada: BGP Pharma; January 2017.

Lipofen (fenofibrate) capsules [prescribing information]. Montgomery, AL: Kowa Pharmaceuticals America Inc; November 2018.

Lofibra (fenofibrate) tablets [prescribing information]. Horsham, PA: Teva Pharmaceuticals; January 2017.

Mohiuddin SM, Pepine CJ, Kelly MT, et al. Efficacy and safety of ABT-335 (fenofibric acid) in combination with simvastatin in patients with mixed dyslipidemia: a phase 3, randomized, controlled study. Am Heart J. 2009;157(1):195-203.[PubMed 19081418]

Mychaleckyj JC, Craven T, Nayak U, et al, "Reversibility of Fenofibrate Therapy-Induced Renal Function Impairment in ACCORD Type 2 Diabetic Participants," Diabetes Care, 2012, 35(5):1008-14.[PubMed 22432114]

National Institute for Health and Care Excellence (2008) Clinical guidelines and evidence review for familial hypercholesterolaemia: the identification and management of adults and children with familial hypercholesterolaemia. London: NICE. (Clinical Guideline 71).Available at http://www.nice.org.uk/CG71.

Stone NJ, Robinson J, Lichtenstein AH, et al, 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [published online ahead of print November 12, 2013].Circulation. 2013; doi: 10.1161/01.cir.0000437738.63853.7a.

Taskinen M, Sullivan DR, Ehnholm, et al, “Relationships of HDL Cholesterol, ApoA-I, and ApoA-II With Homocysteine and Creatinine in Patients With Type 2 Diabetes Treated With Fenofibrate,” Arterioscler Thromb Vasc Biol, 2009, 29(6):950-5.[PubMed 19325138]

Tricor (fenofibrate) tablets [prescribing information]. North Chicago, IL: Abbvie Inc; November 2018.

Triglide (fenofibric acid) [prescribing information]. East Brunswick, NJ: Casper Pharma LLC; May 2018.

Trilipix (fenofibric acid) [prescribing information]. North Chicago, IL: Abbvie Inc; November 2018.

Wong B, Ooi TC, Keely E. Severe gestational hypertriglyceridemia: A practical approach for clinicians. Obstet Med. 2015;8(4):158-167. doi: 10.1177/1753495X15594082.[PubMed 27512474]

Brand Names: International

Apo-Feno (PL); Apo-Feno-Micro (MY); Biofibrat (PL); Catalip (PT); Cholecaps (ID); Cholib (PH); CIL (FI); Controlip (AR, CR, DO, EC, GT, HN, MX, NI, PA, PE, SV); Cordialibrel (MX); Craveril (AR); Daunlip (AR); Diafeno (PH); Durafenat (DE); Eticer (CN); Evothyl (ID); Exlip (RU); Febira (CZ); Febira 200 (SK); Febrate (TH); Fegenor (FR, LB); Fenacor (IN); Fenardin (PL); Fenatrol (BD); Fenobrat (GR, HU, PE); Fenobrate (AR); Fenobraty (BR); Fenocap (BD); Fenocor (IN); Fenofast (PH); Fenofix (CZ, SK); Fenoflex (ID, VN); Fenogal (BE, GB, KW, LB, LU, PH, SA, TR); Fenoget (LK, PK); Fenogetz (VN); Fenolip (AT, CO, EG, HR, IN, RO); Fenopidil (KR); Fenosup (BE, FI, MY, SG); Fenosup Lidose (LB, VN); Fenoswiss (HU); Fenox (TH); Fiba (LK); Fibra (PK); Fibrafen (PH); Fibral (IN); Fibranor (BG); Fibrate (BD, IN); Fibronil (CL); Fulcro (IT); Fulcrosupra (IT); Grofibrat (PL); Hafenthyl (VN); Kemifib (EG); Lexemin (HK, SG, TH); Lifen (ID); Lipanon (BR); Lipanthyl (AE, BE, BG, CH, CN, CZ, DE, EE, EG, FI, FR, HK, JO, KW, LB, LT, LU, LV, MT, MY, PH, PL, QA, RO, RU, SA, SE, SG, SK, TH, TR, UA, VN, ZA); Lipanthyl NT (VN); Lipanthyl Penta 145 (HK); Lipanthyl Supra (MY, SG); Lipanthyl Supra 150 (HK); Lipantil (GB, IE, RO); Lipantil Supra (MT); Lipcor (AT); Liperial (IT); Lipicard (IN, LK, UA); Lipidil (AU, BR, DE, EC, GR, HR, HU, MX, TR); Lipidil Supra (KR); Lipidof (BD, PK); Lipiduce (PH); Lipifen T.U. (PY); Lipilfen (CN, KR); Lipilo (CN); Lipired (BD); Lipirex (CZ); Lipivim (RO); Lipofen (PT, TR, UA); Lipofib (RO); Lipsin (IT); Lipway (PH); Lofat (BD); Lofibra (PH); Lofibrate (TH); Lolipid (BD); Lotrilip (PH); Lowpirol S (KR); Minuslip (AR); Nanofib (LB); Nofibra (EG); Nopid (KR); Normalip (DE); Normolip (CO, PE); Notricol (CO); Nubrex (PH); Qi Shu (CN); Qualipantyl (HK); Redose (KR); Reducofen (BR); Sclerofin (AR); Sclerofin UD (PY); Secalip (ES, FR, TR); Secalip Retard (ES); Secalip Supra (ES); Stanlip (BH, TH, VN); Sulnit (PY); Sulnit CD (PY); Supralip (GB, PT); Suprelip (CZ, SK); Tilene (IT); Tizabate (BD); Trichek (LK, PH); Tricor (HR, JP, RU, UA); Trilipix (CH, CL, RU); Trolip (ID, LK, PH, SG); Ziglip (HR); Zigotrig (HR); Zinof (PH); Zumafib (ID)

Last Updated 10/21/20