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fenofibrate 145 mg tablet generic tricor

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Uses

Dyslipidemias

Fenofibrate and fenofibric acid are used as adjuncts to dietary therapy in the management of primary hypercholesterolemia and mixed dyslipidemia. The drugs also are used as adjuncts to dietary therapy in the management of severe hypertriglyceridemia. In addition, fenofibric acid is used in combination with a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) for the treatment of mixed dyslipidemia in patients with coronary heart disease (CHD) or CHD risk equivalents who are receiving optimal statin therapy; however, no additional benefit on cardiovascular morbidity and mortality has been demonstrated with such combination therapy beyond that already established with statin monotherapy. (See Primary Hypercholesterolemia and Mixed Dyslipidemia under Uses: Dyslipidemias and also see Effects on Morbidity and Mortality under Cautions: Warnings/Precautions.)

The American College of Cardiology (ACC)/American Heart Association (AHA) guideline for management of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults states that nondrug therapies (i.e., lifestyle modifications), which include adherence to a heart-healthy diet, regular exercise, avoidance of tobacco products, and maintenance of a healthy weight, are the foundation of atherosclerotic cardiovascular disease (ASCVD) prevention. Drug therapy is not a substitute for, but an adjunct to, these nondrug therapies and measures, which should be continued when drug therapy is initiated. For additional details on lifestyle modifications, consult the most recent AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk (available at http://www.cardiosource.org or http://my.americanheart.org).

The effects of fenofibrate and fenofibric acid on cardiovascular morbidity and mortality or noncardiovascular mortality have not been established.

Primary Hypercholesterolemia and Mixed Dyslipidemia

Fenofibrate and fenofibric acid are used as adjuncts to dietary therapy to decrease elevated serum total and low-density lipoprotein (LDL)-cholesterol, triglyceride, and apolipoprotein B (apo B) concentrations, and to increase high-density-lipoprotein (HDL)-cholesterol concentrations in the management of primary hypercholesterolemia and mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia. Fenofibric acid also is used in combination with a 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; CHD risk equivalents include diabetes mellitus, multiple risk factors that confer a 10-year risk of CHD exceeding 20%, or other types of atherosclerotic disease such as peripheral arterial disease, abdominal aortic aneurysm, and symptomatic carotid artery disease. The addition of fenofibrate to statin therapy has not been shown to provide an incremental benefit on cardiovascular morbidity and mortality beyond that already established with statin monotherapy.(See Effects on Morbidity and Mortality under Cautions: Warnings/Precautions.)

The ACC/AHA cholesterol management guideline states that nonstatin therapies (e.g., fibric acid derivatives) do not provide acceptable ASCVD risk reduction benefits compared to their potential for adverse effects in the routine prevention of ASCVD. The guideline states that nonstatin drugs may be useful as adjuncts to statin therapy in certain high-risk patients (e.g., patients with ASCVD, patients with LDL-cholesterol concentrations of 190 mg/dL or higher, 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, the ACC/AHA cholesterol management guideline states that the combination of fenofibrate (or fenofibric acid) and low- or moderate-intensity statin therapy may be considered only if the benefits from ASCVD risk reduction or triglyceride lowering (when triglyceride concentrations exceed 500 mg/dL) outweigh the potential risks of adverse effects and drug interactions. and also consult the most recent ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults (available at http://www.cardiosource.org or http://my.americanheart.org).

Efficacy and safety of fenofibrate and fenofibric acid in the management of hypercholesterolemia were established in 4 randomized, double-blind, placebo-controlled studies of 3-6 months' duration in patients with primary hypercholesterolemia or mixed dyslipidemia. In these studies, patients who received fenofibrate in dosages equivalent to 90 mg (as Antara micronized capsules), 120 mg (as Fenoglide tablets), 150 mg (as Lipofen capsules), 160 mg (as Triglide tablets), 200 mg (as micronized Lofibra capsules), or 145 mg (as Lofibra or TriCor tablets) daily or fenofibric acid at dosages equivalent to 135 mg once daily (as Trilipix capsules) had mean reductions of about 17-22% in total cholesterol, 20-31% in LDL-cholesterol, 24-36% in triglyceride, and (in a subset of patients) 25% in apo B concentrations; mean increases of 10-15% in HDL-cholesterol concentrations also were reported.

Efficacy and safety of fenofibric acid in combination with a statin were established in 3 randomized, double-blind studies of 12 weeks' duration and a long-term (52-week) open-label extension study in patients with mixed dyslipidemia. In these studies, the combination of fenofibric acid (135 mg daily) and a statin (atorvastatin 20 or 40 mg daily, rosuvastatin 10 or 20 mg daily, or simvastatin 20 or 40 mg daily) substantially increased HDL-cholesterol and reduced triglyceride concentrations compared with the corresponding statin monotherapy and substantially reduced LDL-cholesterol concentrations compared with fenofibric acid monotherapy. Patients who received the combination antilipemic regimens in these studies had mean increases of about 18% in HDL-cholesterol concentrations and mean decreases of about 42-44 and 33-35% in triglyceride and LDL-cholesterol concentrations, respectively. In the 52-week extension study, patients continued to receive fenofibric acid in combination with a moderate dosage of statin; reductions of about 48% in triglyceride concentrations, 35% in total cholesterol concentrations, 38% in LDL-cholesterol concentrations, 44% in apo B concentrations, and 46% in non-HDL-cholesterol concentrations were observed, in addition to an increase of approximately 24% in HDL-cholesterol concentrations. Such effects were observed within 4 weeks and sustained throughout the duration of the study.

Use of fenofibrate in combination with a statin was evaluated in another randomized, controlled study (the Action to Control Cardiovascular Risk in Diabetes [ACCORD Lipid] study). In this study, the combination of fenofibrate (160 mg daily) and a statin (simvastatin at dosages up to 40 mg daily) was compared with statin therapy alone in patients with type 2 diabetes mellitus at high risk for cardiovascular disease. Despite a favorable effect on serum lipid concentrations (e.g., increased HDL-cholesterol, reduced triglycerides), the addition of fenofibrate to simvastatin therapy did not substantially reduce the rate of cardiovascular events (i.e., nonfatal myocardial infarction, nonfatal stroke, death from cardiovascular causes) compared with simvastatin monotherapy over a mean follow-up period of 4.7 years.(See Effects on Morbidity and Mortality under Cautions: Warnings/Precautions.) In general, routine use of fenofibrate in combination with a statin is not recommended to further reduce cardiovascular risk in patients with type 2 diabetes mellitus; while subgroup analyses indicate that such a combination may provide some benefit in certain groups of patients (e.g., those with type 2 diabetes mellitus and atherogenic dyslipidemia), further study is required to confirm these findings.

While few studies are available on the comparative efficacy of fenofibrate and other antilipemic agents, limited data suggest that fenofibrate may have more favorable effects on serum total cholesterol and LDL-cholesterol concentrations than gemfibrozil. Fenofibrate appears to be more effective than statins in lowering triglyceride and increasing HDL-cholesterol concentrations but generally is less effective in reducing LDL-cholesterol concentrations.

Data from several studies indicate that combination therapy with fenofibrate and other antilipemic agents (e.g., colesevelam, ezetimibe) may produce additive antilipemic effects. In one study, the addition of colesevelam hydrochloride (3.8 g daily) to current fenofibrate therapy (160 mg daily as micronized formulations) in patients with mixed dyslipidemia further reduced total and LDL-cholesterol concentrations by 8 and 12%, respectively, but increased triglyceride concentrations by 9%. In another study in patients with mixed dyslipidemia, combination therapy with fenofibrate (160 mg daily as micronized formulations) and ezetimibe was superior to fenofibrate monotherapy in reducing total cholesterol (22 versus 11%), LDL-cholesterol (20 versus 6%), apo B (26 versus 15%), and non-HDL-cholesterol concentrations (30 versus 16%) following up to 60 weeks of therapy; effects on triglyceride and HDL-cholesterol concentrations in patients receiving combination therapy were comparable to those in patients receiving fenofibrate monotherapy.

Hypertriglyceridemia

Fenofibrate and fenofibric acid are used as adjuncts to dietary therapy in the management of severe hypertriglyceridemia. Efficacy of the drugs in reducing the risk of pancreatitis in patients with marked elevations in triglyceride concentrations (i.e., exceeding 2000 mg/dL) has not been established. In patients with diabetes mellitus who have fasting chylomicronemia, improving glycemic control usually will reduce fasting triglycerides and eliminate the need for pharmacologic therapy.

Efficacy and safety of fenofibrate and fenofibric acid in the management of hypertriglyceridemia were established in 2 randomized, double-blind, placebo-controlled studies of 8 weeks' duration in patients with type IV or V hyperlipoproteinemia. In these studies, patients who received fenofibrate in dosages equivalent to 90 mg (as Antara micronized capsules), 120 mg (as Fenoglide tablets), 150 mg (as Lipofen capsules), 145 mg (as Lofibra or TriCor tablets), 200 mg (as Lofibra micronized capsules), or 160 mg (as Triglide tablets) daily or fenofibric acid at a dosage equivalent to 135 mg daily (as Trilipix capsules) had mean reductions of 46-55 and 45-49% in triglyceride and very low-density lipoprotein (VLDL)-cholesterol concentrations, respectively; mean increases of 20-23% in HDL-cholesterol concentrations also were reported.

Treatment of patients with type IV hyperlipoproteinemia and elevated triglycerides with fenofibrate often is associated with increases in LDL-cholesterol concentrations. In clinical studies with fenofibrate, LDL-cholesterol concentrations were increased by 15 or 45% in patients with baseline triglyceride concentrations of 350-499 or 500-1500 mg/dL, respectively.

Dosage and Administration

General

Fenofibrate and fenofibric acid are administered orally once daily. When fenofibric acid is used in combination with a hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor (statin), the daily dose of fenofibric acid may be administered at the same time as the statin, in accordance with the recommended dosing schedule for each drug.

Fenofibrate is commercially available in several different formulations (see Description); each formulation has been developed specifically to overcome the inherent insolubility of the drug. With the exception of generic equivalents, these preparations are not bioequivalent and vary substantially with respect to food effects and potency. Some preparations such as Fenoglide tablets, Lipofen capsules, and Lofibra micronized capsules require administration with food to further increase absorption and bioavailability of the drug. Other fenofibrate preparations such as Antara micronized capsules, Lofibra tablets, TriCor tablets, and Triglide tablets may be administered without regard to meals. Fenofibric acid (Trilipix delayed-release capsules) also may be administered without regard to meals.

The manufacturers state that patients should be placed on a standard cholesterol-lowering diet before initiation of fenofibrate or fenofibric acid therapy and should remain on this diet during treatment.

Serum lipoprotein concentrations should be determined prior to initiating antilipemic therapy (to confirm an abnormality) and monitored periodically during fenofibrate or fenofibric acid therapy. Reduction of fenofibrate dosage should be considered in patients whose serum cholesterol concentrations fall below the desired target range.

Patients should be advised that Antara capsules, Fenoglide tablets, Lipofen capsules, and Trilipix delayed-release capsules should be swallowed intact and not opened, crushed, dissolved, or chewed.

Dyslipidemias

The recommended initial dosage of fenofibrate for the management of primary hypercholesterolemia or mixed dyslipidemia in adults is 90 mg daily (as Antara micronized capsules), 120 mg daily (as Fenoglide tablets), 150 mg daily (as Lipofen capsules), 160 mg daily (as Triglide tablets or Lofibra tablets), 200 mg daily (as Lofibra micronized capsules or generic equivalents), or 145 mg daily (as TriCor tablets or generic equivalents).

The recommended dosage of fenofibric acid for the management of primary hypercholesterolemia or mixed dyslipidemia in adults is 135 mg once daily (as Trilipix delayed-release capsules or generic equivalents). When used in combination with a statin in adults with mixed dyslipidemia and coronary heart disease (CHD) or CHD risk equivalents, fenofibric acid also is administered at a dosage of 135 mg daily. Concomitant use of fenofibric acid with maximum dosages of statins has not been evaluated and should be avoided unless the benefits are expected to outweigh the risks.

The recommended initial dosage of fenofibrate for the management of severe hypertriglyceridemia in adults is 30-90 mg daily (as Antara micronized capsules), 40-120 mg daily (as Fenoglide tablets), 50-150 mg daily (as Lipofen capsules), 54-160 mg daily (as Lofibra tablets), 67-200 mg daily (as Lofibra micronized capsules or generic equivalents), 48-145 mg daily (as TriCor tablets or generic equivalents), or 50-160 mg daily (as Triglide tablets). The recommended initial dosage of fenofibric acid for the management of severe hypertriglyceridemia in adults is 45-135 mg once daily (as Trilipix delayed-release capsules or generic equivalents). Dosage should be adjusted at intervals of 4-8 weeks until the desired effect on lipoprotein concentrations is observed or a maximum dosage of 90 mg daily (as Antara micronized capsules), 120 mg daily (as Fenoglide tablets), 150 mg daily (as Lipofen capsules), 160 mg daily (as Lofibra tablets or Triglide tablets), 200 mg daily (as Lofibra micronized capsules), 145 mg daily (as TriCor tablets or generic equivalents), or 135 mg daily (as Trilipix delayed-release capsules) is reached. Dosage of fenofibrate and fenofibric acid must be carefully adjusted according to individual requirements and response.

Fenofibrate should be discontinued in patients who fail to achieve an adequate response after 2 months of therapy with the maximum recommended dosages.

Special Populations

Fenofibrate or fenofibric acid should be initiated at a reduced dosage in patients with mild to moderate renal impairment; dosage should be increased only after effects of the drug on renal function and lipid concentrations have been evaluated. In patients with mild to moderate renal impairment (estimated glomerular filtration rate [GFR] 30-59 mL/minute per 1.73 m), the recommended initial dosage of fenofibrate is 30 mg daily (as Antara micronized capsules), 40 mg daily (as Fenoglide tablets), 50 mg daily (as Lipofen capsules), 54 mg daily (as Lofibra tablets), 67 mg daily (as Lofibra micronized capsules or generic equivalents), 48 mg daily (as TriCor tablets or generic equivalents), or 50 mg daily (as Triglide tablets); the recommended initial dosage of fenofibric acid in such patients is 45 mg once daily (as Trilipix delayed-release capsules or generic equivalents). Use of fenofibrate and fenofibric acid should be avoided in patients with severe renal impairment (estimated GFR less than 30 mL/minute per 1.73 m).

In geriatric patients, dosage of fenofibrate and fenofibric acid should be selected based on renal function.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.) No dosage adjustment is required in geriatric patients with normal renal function.

Cautions

Contraindications

Fenofibrate and fenofibric acid are contraindicated in patients with severe renal impairment (including those undergoing dialysis), active liver disease (including primary biliary cirrhosis and unexplained and persistent liver function abnormality), or preexisting gallbladder disease. The drugs also are contraindicated in nursing women and in patients with known hypersensitivity to fenofibrate or fenofibric acid.

Warnings/Precautions

Sensitivity Reactions

Acute hypersensitivity reactions requiring hospitalization and corticosteroid therapy, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in patients receiving fenofibrate. Urticaria and rash also have been reported in approximately 1% of patients receiving fenofibrate therapy in controlled trials.

Effects on Morbidity and Mortality

The effects of fenofibrate and fenofibric acid on cardiovascular morbidity and mortality and noncardiovascular mortality have not been established.

In several randomized controlled studies evaluating the use of fenofibrate in patients with type 2 diabetes mellitus, fenofibrate therapy was not shown to reduce the risk of cardiovascular events despite favorable effects of the drug on plasma lipid concentrations. Because of similarities between fenofibrate and fenofibric acid, findings from these studies also may apply to fenofibric acid. In the Action to Control Cardiovascular Risk in Diabetes (ACCORD Lipid) study in patients with type 2 diabetes mellitus at high risk for cardiovascular disease, combination therapy with fenofibrate and a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) (simvastatin) did not substantially reduce the rate of major adverse cardiovascular events (i.e., nonfatal myocardial infarction, nonfatal stroke, fatal cardiovascular events) compared with statin monotherapy (2.2 versus 2.4%). A gender effect was noted in this study in which men, but not women, appeared to benefit from combination therapy; however, the clinical importance of these findings is not clear. In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study, fenofibrate therapy also was not associated with a substantial reduction in cardiovascular outcomes in patients with type 2 diabetes mellitus. At 5 years, the primary outcome of coronary heart disease (CHD)-related events (death or nonfatal myocardial infarction) occurred in 5.2% of patients receiving fenofibrate therapy and 5.9% of those receiving placebo; fenofibrate was associated with a nonsignificant (11%) increase in the risk of all-cause mortality and CHD mortality.

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 the US]), adverse findings from several large randomized placebo-controlled studies with these other drugs may also apply to fenofibrate and fenofibric acid; such findings include an increased incidence of cholelithiasis, cholecystitis requiring surgery, postcholecystectomy complications, malignancy, pancreatitis, and gallbladder disease, and increased overall mortality..

Musculoskeletal Effects

Serious muscle toxicity, including myopathy and rhabdomyolysis, has been 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. In addition, concomitant use with statins or other drugs (e.g., colchicine) also may increase the risk of rhabdomyolysis.(See Drug Interactions.) In clinical studies evaluating safety and efficacy of fenofibric acid in combination with a statin, elevations of serum creatine kinase (CK, creatine phosphokinase, CPK) concentrations exceeding 5 times the upper limit of normal were reported in 0.2-1.2% of patients receiving the combination antilipemic regimen and in 0.4-1.3% of those receiving statin monotherapy; these elevations did not occur in any patient receiving fenofibric acid alone.

Patients receiving fenofibrate or fenofibric acid should be advised to report promptly any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever. Serum CK concentrations should be monitored periodically in patients reporting these adverse effects. Myopathy should be considered in any patient who develops diffuse myalgias, muscle tenderness or weakness, and/or marked increases in CK concentrations. Fenofibrate or fenofibric acid therapy should be discontinued if serum CK concentrations become markedly elevated or if myositis/myopathy is suspected or diagnosed.

Hepatic Effects

Elevations in serum aminotransferase concentrations (i.e., AST, ALT) exceeding 3 times the upper limit of normal were reported in approximately 5% of patients receiving fenofibrate in clinical studies. These increases appear to be dose related and reportedly occurred within the recommended dosage ranges for fenofibrate. In a pooled analysis of controlled studies of fenofibric acid administered as monotherapy or in combination with a statin, elevations in ALT and AST concentrations exceeding 3 times the upper limit of normal (on 2 consecutive occasions) occurred in 1.9 and 0.2%, respectively, of patients receiving fenofibric acid monotherapy and in 1.3 and 0.4%, respectively, of those receiving the combination antilipemic regimen. Similar incidences of serum aminotransferase elevations to more than 3 times the upper limit of normal were reported in a long-term study evaluating the use of fenofibric acid in combination with statin therapy for up to 52 weeks. In all of these studies, serum aminotransferase concentrations usually returned to pretreatment values during continued therapy or following discontinuance of fenofibrate or fenofibric acid.

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

Liver function tests should be performed prior to initiating therapy and periodically during therapy. If serum aminotransferase concentrations of 3 times the upper limit of normal or higher persist, fenofibrate or fenofibric acid therapy should be discontinued.

Renal Effects

Transient elevations of serum creatinine concentrations have been reported in patients receiving fenofibrate or fenofibric acid (alone or in combination with a statin) in clinical studies. In a pooled analysis of controlled studies of fenofibric acid administered as monotherapy or in combination with a statin, increases in serum creatinine concentrations to more than 2 mg/dL occurred in 0.8% of patients receiving fenofibric acid monotherapy and in 1.1-1.3% of those receiving the combination antilipemic regimen. Elevations in serum creatinine concentrations generally were stable over time, with no evidence of continued increases following long-term therapy; such elevations usually returned to baseline following discontinuance of therapy. The clinical importance of these findings is not known.(See Renal Impairment under Warnings/Precautions: Specific Populations, in Cautions.)

The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline states that renal status should be evaluated before initiation of fenofibrate or fenofibric acid, within 3 months after initiation of therapy, and every 6 months thereafter.

Cholelithiasis

Fenofibrate and fenofibric acid, like other fibric acid derivatives (e.g., gemfibrozil), may increase cholesterol excretion in bile, resulting in cholelithiasis. If gallbladder studies indicate the presence of gallstones, fenofibrate or fenofibric acid should be discontinued.

Pancreatitis

Pancreatitis has been reported in patients receiving fenofibrate, fenofibric acid, and other fibric acid derivatives. This occurrence may be attributed 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 leukocyte counts have occurred in patients receiving fenofibrate or fenofibric acid; these counts usually stabilize during long-term therapy. Thrombocytopenia and agranulocytosis also have been reported. Blood cell counts should be monitored periodically during the first 12 months of fenofibrate or fenofibric acid therapy.

Fenofibrate and fenofibric acid can potentiate the anticoagulant effects of coumarin anticoagulants (e.g., warfarin) and increase the risk of bleeding; caution is advised when these drugs are used concomitantly.(See Drug Interactions: Oral Anticoagulants.)

Thromboembolism

An increased incidence of venous thromboembolic events (e.g., deep-vein thrombosis, pulmonary embolism, thrombophlebitis) has been observed in patients receiving fibric acid derivatives (fenofibrate, clofibrate [no longer commercially available in the US]) compared with those receiving placebo in clinical studies.

Decreased High-density Lipoprotein (HDL)-cholesterol Concentrations

A paradoxical decrease in HDL-cholesterol concentrations to as low as 2 mg/dL has been reported in patients receiving fibric acid derivatives. This reduction was accompanied by a decrease in apolipoprotein A1 concentrations, and occurred as early as 2 weeks to as late as several years after initiation of such therapy. Upon discontinuance of therapy, HDL-cholesterol concentrations rapidly returned to baseline and remained at normal levels.

Although the clinical importance of this paradoxical decrease in HDL-cholesterol concentrations is not known, the manufacturers recommend that HDL-cholesterol concentrations be determined within the first few months of initiating fenofibrate or fenofibric acid therapy. If severely depressed HDL-cholesterol concentrations are detected, the drug should be permanently discontinued and HDL-cholesterol concentrations monitored until levels return to normal.

Specific Populations

Pregnancy

Category C.

Lactation

Because of the potential for serious adverse effects in nursing infants, fenofibrate and fenofibric acid should not be used in nursing women; a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.(See Cautions: Contraindications.)

Pediatric Use

Safety and efficacy of fenofibrate and fenofibric acid have not been established in pediatric patients.

Geriatric Use

Because fenofibric acid is substantially excreted by the kidneys, and geriatric patients are more likely to have decreased renal function, dosage of fenofibrate and fenofibric acid for geriatric patients should be selected based on renal function. (See Dosage and Administration: Special Populations.) Renal function monitoring should be considered in geriatric patients receiving fenofibrate or fenofibric acid therapy.

Hepatic Impairment

Fenofibrate and fenofibric acid have not been evaluated in patients with hepatic impairment.

Renal Impairment

Because fenofibric acid is substantially excreted in urine (about 60% of a dose), the drug may accumulate in patients with diminished renal function. In patients with severe renal impairment (estimated glomerular filtration rate [GFR] less than 30 mL/minute per 1.73 m), fenofibric acid exposure is substantially increased (by 2.7-fold), and drug accumulation also is increased during repeated dosing, compared with healthy individuals. In patients with mild to moderate renal impairment (estimated GFR 30-59 mL/minute per 1.73 m), half-life of fenofibric acid is prolonged, but exposure to the drug is similar to that observed in healthy individuals.

Dosage adjustments of fenofibrate and fenofibric acid are required in patients with mild to moderate renal impairment; use of the drugs should be avoided in patients with severe renal impairment.(See Dosage and Administration: Special Populations.)

Renal function should be monitored in patients with preexisting renal impairment; monitoring of renal function also should be considered in patients at risk for developing renal impairment (e.g., geriatric patients, those with diabetes mellitus).

Common Adverse Effects

Adverse effects occurring in 2% or more of patients receiving fenofibrate include 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, and flu syndrome.

Adverse effects occurring in 3% or more of patients receiving fenofibric acid alone or in combination with a statin include headache, back pain, nasopharyngitis, nausea, myalgia, diarrhea, and upper respiratory tract infection.

Drug Interactions

Drugs Metabolized by Cytochrome P-450 (CYP) Isoenzymes

Data from in vitro studies indicate that fenofibrate and fenofibric acid are mild to moderate inhibitors of CYP2C9 and weak inhibitors of CYP isoenzymes 2C8, 2A6, and 2C19; pharmacokinetic interactions are possible with concomitant use of drugs metabolized by these isoenzymes. Fenofibrate and fenofibric acid do not inhibit CYP isoenzymes 3A4, 2D6, 2E1, or 1A2 in vitro.

Antidiabetic Agents

In healthy individuals, concomitant administration of fenofibrate (145 mg once daily for 10 days) and glimepiride (single 1-mg dose) resulted in a 35% increase in systemic exposure and an 18% increase in peak plasma concentrations of glimepiride; in addition, glucose concentrations were substantially reduced. Pharmacokinetics of fenofibrate were not altered.

In healthy individuals, concomitant use of fenofibrate and other antidiabetic agents (i.e., metformin, rosiglitazone) resulted in only slight alterations in the pharmacokinetics of fenofibric acid and the respective antidiabetic drugs.

Bile Acid Sequestrants

Because of their potential binding effects, bile acid sequestrants may decrease absorption of fenofibrate or fenofibric acid when administered concurrently. Fenofibrate and fenofibric acid should be administered 1 hour before or 4-6 hours after a bile acid sequestrant.

Colchicine

Myopathy, including rhabdomyolysis, has been reported in patients receiving fibric acid derivatives with colchicine; caution is advised when these drugs are used concomitantly.(See Musculoskeletal Effects under Cautions: Warnings/Precautions.)

Ezetimibe

Following concomitant administration of fenofibric acid (135 mg once daily for 10 days) with the combination of ezetimibe (10 mg once daily for 10 days) and atorvastatin (80 mg once daily for 10 days), peak plasma concentrations and systemic exposure of ezetimibe were increased by 26 and 27%, respectively, compared with administration of ezetimibe and atorvastatin alone; pharmacokinetics of atorvastatin and fenofibric acid were not substantially altered.

HMG-CoA Reductase Inhibitors (Statins)

Risk of rhabdomyolysis and other adverse musculoskeletal effects (i.e., increased creatine kinase [CK], myoglobinuria) is increased when fibric acid derivatives (particularly gemfibrozil) are used concomitantly with a statin. The manufacturers of fenofibrate state that concomitant use of fenofibrate with statins generally should be avoided unless the potential benefits of further alteration in lipid concentrations are likely to outweigh the increased risks. At least one manufacturer of fenofibric acid states that the drug may be used concomitantly with a statin (see Uses: Dyslipidemias); however, concomitant use of fenofibric acid with the maximum dosage of a statin has not been evaluated in clinical studies and should be avoided unless the benefits are expected to outweigh the risks.(See Musculoskeletal Effects under Cautions: Warnings/Precautions.)

Concomitant use of fenofibrate or fenofibric acid with various statins (i.e., atorvastatin, fluvastatin, pravastatin, rosuvastatin, simvastatin) resulted in only slight alterations in the pharmacokinetics of fenofibric acid, with decreases in peak plasma concentrations ranging from 2-11% and decreases in systemic exposure ranging from 1-5%. The effects of the fibric acid derivative on the pharmacokinetics of the individual statins were more pronounced. Following concomitant administration, peak plasma concentrations of fluvastatin, pravastatin (and its metabolite), and rosuvastatin were increased by approximately 13-29%, and systemic exposure to these respective drugs was increased by approximately 6-26%. Systemic exposure to atorvastatin was decreased by 17%, while peak plasma concentrations of the drug remained unchanged. Systemic exposure to simvastatin (and its active metabolites) was decreased by 11-36%, and peak plasma concentrations of the drug (and its active metabolites) were decreased by 11-17%. The American College of Cardiology (ACC)/American Heart Association (AHA) cholesterol management guideline states that the combination of fenofibrate and low- or moderate-intensity statin therapy may be considered only if the benefits from atherosclerotic cardiovascular disease (ASCVD) risk reduction or triglyceride lowering (when triglyceride concentrations exceed 500 mg/dL) outweigh the potential risk of adverse effects.

Immunosuppressive Agents

Because fenofibric acid derivatives are substantially excreted by the kidneys, concomitant use of nephrotoxic immunosuppressants (e.g., cyclosporine, tacrolimus) may result in deterioration of renal function. The risks versus benefits of using fenofibrate or fenofibric acid in combination with such immunosuppressants or other potentially nephrotoxic agents should be carefully considered and the lowest effective dosages employed; renal function should be monitored during concurrent use.

Omeprazole

When fenofibric acid (single 135-mg dose) was administered under fasting conditions with omeprazole (40 mg once daily for 5 days), peak plasma concentrations of fenofibric acid were increased by 17%; this effect was not observed when the dose of fenofibric acid was administered with food. Systemic exposure to fenofibric acid was not substantially altered.

Oral Anticoagulants

Fenofibrate and fenofibric acid can increase prothrombin time (PT)/international normalized ratio (INR) and potentially increase the risk of bleeding in patients receiving coumarin anticoagulants (e.g., warfarin); caution is advised when these drugs are used concomitantly. Frequent monitoring of the PT/INR is recommended until levels are stable, and dosage of the anticoagulant should be adjusted as necessary to prevent bleeding complications.

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