Fenofibrate
Fenofibrate Prescribing Information
Indications and Usage (
• to reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL).
• to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy is not possible.
Limitations of Use
•
• Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Warnings and Precautions and Clinical Studies ].
Fenofibrate is a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as an adjunct to diet:
• to reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL) .
• to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy is not possible .
Limitations of Use:
- Markedly elevated levels of serum TG (e.g., >2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been determined .
- Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus .
Dosage and Administration (
- Severe hypertriglyceridemia: 48 to 145 mg orally once daily; the dosage should be adjusted according to patient response .
- Primary hyperlipidemia:145 mg orally once daily .
- Administer as a single dose, at any time of day, with or without food .
- Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 months of treatment .
- Renal impairment: Initial dosage of 48 mg orally once daily .
- Geriatric patients:Select the dosage on the basis of renal function .
- Assess lipid levels before initiating therapy. Identify other causes (e.g., diabetes mellitus, hypothyroidism, or medications) of high TG levels and manage as appropriate.
- Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablets, and should continue this diet during treatment with fenofibrate tablets.
- In patients with diabetes and fasting chylomicronemia, improve glycemic control prior to considering starting fenofibrate tablets.
• The recommended dosage of fenofibrate tablets is 48 mg or 145 mg orally once daily.
• Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.
• The recommended dosage of fenofibrate tablets is 145 mg orally once daily.
• Administer fenofibrate tablets as a single dose at any time of day, with or without food.
• Advise patients to swallow fenofibrate tablets whole. Do not crush, break, dissolve, or chew tablets.
• Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 months of treatment.
• Advise patients to take fenofibrate tablets at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoid impeding its absorption.
- Assess renal function prior to initiation of fenofibrate tablets and periodically thereafter [see Warnings and Precautions ].
- Treatment with fenofibrate tablets should be initiated at a dosage of 48 mg orally once daily in patients with mild to moderately impaired renal function (eGFR 30 to <60 mL/min/1.73m2), and increased only after evaluation of the effects on renal function and TG levels at this dosage.
- Fenofibrate tablets is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73m2), including those with end-stage renal disease (ESRD) and those receiving dialysis [see Use in Specific Populations and Clinical Pharmacology ].
Dosage selection for geriatric patients should be made on the basis of renal function [
Warnings and Precautions, Mortality and Coronary Heart
Disease Morbidity (
Because of chemical, pharmacological, and clinical similarities between fenofibrates, including fenofibrate tablets; pemafibrate; clofibrate; and gemfibrozil; the findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to fenofibrate tablets.
Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy
In the Coronary Drug Project, a large trial conducted from 1965 to 1985 in men post myocardial infarction, there was no difference in mortality or nonfatal myocardial infarction between the clofibrate group and the placebo group after 5 years of treatment (NCT00000482).
In a trial conducted by the World Health Organization (WHO) from 1965 to 1976, men without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional 1 year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p ≤ 0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis.
The Helsinki Heart Study, conducted from 1982 to 1987, was a large (n=4,081) trial of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5-year open extension afterward. Total mortality was numerically but not statistically higher in the gemfibrozil randomization group versus placebo [95% confidence interval (CI) of the hazard ratio (HR) 0.91 to 1.64].
A secondary prevention component of the Helsinki Heart Study treated middle-aged men with gemfibrozil or placebo for 5 years. The HR for cardiac deaths was 2.2, 95% CI, 0.94 to 5.05.
• to reduce triglyceride (TG) levels in adults with severe hypertriglyceridemia (TG greater than or equal to 500 mg/dL).
• to reduce elevated low-density lipoprotein cholesterol (LDL-C) in adults with primary hyperlipidemia when use of recommended LDL-C lowering therapy is not possible.
Limitations of Use
•
Pancreatitis has been reported in patients taking fenofibrates. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.
• Fenofibrate did not reduce coronary heart disease morbidity and mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Warnings and Precautions (
Because of chemical, pharmacological, and clinical similarities between fenofibrates, including fenofibrate tablets; pemafibrate; clofibrate; and gemfibrozil; the findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to fenofibrate tablets.
Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus on background statin therapy
In the Coronary Drug Project, a large trial conducted from 1965 to 1985 in men post myocardial infarction, there was no difference in mortality or nonfatal myocardial infarction between the clofibrate group and the placebo group after 5 years of treatment (NCT00000482).
In a trial conducted by the World Health Organization (WHO) from 1965 to 1976, men without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional 1 year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p ≤ 0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis.
The Helsinki Heart Study, conducted from 1982 to 1987, was a large (n=4,081) trial of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5-year open extension afterward. Total mortality was numerically but not statistically higher in the gemfibrozil randomization group versus placebo [95% confidence interval (CI) of the hazard ratio (HR) 0.91 to 1.64].
A secondary prevention component of the Helsinki Heart Study treated middle-aged men with gemfibrozil or placebo for 5 years. The HR for cardiac deaths was 2.2, 95% CI, 0.94 to 5.05.
Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus.
The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) (NCT00000620) trial was a randomized placebo-controlled trial of 5,518 patients (2,765 assigned to receive fenofibrate) with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean age at baseline was 62 years and 31% were female. Overall, 68% were White, 15% were Black or African American; 7% identified as Hispanic or Latino ethnicity. The mean duration of follow-up was 4.7 years. The primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death was a HR of 0.92 (95% CI, 0.79 to 1.08) for fenofibrate plus statin combination therapy as compared to statin monotherapy.
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial was a 5-year randomized, placebo-controlled trial of 9,795 patients (4,895 assigned to receive fenofibrate) with type 2 diabetes mellitus treated with fenofibrate. The mean age at baseline was 62 years, 37% were female, and 93% were White. The primary outcome of coronary heart disease events was a HR of 0.89 (95% CI, 0.75 to 1.05) with fenofibrate compared to placebo. The HR for total and coronary heart disease mortality, respectively, was 1.11 (95% CI, 0.95 to 1.29) and 1.19 (95% CI, 0.90 to 1.57) with fenofibrate as compared to placebo.
Because of chemical, pharmacological, and clinical similarities between fenofibrate and pemafibrate, findings in a large randomized, placebo-controlled clinical trial with pemafibrate are relevant for fenofibrate tablets.
Pemafibrate did not reduce cardiovascular disease morbidity or mortality in a large, randomized, placebo-controlled trial of patients with type 2 diabetes mellitus (TG levels of 200 to 499 mg per deciliter and HDL-C levels of 40 mg per deciliter or lower), on background statin therapy (NCT03071692). The trial was a randomized placebo-controlled trial of 10,497 patients (5,240 assigned to receive pemafibrate) with type 2 diabetes mellitus on background lipid-lowering therapy. The median age at baseline was 64 years and 28% were female. Overall, 86% were White, 5% were Asian, 3% were Black or African American; 19% identified as Hispanic or Latino ethnicity. The median duration of follow-up was 3.4 years. The primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal ischemic stroke, coronary revascularization, and death from cardiovascular causes, was a HR of 1.03(95% CI, 0.91 to 1.15) for pemafibrate plus statin combination therapy as compared to statin monotherapy.
- Severe hypertriglyceridemia: 48 to 145 mg orally once daily; the dosage should be adjusted according to patient response ().
2.2 Recommended Dosage and AdministrationSevere hypertriglyceridemia:
• The recommended dosage of fenofibrate tablets is 48 mg or 145 mg orally once daily.
• Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.Primary hyperlipidemia:
• The recommended dosage of fenofibrate tablets is 145 mg orally once daily.
• Administer fenofibrate tablets as a single dose at any time of day, with or without food.
• Advise patients to swallow fenofibrate tablets whole. Do not crush, break, dissolve, or chew tablets.
• Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 months of treatment.• If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose.
• Advise patients to take fenofibrate tablets at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoid impeding its absorption. - Primary hyperlipidemia:145 mg orally once daily ().
2.2 Recommended Dosage and AdministrationSevere hypertriglyceridemia:
• The recommended dosage of fenofibrate tablets is 48 mg or 145 mg orally once daily.
• Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.Primary hyperlipidemia:
• The recommended dosage of fenofibrate tablets is 145 mg orally once daily.
• Administer fenofibrate tablets as a single dose at any time of day, with or without food.
• Advise patients to swallow fenofibrate tablets whole. Do not crush, break, dissolve, or chew tablets.
• Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 months of treatment.• If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose.
• Advise patients to take fenofibrate tablets at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoid impeding its absorption. - Administer as a single dose, at any time of day, with or without food ().
2.2 Recommended Dosage and AdministrationSevere hypertriglyceridemia:
• The recommended dosage of fenofibrate tablets is 48 mg or 145 mg orally once daily.
• Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.Primary hyperlipidemia:
• The recommended dosage of fenofibrate tablets is 145 mg orally once daily.
• Administer fenofibrate tablets as a single dose at any time of day, with or without food.
• Advise patients to swallow fenofibrate tablets whole. Do not crush, break, dissolve, or chew tablets.
• Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 months of treatment.• If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose.
• Advise patients to take fenofibrate tablets at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoid impeding its absorption. - Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 months of treatment ().
2.2 Recommended Dosage and AdministrationSevere hypertriglyceridemia:
• The recommended dosage of fenofibrate tablets is 48 mg or 145 mg orally once daily.
• Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 to 8 week intervals.Primary hyperlipidemia:
• The recommended dosage of fenofibrate tablets is 145 mg orally once daily.
• Administer fenofibrate tablets as a single dose at any time of day, with or without food.
• Advise patients to swallow fenofibrate tablets whole. Do not crush, break, dissolve, or chew tablets.
• Assess TG when clinically appropriate, as early as 4 to 8 weeks after initiating fenofibrate tablets. Discontinue fenofibrate tablets in patients who do not have an adequate response after 2 months of treatment.• If a dose is missed, advise patients not to take an extra dose. Resume treatment with the next dose.
• Advise patients to take fenofibrate tablets at least 1 hour before or 4 hours to 6 hours after a bile acid binding resin to avoid impeding its absorption. - Renal impairment: Initial dosage of 48 mg orally once daily ().
2.3 Recommended Dosage in Patients with Renal Impairment- Assess renal function prior to initiation of fenofibrate tablets and periodically thereafter [see Warnings and Precautions ].
- Treatment with fenofibrate tablets should be initiated at a dosage of 48 mg orally once daily in patients with mild to moderately impaired renal function (eGFR 30 to <60 mL/min/1.73m2), and increased only after evaluation of the effects on renal function and TG levels at this dosage.
- Fenofibrate tablets is contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73m2), including those with end-stage renal disease (ESRD) and those receiving dialysis [see Use in Specific Populations and Clinical Pharmacology ].
- Geriatric patients:Select the dosage on the basis of renal function ().
2.4 Recommended Dosage in Geriatric PatientsDosage selection for geriatric patients should be made on the basis of renal function [
see Use in Specific Populations and Clinical Pharmacology ].
Fenofibrate tablets, USP are available as film-coated tablets containing 48 mg or 145 mg of fenofibrate.
• 48 mg yellow colored tablets, oval shaped, biconvex film coated tablets, debossed with “C50” on one side and plain on other side.
• 145 mg white colored, oval shaped, biconvex film coated tablets, debossed with “C49” on one side and plain surface on the other side.
Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or comparable to the maximum recommended clinical dosage of 145 mg of fenofibrate daily, based on body surface area (mg/m2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data). Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Data
Animal Data
In pregnant rats given oral dietary doses of 14 mg/kg/day, 127 mg/kg/day, and 361 mg/kg/day from gestation day 6 to 15 during the period of organogenesis, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, comparable to 145 mg fenofibrate tablet daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain.
In pregnant rabbits given oral gavage doses of 15 mg/kg/day, 150 mg/kg/day, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain.
In pregnant rats given oral dietary doses of 15 mg/kg/day, 75 mg/kg/day, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.
Fenofibrate tablets are contraindicated in patients with:
• Severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [
Fenofibrate is a pro-drug of the active chemical moiety fenofibric acid. Fenofibrate is converted by ester hydrolysis in the body to fenofibric acid which is the active constituent measurable in the circulation.
The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract,Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.
Exposure to fenofibric acid in plasma, as measured by Cmax and AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.
Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady state are approximately double of those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration of fenofibrate tablets.
Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.
Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.
In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.
After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.
In geriatric volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in geriatric patients with normal renal function, without increasing accumulation of the drug or metabolites
The pharmacokinetics of fenofibrate has not been studied in pediatric populations.
Male and Female Patients
No pharmacokinetic difference between males and females has been observed for fenofibrate.
Racial and Ethnic Groups
The influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.
The pharmacokinetics of fenofibric acid were examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (creatinine clearance [CrCl ≤30 mL/min] or estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2) showed a 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30 mL/min to 80 mL/min or eGFR 30 to 59 mL/min/1.73m2) had similar exposure but an increase in the half-life for fenofibric acid compared to that of healthy subjects.[
No pharmacokinetic studies have been conducted in patients with hepatic impairment.
In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
Table 3 describes the effects of co-administered drugs on fenofibric acid systemic exposure.
Table 4 describes the effects of co-administered fenofibrate or fenofibric acid on other drugs.
Table 3. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration | ||||
Co-Administered Drug | Dosage Regimen of Co-Administered Drug | Dosage Regimen of Fenofibrate | Changes in Fenofibric Acid Exposure | |
AUC | Cmax | |||
Lipid-lowering medications | ||||
| Atorvastatin | 20 mg once daily for 10 days | Fenofibrate 160 mg1once daily for 10 days | ↓2% | ↓4% |
| Pravastatin | 40 mg as a single dose | Fenofibrate 3 x 67 mg2as a single dose | ↓1% | ↓2% |
| Fluvastatin | 40 mg as a single dose | Fenofibrate 160 mg1as a single dose | ↓2% | ↓10% |
Anti-diabetic agents | ||||
| Glimepiride | 1 mg as a single dose | Fenofibrate 145 mg1once daily for 10 days | ↑1% | ↓1% |
| Metformin | 850 mg three times daily for 10 days | Fenofibrate 54 mg1three times daily for 10 days | ↓9% | ↓6% |
| Rosiglitazone | 8 mg once daily for 5 days | Fenofibrate 145 mg1once daily for 14 days | ↑10% | ↑3% |
| 1fenofibrate oral tablet | ||||
| 2fenofibrate oral micronized capsule | ||||
Table 4. Effects of Fenofibrate Co-Administration on Systemic Exposure of Other Drugs | ||||
Dosage Regimen of Fenofibrate | Dosage Regimen of Co-Administered Drug | Change in Co-Administered Drug Exposure | ||
Analyte | AUC | Cmax | ||
Lipid-lowering medications | ||||
| Fenofibrate 160 mg1once daily for 10 days | Atorvastatin, 20 mg once daily for 10 days | Atorvastatin | ↓17% | 0% |
| Fenofibrate 3 x 67 mg2as a single dose | Pravastatin, 40 mg as a single dose | Pravastatin | ↑13% | ↑13% |
| 3α-Hydroxyl-iso-pravastatin | ↑26% | ↑29% | ||
| Fenofibrate 160 mg1as a single dose | Fluvastatin, 40 mg as a single dose | (+)-3R, 5S-Fluvastatin | ↑15% | ↑16% |
Anti-diabetic agents | ||||
| Fenofibrate 145 mg1once daily for 10 days | Glimepiride, 1 mg as a single dose | Glimepiride | ↑35% | ↑18% |
| Fenofibrate 54 mg1three times daily for 10 days | Metformin, 850 mg three times daily for 10 days | Metformin | ↑3% | ↑6% |
| Fenofibrate 145 mg1once daily for 14 days | Rosiglitazone, 8 mg once daily for 5 days | Rosiglitazone | ↑6% | ↓1% |
| 1fenofibrate oral tablet | ||||
| 2fenofibrate oral micronized capsule | ||||
• Active liver disease, including those with unexplained persistent liver function abnormalities
Serious drug-induced liver injury (DILI), including liver transplantation and death, has been reported with postmarketing use of fenofibrates, including fenofibrate tablets DILI has been reported within the first few weeks of treatment or after several months of therapy and in some cases has reversed with discontinuation of fenofibrate tablets treatment. Patients with DILI have experienced signs and symptoms including dark urine, abnormal stool, jaundice, malaise, abdominal pain, myalgia, weight loss, pruritus, and nausea. Many patients had concurrent elevations of total bilirubin, serum alanine transaminase (ALT), and aspartate transaminase (AST). DILI has been characterized as hepatocellular, chronic active, and cholestatic hepatitis, and cirrhosis has occurred in association with chronic active hepatitis.
In clinical trials, an intermediate daily dosage or the maximum recommended daily dosage of fenofibrate have been associated with increases in serum AST or ALT. The incidence of increases in transaminases may be dose related
Fenofibrate tablets is contraindicated in patients with active liver disease, including those with unexplained persistent liver function abnormalities. Monitor patient’s liver function, including serum ALT, AST, and total bilirubin, at baseline and periodically for the duration of therapy with fenofibrate tablets. Discontinue fenofibrate tablets if signs or symptoms of liver injury develop or if elevated enzyme levels persist (ALT or AST > 3 times the upper limit of normal, or if accompanied by elevation of bilirubin). Do not restart fenofibrate in these patients if there is no alternative explanation for the liver injury.
• Pre-existing gallbladder disease
Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate tablets therapy should be discontinued if gallstones are found. Fenofibrate tablets are contraindicated in patients with pre-existing gallbladder disease.
• Hypersensitivity to fenofibrate, fenofibric acid, or any of the excipients in fenofibrate tablets. Serious hypersensitivity reactions including anaphylaxis and angioedema have been reported with fenofibrate
Anaphylaxis and angioedema have been reported with postmarketing use of fenofibrates. In some cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibrate tablets. Fenofibrate tablets is contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in fenofibrate tablets.
Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, Toxic Epidermal Necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported with postmarketing use of fenofibrates occurring days to weeks after treatment initiation. The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory). Discontinue fenofibrate tablets and treat patients appropriately if SCAR is suspected.