Fenofibrate

360.83

360.83

256-376-3

U202363UOS

757822|281319

DTXSID2029874

C29047

Crystals from isopropanol|White solid

C10BA04|C10BA03|C10AB05|C - Cardiovascular system

2932999099

52.6

5.2

off-white powder

1.2±0.1 g/cm3

80.5 °C

469.8ºC at 760 mmHg

165.4±24.9 °C

1.547

H2O: 0.25mg/ml at 25 °C

Store at RT

6.2X10-7 mm Hg at 25 deg C (est)

LD50 in mice: 1600 mg/kg orally (Sornay)

Henry's Law constant = 4.5X10-9 atm-cu m/mol at 25 °C (est)

190.5 Ų [M+H]+ [CCS Type: TW, Method: calibrated with polyalanine and drug standards]

Stable under ordinary conditions|Hydroxyl radical reaction rate constant = 2.5X10-11 cu cm/molec-sec at 25 °C (est)

NONH for all modes of transport

3

22-36/37/38

36-26-24/25

UA2453400

Xn,Xi

Stable at normal temperatures and pressures.

P260, P273, P314, P501

H373

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl fenofibrate, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

|Warning|H373 (90.28%): Causes damage to organs through prolonged or repeated exposure [Warning Specific target organ toxicity, repeated exposure]|P260, P273, P314, and P501|Aggregated GHS information provided by 218 companies from 14 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Fenofibrate was detected in sewage treatment plant effluents at concentrations of 0.12 and 0.02 ug/L (France), 0.16, 0.1, and 0.16 ug/L (Italy), and not detected (Sweden)(1). The concentration in effluent from 2 of 20 German municipal sewage treatment plants sampled was 0.03 ug/L, detection limit = 0.05 ug/L(2). The compound was not detected in sewage influent samples collected at the 26th Ward municipal waste water treatment plant in Brooklyn, NY(3).

The oral LD50 in rats is >2g/kg and in mice is 1600mg/kg. The oral TDLO in rats is 9mg/kg. Treat patients with supportive care including monitoring of vital signs and observing clinical status. Recent overdose may be treated with inducing vomiting or gastric lavage. Due to fenofibrate's extensive protein binding, hemodialysis is not expected to be useful.

Mild, transient serum aminotransferase elevations develop in up to 20% of patients receiving fenofibrate, but values above 3 times normal in only 3% to 5%. These abnormalities are usually asymptomatic and transient, resolving even with continuation of fenofibrate, but they occasionally may require drug discontinuation. Monitoring of aminotransferase levels is recommended for patients receiving fenofibrate and discontinuation if enzymes persist above 3 times the upper limit of normal (ULN).

Caution should be exercised when anticoagulants are given in conjunction with Tricor because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR. The dosage of the anticoagulant should be reduced to maintain the prothrombin time/INR at the desired level to prevent bleeding complications. Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.|Increased risk of adverse musculoskeletal effects (i.e., increased CK, myoglobinuria, rhabdomyolysis). Avoid concomitant use unless potential benefit outweighs risk. Pharmacokinetic interaction reported following concomitant use with atorvastatin (decreased area under the plasma concentration-time curve [AUC] of atorvastatin) or pravastatin (increased peak plasma concentration and AUC of pravastatin).|Increased risk of cyclosporine-induced nephrotoxicity (i.e., deterioration in renal function). Use with caution.|Potential pharmacokinetic interaction (decreased absorption of fenofibrate). Fenofibrate should be administered 1 hour before or 4-6 hours after a bile acid sequestrant.|For more Interactions (Complete) data for Fenofibrate (7 total), please visit the HSDB record page.

/AQUATIC SPECIES/ Pharmaceuticals are found in the aquatic environment but their potential effects on non-target species like fish remain unknown. This in vitro study is a first approach in the toxicity assessment of human drugs on fish. Nine pharmaceuticals were tested on two fish hepatocyte models: primary cultures of rainbow trout hepatocytes (PRTH) and PLHC-1 fish cell line. Cell viability, interaction with cytochrome P450 1A (CYP1A) enzyme and oxidative stress were assessed by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrasodium bromide tetrazolium (MTT), 7-ethoxyresorufin-o-deethylase (EROD) and dichlorofluorescein (DCFH-DA) assays, respectively. The tested drugs were clofibrate (CF), fenofibrate (FF), carbamazepine (CBZ), fluoxetine (FX), diclofenac (DiCF), propranolol (POH), sulfamethoxazole (SFX), amoxicillin (AMX) and gadolinium chloride (GdCl3). All substances were cytotoxic, except AMX at concentration up to 500 uM. The calculated MTT EC50 values ranged from 2 uM (CF) to 651 uM (CBZ) in PLHC-1, and from 53 uM (FF) to 962 uM (GdCl3) in PRTH. CF, FF, and FX were the most cytotoxic drugs and induced oxidative stress before being cytotoxic. Compared to hepatocytes from human and dog, fish hepatocytes seemed to be more susceptible to the peroxisome proliferators (PPs) CF and FF. In PLHC-1 cells none of the tested drugs induced the EROD activity whereas POH appeared as a weak EROD inducer in PRTH. Moreover, in PRTH, SFX, DiCF, CBZ and to a lesser extend, FF and CF inhibited the basal EROD activity at clearly sublethal concentrations which may be of concern at the biological and chemical levels in a multipollution context.|/ENDOCRINE MODULATION/ In the last years pharmaceuticals have /increased/ interest as environmental pollutants for their toxic effects towards non target organisms. This study /draws/ attention to a further adverse effect of drugs, the endocrine interference. The most representative drugs of the widespread classes in environment were investigated. The /Yeast Estrogen System/ (YES)-test and the E-screen assay were performed to detect the capability of these substances to bind the human estrogenic receptor a (hERa) in comparison with 17beta-estradiol. Out of 14 tested pharmaceuticals, 9 were positive to YES-assay and 11 were positive to E-screen assay; in particular, Furosemide and the fibrates (Bezafibrate, Fenofibrate and Gemfibrozil) gave the maximal estrogenic response. Tamoxifen showed its dual activity as agonist and antagonist of hERa.

In the last years pharmaceuticals have /increased/ interest as environmental pollutants for their toxic effects towards non target organisms. This study /draws/ attention to a further adverse effect of drugs, the endocrine interference. The most representative drugs of the widespread classes in environment were investigated. The /Yeast Estrogen System/ (YES)-test and the E-screen assay were performed to detect the capability of these substances to bind the human estrogenic receptor a (hERa) in comparison with 17beta-estradiol. Out of 14 tested pharmaceuticals, 9 were positive to YES-assay and 11 were positive to E-screen assay; in particular, Furosemide and the fibrates (Bezafibrate, Fenofibrate and Gemfibrozil) gave the maximal estrogenic response. Tamoxifen showed its dual activity as agonist and antagonist of hERa.|Apolipoprotein A5 is a key gene controlling VLDL synthesis and hydrolysis and is the target of the main pharmacological agent to lower triglycerides (fibrates). /It was/ hypothesised that variability in the promoter of the APOA5 gene may affect the individual response to fibrate therapy, in both the fasting and postprandial states. Fifty subjects with the metabolic syndrome who also had important increase in fasting triglycerides /were selected/. A subgroup of 36 patients underwent lipid-lowering treatment with 160 mg/day of fenofibrate (Secalip) for 3 months. The participants underwent a 60 g fat overload with a commercial preparation, after which ... the influence of the -1131T>C APOA5 SNP on the postprandial response /was assessed/. Compared with non-carriers, the C allele carriers had significantly higher triglyceride levels at baseline (54.87%), and at 3 hr (61.08%) and 4 hr (68.35%). Other lipid parameters were not affected by the APOA5 genotype. ... /The/ results indicate that carriers of the -1131C allele had a better response to fenofibrate treatment (reduction in triglyceride levels of 40.33% at baseline, P=0.018; and postprandially, 37.64% at 3 hr, P=0.028 and 42.58% at 4 hr after the high-fat meal, P=0.018) than wild-type subjects (30.91% decrease at baseline, P<0.001; and 26.61% at 3 hr P=0.005 and 22.95% at 4 hr P=0.033 after the high-fat meal). Thus, the treatment for patients with the metabolic syndrome and elevated plasma triglyceride levels may vary according to whether they carry the APOA5 -1131T>C polymorphism.

Fenofibrate is 99% protein bound in serum, primarily to albumin.

Fenofibrate's production and use as an antilipemic(1) may result in its release to the environment through various waste streams(SRC).

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3,800(SRC), determined from a structure estimation method(2), indicates that fenofibrate is expected to have slight mobility in soil(SRC). Volatilization of fenofibrate from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 4.5X10-9 atm-cu m/mole(SRC), using a fragment constant estimation method(3). Fenofibrate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.2x10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(4). Fenofibrate was 64% removed during passage through a municipal sewage treatment plant; however, removal could be attributed to adsorption to sludge(5).|AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3,800(SRC), determined from a structure estimation method(2), indicates that fenofibrate is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces is not expected(3) based upon an estimated Henry's Law constant of 4.5X10-9 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). According to a classification scheme(5), an estimated BCF of 320(SRC), from an estimated log Kow of 5.2(6) and a regression-derived equation(7), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Fenofibrate was 64% removed during passage through a municipal sewage treatment plant; however, removal could be attributed to adsorption to sludge(8).|ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), fenofibrate, which has an estimated vapor pressure of 6.2X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase fenofibrate is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 15 hours(SRC), calculated from its rate constant of 2.5X10-11 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase fenofibrate may be removed from the air by wet or dry deposition(SRC). Fenofibrate contains chromophores that absorb at wavelengths >290 nm(4) and therefore may be susceptible to direct photolysis by sunlight(SRC).

The rate constant for the vapor-phase reaction of fenofibrate with photochemically-produced hydroxyl radicals has been estimated as 2.5X10-11 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 15 hours at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). A base-catalyzed second-order hydrolysis rate constant of 4.4X10-3 L/mole-sec(SRC) was estimated using a structure estimation method(2); this corresponds to half-lives of 50 and 5 years at pH values of 7 and 8, respectively(2). Fenofibrate contains chromophores that absorb at wavelengths >290 nm(3) and therefore may be susceptible to direct photolysis by sunlight(SRC).

An estimated BCF of 320 was calculated in fish for fenofibrate(SRC), using an estimated log Kow of 5.2(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC).

Using a structure estimation method based on molecular connectivity indices(1), the Koc of fenofibrate can be estimated to be 3,800(SRC). According to a classification scheme(2), this estimated Koc value suggests that fenofibrate is expected to have slight mobility in soil.

The Henry's Law constant for fenofibrate is estimated as 4.5X10-9 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that fenofibrate is expected to be essentially nonvolatile from water surfaces(2). Fenofibrate is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 6.2X10-7 mm Hg(SRC), determined from a fragment constant method(3).

SURFACE WATER: Fenofibrate was not detected in 36 samples from 22 German rivers and streams, detection limit = 0.010 ug/L(1). The compound concentration in unspecified German surface waters has been reported to range from 0.001 to 0.10 ug/L(2).|SEAWATER: Fenofibrate was not detected in estuary samples collected in October, 2004 from Jamaica Bay, Long Island(1).

Occupational exposure to fenofibrate may occur through inhalation of dust and dermal contact with this compound at workplaces where fenofibrate is produced or used. Monitoring and use data indicate that the general population may be exposed to fenofibrate via ingestion of contaminated water and limited exposure to those administered the drug, a lipid regulator. (SRC)

Fenofibrate is indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, Triglycerides, and Apo B, and to increase HDL-C adults with primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate is also indicated to treat adults with severe hypertriglyceridemia.|FDA Label|Cholib is indicated as adjunctive therapy to diet and exercise in high cardiovascular risk adult patients with mixed dyslipidaemia to reduce triglycerides and increase HDL C levels when LDL C levels are adequately controlled with the corresponding dose of simvastatin monotherapy.|Pravafenix is indicated for the treatment of high-coronary-heart-disease (CHD)-risk adult patients with mixed dyslipidaemia characterised by high triglycerides and low HDL-cholesterol (C) levels whose LDL-C levels are adequately controlled while on a treatment with pravastatin-40-mg monotherapy.|Disorders of lipoprotein metabolism and other hyperlipidaemias|Combined dyslipidemia|Treatment of mixed dyslipidaemia|Treatment of elevated cholesterol with elevated triglycerides|Treatment of mixed hyperlipidaemia

Fenofibrate is a fibric acid derivative used in the therapy of hypertriglyceridemia and dyslipidemia. Fenofibrate therapy is associated with mild and transient serum aminotransferase elevations and with rare instances of acute liver injury, which can be severe and prolonged and lead to significant hepatic fibrosis.

Antilipemic Agents

Fenofibrate has known transformation products that include Fenofibric acid.

Fenofibrate is used as an adjunct to dietary therapy to decrease elevated serum total and LDL-cholesterol, triglyceride, and apo B concentrations, and to increase HDL-cholesterol concentrations in the management of primary hypercholesterolemia and mixed dyslipidemia, including heterozygous familial hypercholesterolemia and other causes of hypercholesterolemia.|Fenofibrate also is used as an adjunct to dietary therapy in the management of patients with elevated serum triglyceride concentrations. Efficacy of the drug in reducing the risk of pancreatitis in patients with marked elevations in triglyceride concentrations (i.e., greater than 2000 mg/dL) has not been established. Fenofibrate is not indicated for use in patients with type I hyperlipoproteinemia who have elevated triglyceride and chylomicron concentrations but normal VLDL-cholesterol concentrations.|/EXPL THER/ Inflammation is implicated in chronic heart failure. In this study, the potential inhibitory effect of peroxisome proliferator-activated receptor-alpha (PPARalpha) activator fenofibrate on monocyte adhesion in chronic heart failure patients was investigated in vitro. ... Isolated peripheral blood mononuclear cells were collected from 36 patients (aged 65 +/- 8 years) with symptomatic chronic heart failure and from 12 healthy control subjects. The cultured human aortic endothelial cells were stimulated with or without 2 ng mL(-1) tumor necrosis factor-alpha (TNF-alpha) and the inhibitory effects of fenofibrate at 25, 50, 100 and 200 uM on endothelial mononuclear cell adhesion were tested. Furthermore, the human aortic endothelial cells were stimulated with 70% sera obtained from chronic heart failure patients and control individuals, respectively, with or without pretreatments with fenofibrate. The endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) was then confirmed by mRNA expression and Western blot. ... The increased adhesion of peripheral blood mononuclear cells to TNF-alpha-stimulated human aortic endothelial cells in chronic heart failure patients was reduced when the human aortic endothelial cells were pretreated with fenofibrate (31% inhibition, P = 0.0121). However, pretreatment of the isolated peripheral blood mononuclear cells collected from chronic heart failure patients with fenofibrate failed to suppress their adherence to TNF-alpha-stimulated human aortic endothelial cells. Furthermore, stimulation of cultured human aortic endothelial cells with chronic heart failure patient sera significantly increased VCAM-1 and ICAM-1 expression, which could also be inhibited by fenofibrate. The fenofibrate directly inhibits monocyte binding by TNF-alpha-activated human aortic endothelial cells, probably through preventing up-regulation of cell adhesion molecules by endothelial cells in response to inflammatory stimuli. This PPARalpha activator may have the potential to ameliorate vascular inflammation in patients with chronic heart failure.

Severe rashes requiring hospitalization and corticosteroid therapy, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported rarely with fenofibrate in clinical studies. Urticaria and rash also have been reported in approximately 1% of patients receiving fenofibrate therapy in controlled trials.|Fenofibrate, 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 should be discontinued.|Liver function tests should be performed periodically (i.e., every 3 months) during the first 12 months of therapy. If serum aminotransferase concentrations of 3 times the upper limit of normal or higher persist, fenofibrate therapy should be discontinued.|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.|For more Drug Warnings (Complete) data for Fenofibrate (17 total), please visit the HSDB record page.

Fenofibrate is a fibrate that activates peroxisome proliferator activated receptor alpha (PPARα) to alter lipid metabolism and treat primary hypercholesterolemia, mixed dyslipidemia, and severe hypertriglyceridemia. Fenofibrate requires once daily dosing and has a half life of 19-27 hours so its duration of action is long. Fenofibrate capsules are given at a dose of 50-150mg daily so the therapeutic index is wide. Patients should be counselled about the risk of rhabdomyolysis, myopathy, and cholelithiasis when taking fibrates.

Substances that lower the levels of certain LIPIDS in the BLOOD. They are used to treat HYPERLIPIDEMIAS. (See all compounds classified as Hypolipidemic Agents.)

A single 300mg oral dose of fenofibrate reaches a C_max of 6-9.5mg/L with a T_max of 4-6h in healthy, fasting volunteers.|5-25% of a dose of fenofibrate is eliminated in the feces, while 60-88% is eliminated in the urine. 70-75% of the dose recovered in the urine is in the form of fenofibryl glucuronide and 16% as fenofibric acid.|The volume of distribution of fenofibrate is 0.89L/kg, and can be as high as 60L.|The oral clearance of fenofibrate is 1.1L/h in young adults and 1.2L/h in the elderly.|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 those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.|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. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.|After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.|The metabolism and disposition of orally administered single doses of (14)C fenofibrate (isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2- methylpropionate) have been studied in rat, guinea pig, and dog. In rats, the urinary excretion of (14)C in 5 days varied from 11 to 51% of the dose and was markedly dependent upon the dose form given. The interpretation of these data in terms of factors affecting the absorption of fenofibrate from the gut is complicated by the enterohepatic recirculation of metabolites. The tissue distribution of (14)C after oral administration of an ethanolic solution of fenofibrate has been studied in the rat. The only tissues in which the concentration of (14)C exceeded that in the blood were the organs of absorption and elimination, the gut, liver, and kidneys. Guinea pigs excreted 53% of the dose in the urine in 5 days, with a further 34% in the feces, while in dogs the corresponding figures were 9% and 81%, respectively. In all three species, all the urinary metabolites were products of ester hydrolysis, and the principal excretion product was "reduced fenofibric acid" which arose by subsequent carbonyl reduction. Glucuronidation of fenofibric acid and "reduced fenofibric acid" was a very minor reaction in the rat and guinea pig and was not detected in the dog. In addition, polar unknown metabolite(s) were detected in all three species, but were not investigated further. The results are discussed in terms of the comparative disposition of fenofibrate and other hypolipidemic agents and the contribution of these findings to the safety assessment of such drugs.

Fenofibrate is completely hydrolyzed by liver carboxylesterase 1 to fenofibric acid. Fenofibric acid is either glucuronidated or has its carbonyl group reduced to a benzhydrol that is then glucuronidated. Glucuronidation of fenofibrate metabolites is mediated by UGT1A9. Reduction of the carbonyl group is primarily mediated by CBR1 and minorly by AKR1C1, AKR1C2, AKR1C3, and AKR1B1.|... The metabolism of fenofibrate was investigated in cynomolgus monkeys by ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOFMS)-based metabolomics. Urine samples were collected before and after oral doses of fenofibrate. The samples were analyzed in both positive-ion and negative-ion modes by UPLC-QTOFMS, and after data deconvolution, the resulting data matrices were subjected to multivariate data analysis. Pattern recognition was performed on the retention time, mass/charge ratio, and other metabolite-related variables. Synthesized or purchased authentic compounds were used for metabolite identification and structure elucidation by liquid chromatography tandem mass spectrometry. Several metabolites were identified, including fenofibric acid, reduced fenofibric acid, fenofibric acid ester glucuronide, reduced fenofibric acid ester glucuronide, and compound X. Another two metabolites (compound B and compound AR), not previously reported in other species, were characterized in cynomolgus monkeys. More importantly, previously unknown metabolites, fenofibric acid taurine conjugate and reduced fenofibric acid taurine conjugate were identified, revealing a previously unrecognized conjugation pathway for fenofibrate.|Fenofibrate has been widely used for the treatment of dyslipidemia with a long history. Species differences of its metabolism were reported, but its metabolites in rodent have not been fully investigated. Urine and plasma samples were collected before and after oral dosages of fenofibrate in Sprague-Dawley rats. Urine samples were subjected to ultra-performance liquid chromatography-electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) analysis, and projection to latent structures discriminant analysis was used for the identification of metabolites. New metabolites in urine and plasma were also studied by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The metabolism pathway was studied in rat hepatocytes. Synthesized and purchased authentic compounds were used for metabolite identification by LC-MS/MS. Five ever-reported metabolites were identified and another four new ones were found. Among these new metabolites, fenofibric acid taurine and reduced fenofibric acid taurine indicate new phase II conjugation pathway of fenofibrate.|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.|The metabolism and disposition of orally administered single doses of (14)C fenofibrate (isopropyl 2-[4-(4-chlorobenzoyl)phenoxy]-2- methylpropionate) have been studied in rat, guinea pig, and dog. In rats, the urinary excretion of (14)C in 5 days varied from 11 to 51% of the dose and was markedly dependent upon the dose form given. The interpretation of these data in terms of factors affecting the absorption of fenofibrate from the gut is complicated by the enterohepatic recirculation of metabolites. The tissue distribution of (14)C after oral administration of an ethanolic solution of fenofibrate has been studied in the rat. The only tissues in which the concentration of (14)C exceeded that in the blood were the organs of absorption and elimination, the gut, liver, and kidneys. Guinea pigs excreted 53% of the dose in the urine in 5 days, with a further 34% in the feces, while in dogs the corresponding figures were 9% and 81%, respectively. In all three species, all the urinary metabolites were products of ester hydrolysis, and the principal excretion product was "reduced fenofibric acid" which arose by subsequent carbonyl reduction. Glucuronidation of fenofibric acid and "reduced fenofibric acid" was a very minor reaction in the rat and guinea pig and was not detected in the dog. In addition, polar unknown metabolite(s) were detected in all three species, but were not investigated further. The results are discussed in terms of the comparative disposition of fenofibrate and other hypolipidemic agents and the contribution of these findings to the safety assessment of such drugs.

Fenofibric acid, the active metabolite of fenofibrate, has a half life of 23 hours. Fenofibrate has a half life of 19-27 hours in healthy subjects and up to 143 hours in patients with renal failure.|Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration in a clinical setting. /Fenofibric acid/

Fenofibrate activates peroxisome proliferator activated receptor alpha (PPARα), increasing lipolysis, activating lipoprotein lipase, and reducing apoprotein C-III. PPARα is a nuclear receptor and its activation alters lipid, glucose, and amino acid homeostasis. Activation of PPARα activates transcription of gene transcription and translation that generates peroxisomes filled with hydrogen peroxide, reactive oxygen species, and hydroxyl radicals that also participate in lipolysis. This mechanism of increased lipid metabolism is also associated with increased oxidative stress on the liver. In rare cases this stress can lead to cirrhosis and chronic active hepatitis.|Fenofibrate is a synthetic ligand for the nuclear receptor peroxisome proliferator-activated receptor (PPAR) alpha and has been widely used in the treatment of metabolic disorders, especially hyperlipemia, due to its lipid-lowering effect. The molecular mechanism of lipid-lowering is relatively well defined: an activated PPARalpha forms a PPAR-RXR heterodimer and this regulates the transcription of genes involved in energy metabolism by binding to PPAR response elements in their promoter regions, so-called "trans-activation". In addition, fenofibrate also has anti-inflammatory and anti-athrogenic effects in vascular endothelial and smooth muscle cells. /There is/ limited information about the anti-inflammatory mechanism of fenofibrate; however, "trans-repression" which suppresses production of inflammatory cytokines and adhesion molecules probably contributes to this mechanism. Furthermore, there are reports that fenofibrate affects endothelial cells in a PPARalpha-independent manner. In order to identify PPARalpha-dependently and PPARalpha-independently regulated transcripts, ... microarray data from human endothelial cells treated with fenofibrate, and with and without siRNA-mediated knock-down of PPARalpha /were obtained/. ... Dynamic Bayesian transcriptome networks /were used/ to reveal PPARalpha-dependent and -independent pathways. Transcriptome network analysis identified growth differentiation factor 15 (GDF15) as a hub gene having PPARalpha-independently regulated transcripts as its direct downstream children. This result suggests that GDF15 may be PPARalpha-independent master-regulator of fenofibrate action in human endothelial cells.|The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor a (PPARa). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARa also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.|... /This study/ investigated whether fenofibrate affects serum levels of retinol-binding protein-4 (RBP4), an adipocytokine that has recently been shown to link obesity and insulin resistance. Fenofibrate treatment significantly decreased serum RBP4 levels of dyslipidemic patients, which correlated with reduced body weight and increased insulin sensitivity. ... the effect of fenofibrate on RBP4 expression in obese rats /were also examined/. Fenofibrate greatly decreased RBP4 mRNA levels in adipose tissue but not in the liver, which correlated with decreased serum RBP4 levels and increased insulin sensitivity in obese rats. Consistent with a direct effect on RBP4 expression, fenofibrate treatment significantly reduced the mRNA expression levels of RPB4 in 3T3-L1 adipocytes. ...

(4-chlorophenyl)(4-hydroxyphenyl)methanone|fenofibric acid|(3RS)-3-[4-(4-chlorobenzoyl)phenoxy]butan-2-one|methyl 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate|For more Impurities (Complete) data for Fenofibrate (7 total), please visit the HSDB record page.

There is no specific treatment for overdose with Tricor. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis ...; usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.|/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/|/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/|/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SIGNS AND SYMPTOMS/ Severe rashes requiring hospitalization and corticosteroid therapy, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported rarely with fenofibrate in clinical studies. Urticaria and rash also have been reported in approximately 1% of patients receiving fenofibrate therapy in controlled trials.|/CASE REPORTS/ Lipid disorders have been treated with fibrates for many years. Rhabdomyolysis is one of the side effects of these drugs. ... A case of a septic-toxic shock due to rhabdomyolysis in a 75-year old patient, who had been treated with fenofibrate for 2 years /is reported/. This case shows necessity of the standard monitoring of aminotransferase, phosphocreatine kinase and creatinine levels during treatment with fibrates.|/CASE REPORTS/ A 56-year-old white hypercholesterolemic man was treated with fenofibrate 160 mg/day for 1 year. During the course of treatment, he developed gynecomastia on the left side, which resolved after the drug was stopped and replaced with alpha tocopherol acetate. Sixteen months after fenofibrate discontinuation, the patient was rechallenged and subsequently developed gynecomastia symptoms on the right side. The usual etiologies of gynecomastia were excluded by careful assessment of the patient's medical history, physical examination, and results of diagnostic tests such as chest X-ray, mammography, scrotal ultrasonography, routine blood chemistry, and extensive hormonal panel. Gynecomastia again resolved after discontinuation of fenofibrate.In this case, the resolution of gynecomastia on discontinuation of fenofibrate and recurrence after rechallenge highly suggest the role of fenofibrate. Use of the Naranjo probability scale registered causality as probable. ...|/CASE REPORTS/ Fenofibrate therapy was initiated for a 60-year old Hispanic man with stage 4 chronic kidney disease (CKD) for the treatment of hypertriglyceridemia. Two weeks after taking 48 mg of fenofibrate daily, the patient's SCr and blood urea nitrogen concentrations increased from 3.0 and 25 mg/dL, respectively, to 3.5 and 30 mg/dL, respectively. His estimated glomerular filtration rate (eGFR) had decreased from 24.8 to 17.9 mL/min/1.73 sq m. One month after initiating fenofibrate, his SCr concentration had increased to 3.7 mg/dL, a 32% increase from baseline. Because of persistently high triglyceride concentrations (e.g., 402 mg/dL), the fenofibrate dosage was increased to 145 mg daily. The patient's SCr concentration rose to 4.7 mg/dL (a 62% increase from baseline), and his eGFR was calculated as 13 mL/min/1.73 sq m. The patient was referred by the nephrology service for vascular-access placement in preparation for hemodialysis. Four days after discontinuation of fenofibrate, the patient's SCr concentration dropped to 3.3 mg/dL and returned to baseline approximately six weeks later, with an eGFR of 20.5 mL/min/1.73 sq m. Preparation for hemodialysis was terminated, and the patient's eGFR remained stable at 20.2 mL/min/1.73 sq m for the 12 months after fenofibrate discontinuation. A score of 4 on the Naranjo et al. probability scale indicated that there was a possible association between fenofibrate and renal dysfunction in this patient. A 60-year-old patient developed renal impairment after receiving fenofibrate for the treatment of hypertriglyceridemia.

Antara Micronized Procetofen

Table: Fenofibrate Preparations [Table#7415]|Table: Fenofibrate (micronized) Preparations [Table#7416]

Analyte: fenofibrate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards|Analyte: fenofibrate; matrix: chemical purity; procedure: liquid chromatography with with ultraviolet detection at 286 nm and comparison to standards|Analyte: fenofibrate; matrix: chemical purity; procedure: liquid chromatography with ultraviolet detection at 286 nm and comparison to standards

Analyte: fenofibrate: matrix: blood (plasma), urine; procedure: high-performance liquid chromatography with ultraviolet detection at 254 nm; limit of quantitation: 500 ng/mL|Analyte: fenofibrate: matrix: blood (whole), urine; procedure: high-performance liquid chromatography with ultraviolet detection at 200.5 nm

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