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FIBRICOR is a lipid regulating agent available as tablets for oral administration. Each tablet contains 35 mg or 105 mg of fenofibric acid. The chemical name for fenofibric acid is 2-[4-(4-chlorobenzoyl)phenoxy]-2methylpropanoic acid with the following structural formula:
 |
Fenofibric acid is a white to almost white crystalline powder that is stable under ordinary conditions, and has a melting point of 179 – 183°C. Its empirical formula is C17H15ClO4 and molecular weight 318.75. Fenofibric acid is insoluble in water; its solubility increases with pH in buffered media.
Inactive Ingredients
Each tablet contains copovidone, crospovidone, magnesium stearate and microcrystalline cellulose.
FIBRICOR is indicated as adjunctive therapy to diet:
Dosage selection for geriatric patients should be made on the basis of renal function [see Use in Specific Populations (8.5) and Clinical Pharmacology (12.3)].
Tablets:
FIBRICOR® (fenofibric acid) Tablets 35 mg, are white, round tablets, debossed "AR 787" on one side and blank on the other side.
Bottles of 30 NDC 71511-501-30
FIBRICOR® (fenofibric acid) Tablets 105 mg, are white, modified oval tablets, debossed "AR 788" on one side and blank on the other side.
Bottles of 30 NDC 71511-502-30
Store at USP controlled room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF) DISPENSE IN TIGHT, LIGHT-RESISTANT CONTAINER.
Manufactured for: Athena Bioscience LLC Athens, GA 30601
The following serious adverse reactions are described below and elsewhere in the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of FIBRICOR has been established in adults with hypertriglyceridemia or primary hyperlipidemia based on adequate and well-controlled trials of other formulations of fenofibrate, referenced below as “fenofibrate” [see Clinical Studies (14)].
Dosages of fenofibrate used in these trials were comparable to FIBRICOR 105 mg per day [see Clinical Pharmacology (12.3)].
Adverse reactions reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double- blind, placebo-controlled trials are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% treated with placebo. Increases in liver function tests were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.
Table 1. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate* and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials
| Adverse Reaction | Placebo (N =365) | Fenofibrate (N = 439) |
| Abnormal Liver Tests | 1% | 8% |
| Abdominal Pain | 4% | 5% |
| Increased ALT | 2% | 3% |
| Increased AST | 1% | 3% |
| Increased Creatine Phosphokinase | 1% | 3% |
| Constipation | 1% | 2% |
| Rhinitis | 1% | 2% |
Urticaria
Urticaria was seen in 1.1 vs. 0%, and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials.
Increases in Liver Enzymes
In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses comparable to 105 mg FIBRICOR daily versus 1.1% of patients treated with placebo. In an 8-week study, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages comparable to 35 mg to105 mgFIBRICOR daily and was 0% in those receiving dosages comparable to 35 mgor less FIBRICOR daily or placebo [see Warnings and Precautions (5.2)].
The following adverse reactions have been identified during post approval use of fenofibrate. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Blood: Anemia Gastrointestinal: Pancreatitis General: Asthenia
Hepatobiliary: Increased total bilirubin, hepatitis, cirrhosis
Immune System: Anaphylaxis, angioedema
Lipid Disorders: Severely depressed HDL-cholesterol levels
Musculoskeletal and Connective Tissue: Myalgia, muscle spasms, rhabdomyolysis, arthralgia
Renal and Urinary: Acute renal failure
Respiratory: Interstitial lung disease
Skin and Subcutaneous Tissue: Photosensitivity reactions days to months after initiation. This may occur in patients who report a prior photosensitivity reaction to ketoprofen.
Table 2 presents clinically important drug interactions with FIBRICOR.
Table 2. Clinically Important Drug Interactions with FIBRICOR
| Statins | |
| Clinical Impact: | Fibrates may cause myopathy when given alone. The risk of myopathy and rhabdomyolysis is increased with concomitant use of fibrates with statins. |
| Intervention: | Consider if the benefit of using FIBRICOR concomitantly with statin therapy outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of statin therapy. |
| Colchicine | |
| Clinical Impact: | Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine with fenofibrates. |
| Intervention: | Consider if the benefit of using colchicine concomitantly with FIBRICOR outweighs the increased risk of myopathy and rhabdomyolysis. If concomitant use is decided, monitor patients for signs and symptoms of myopathy, particularly during initiation of therapy and during upward dosage titration of colchicine. |
| Coumarin Anticoagulants | |
| Clinical Impact: | Fibrates may cause potentiation of coumarin-type anticoagulant effects with prolongation of the PT/INR. |
| Intervention: | Caution should be exercised when coumarin anticoagulants are given in conjunction with FIBRICOR. The dosage of the anticoagulants should be reduced to maintain the PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are advisable until it has been definitely determined that the PT/INR has stabilized |
| Immunosuppressants | |
| Clinical Impact: | Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of fibrate drugs including FIBRICOR, there is a risk that an interaction will lead to deterioration of renal function. |
| Intervention: | The benefits and risks of using FIBRICOR with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dosage employed and renal function monitored. |
| Bile-Acid Binding Resins | |
| Clinical Impact: | Bile-acid binding resins may bind other drugs given concurrently. |
| Intervention: | In patients taking a bile acid resin, administer FIBRICOR at least 1 hour before or 4 to 6 hours after the bile acid resin to avoid impeding its absorption. |
Included as part of the PRECAUTIONS section.
Fenofibrate did not reduce cardiovascular disease morbidity or mortality in two large, randomized controlled trials of patients with type 2 diabetes mellitus [see Clinical Studies (14.4)].
Because of chemical, pharmacological, and clinical similarities between fenofibrates, including FIBRICOR;
pemafibrate; clofibrate; and gemfibrozil; findings in 5 large randomized, placebo-controlled clinical trials with these other fibrate drugs may also apply to FIBRICOR.
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 [see Clinical Studies (14.4)].
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 one 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.
Serious drug-induced liver injury (DILI), including liver transplantation and death, has been reported with postmarketing use of fenofibrates, including FIBRICOR. 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 fenofibric acid 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 [see Adverse Reactions (6.1)].
FIBRICOR 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 FIBRICOR. Discontinue FIBRICOR 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 FIBRICOR in these patients if there is no alternative explanation for the liver injury.
FIBRICOR may cause myopathy [muscle pain, tenderness, or weakness associated with elevated creatine kinase (CK)] and rhabdomyolysis.
Risk factors for myopathy include age 65 years or older, uncontrolled hypothyroidism, renal impairment, and concomitant use with certain other drugs [see Drug Interaction (7) and Uses in Specific Populations (8.6)].
Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, including fenofibrates, are co-administered with a statin. Avoid concomitant use unless the benefit of further alterations in TG levels is likely to outweigh the increased risk of this drug combination [see Drug Interactions (7), Clinical Pharmacology (12.3) and Clinical Studies (14.4)].
Cases of myopathy, including rhabdomyolysis, have been reported with FIBRICOR co-administered with colchicine. Consider whether the benefit of using colchicine concomitantly with FIBRICOR outweighs the increased risk of myopathy [see Drug Interactions (7)].
Discontinue FIBRICOR if markedly elevated CK levels occur or if myopathy is either diagnosed or suspected. Muscle symptoms and CK elevations may resolve if FIBRICOR is discontinued. Temporarily discontinue FIBRICOR in patients experiencing an acute or serious condition at high risk of developing renal failure secondary to rhabdomyolysis (e.g., sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic, endocrine, or electrolyte disorders; or uncontrolled epilepsy).
Inform patients of the risk of myopathy and rhabdomyolysis when starting or increasing the FIBRICOR dosage. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
Increases in serum creatinine have been reported in patients receiving fenofibrates. These increases tend to return to baseline following discontinuation of FIBRICOR. The clinical significance of this finding is unknown. Monitor renal function in patients with renal impairment taking FIBRICOR. Renal monitoring should also be considered for patients taking FIBRICOR at risk for renal insufficiency, such as geriatric patients and patients with diabetes. FIBRICOR is contraindicated in patients with severe renal impairment, including those with end-stage renal disease (ESRD) and those receiving dialysis [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].
Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected,
gallbladder studies are indicated. FIBRICOR therapy should be discontinued if gallstones are found. FIBRICOR is contraindicated in patients with pre-existing gallbladder disease
Exercise caution when co-administering anticoagulants with FIBRICOR because of the potentiation of coumarin-type anticoagulant effects in prolonging the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, monitor the PT/INR frequently and adjust the dosage of the anticoagulant until the PT/INR has stabilized [see Drug Interactions (7.1)].
Pancreatitis has been reported in patients taking fenofibrate. 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.
Mild-to-moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of therapy with fenofibrates. However, these levels stabilize during long-term administration.
Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts is recommended during the first 12 months of FIBRICOR administration.
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 FIBRICOR. FIBRICOR is contraindicated in patients with a hypersensitivity to fenofibrate, fenofibric acid, or any of the ingredients in FIBRICOR.
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 FIBRICOR and treat patients appropriately if SCAR is suspected.
In the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1.4%) in the fenofibrate group (p=0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1.1%) in the fenofibrate group (p=0.022).
In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p<0.01).
In the cardiovascular outcome trial with pemafibrate, pulmonary embolism was reported for 37 (0.7%) subjects in the pemafibrate group and 16 (0.3%) subjects in the placebo group. Deep vein thrombosis was reported for 36 (0.7%) subjects in the pemafibrate group and 13 (0.2%) subjects in the placebo group.
There have been postmarketing and clinical trial reports of severe decreases in high-density lipoprotein cholesterol (HDL-C) levels (as low as 2 mg/dL) occurring in patients with and without diabetes initiated on fibrate therapy. The
decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and sustained. The clinical significance of this decrease in HDL-C is unknown. Check HDL-C levels within the first few months after initiation of FIBRICOR. If a severely
depressed HDL-C level is detected, discontinue FIBRICOR and monitor HDL-C until it has returned to baseline. FIBRICOR should not be re-initiated.
FIBRICOR (fenofibric acid)
No carcinogenicity and fertility studies have been conducted with choline fenofibrate or fenofibric acid. However, because fenofibrate is rapidly converted to its active metabolite, fenofibric acid, either during or immediately following absorption both in animals and humans, studies conducted with fenofibrate are relevant for the assessment of the toxicity profile of fenofibric acid. A similar toxicity spectrum is expected after treatment with either FIBRICOR or fenofibrate.
Fenofibrate
Carcinogenesis: Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24-month study, Wistar rats were dosed with fenofibrate at 10 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day, approximately 0.3 times, 1 time, and 6 times the maximum recommended human dose (MRHD) based on body surface area comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times the MRHD), the incidence of liver carcinomas was significantly increased in both sexes. A statistically significant increase in pancreatic carcinomas was observed in males at 1 and 6 times the MRHD; an increase in pancreatic adenomas and benign testicular interstitial cell tumors was observed at 6 times the MRHD in males. In a second
24-month study in a different strain of rats (Sprague-Dawley), doses of 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD) produced significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in testicular interstitial cell tumors in males at 2 times the MRHD.
A 117-week carcinogenicity study was conducted in rats comparing three drugs: fenofibrate 10 mg/kg/day and 60 mg/kg/day (0.3 and 2 times the MRHD), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas in males and hepatic neoplastic nodules in females.
Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.
In a 21-month study in CF-1 mice, fenofibrate 10 mg/kg/day, 45 mg/kg/day, and 200 mg/kg/day (approximately 0.2 times, 1 time, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10 mg/kg/day, 60 mg/kg/day, and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.
Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.
Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes.
Impairment of Fertility: In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (approximately 10 times the MRHD, based on mg/m2 surface area comparisons).
In the event of an overdose of FIBRICOR, consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for additional overdosage management recommendations. There is no specific treatment for overdose with FIBRICOR. 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 or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered.
FIBRICOR is contraindicated in the following conditions:
The active moiety of FIBRICOR is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been studied through oral administration of fenofibrate.
The lipid-modifying 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 PPAR alpha receptor. Through this mechanism, fenofibric acid 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).
Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol (Total-C), total triglycerides, and triglyceride rich lipoprotein (VLDL) in treated patients with severe hypertriglyceridemia.
FIBRICOR contains fenofibric acid, which is the circulating pharmacologically active moiety in plasma after oral administration of FIBRICOR. Fenofibric acid is also the circulating pharmacologically active moiety in plasma after oral administration of fenofibrate, the ester of fenofibric acid.
The absolute bioavailability of fenofibric acid has not been determined as the compound is virtually insoluble in aqueous media suitable for injection. Fenofibrate is insoluble in water and its bioavailability is increased when taken with meals.
However, after fenofibrate is dissolved, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration of FIBRICOR in healthy volunteers, approximately median peak plasma levels of fenofibric acid occur by approximately 2.5 hours after administration. Exposure after administration of three 35 mg FIBRICOR tablets is comparable to one 105 mg FIBRICOR tablet.
Effect of Food
A food-effect study involving administration of FIBRICOR to healthy volunteers under fasting conditions and with a high- fat meal indicated that the Cmax was decreased by approximately 35% while the AUC remained unchanged. This decrease in exposure is not considered clinically significant, and therefore FIBRICOR can be taken without regards to meals.
Upon multiple dosing of fenofibrate, fenofibric acid levels reached steady state 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 dyslipidemic subjects.
Metabolism
In vitro and in vivo metabolism data indicate that fenofibric acid does not undergo oxidative metabolism (e.g. cytochrome P450) to a significant extent. The enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 do not play a role in the metabolism of fenofibric acid.
Excretion
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. After absorption, fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once- daily dosing.
Geriatric Patients:
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 [see Dosage and Administration (2.4) and Use in Specific Populations (8.5)].
Pediatric Patients:
The pharmacokinetics of FIBRICOR has not been studied in pediatric populations.
Male and Female Patients:
No pharmacokinetic difference between males and females has been observed for fenofibric acid.
Racial and Ethnic Groups:
The influence of race on the pharmacokinetics of fenofibric acid has not been studied, however, fenofibric acid is not metabolized by enzymes known for exhibiting inter-ethnic variability.
Patients with Renal Impairment:
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) <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. Based on these findings, the use of FIBRICOR is contraindicated in patients with severe renal impairment, including end-stage renal disease (ESRD) or those receiving dialysis. Dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration (2.3)].
Patients with Hepatic Impairment:
No pharmacokinetic studies of fenofibric acid have been conducted in patients with hepatic impairment. Drug-Drug Interaction Studies:
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 inhibitor 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 fenofibric acid on systemic exposure to other drugs.
Table 3. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from FIBRICOR or 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 mg1 once daily for 10 days | ↓ | 2% | ↓ | 4% |
| Pravastatin | 40 mg as a single dose | Fenofibrate 3 x 67 mg2 as a single dose | ↓ | 1% | ↓ | 2% |
| Fluvastatin | 40 mg as a single dose | Fenofibrate 160 mg1 as a single dose | ↓ | 2% | ↓ | 10% |
| Anti-diabetic medications | ||||||
| Glimepiride | 1 mg as a single dose | Fenofibrate 145 mg1 once daily for 10 days | ↑ | 1% | ↓ | 1% |
| Metformin | 850 mg three times daily for 10 days | Fenofibrate 54 mg1 three times daily for 10 days | ↓ | 9% | ↓ | 6% |
| Rosiglitazone | 8 mg once daily for 5 days | Fenofibrate 145 mg1 once daily for 14 days | ↑ | 10% | ↑ | 3% |
| 1 TriCor® (fenofibrate) oral tablet 2 TriCor® (fenofibrate) oral micronized capsule |
||||||
Table 4. Effects of FIBRICOR or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs
| Dosage Regimen of Fenofibrate |
Dosage Regimen of Co-Administered Drug |
Changes in Co-Administered Drug Exposure | ||
| Analyte | AUC | Cmax | ||
| Lipid-lowering medications | ||||
| Fenofibrate 160 mg1 once daily for 10 days | Atorvastatin, 20 mg once daily for 10 days | Atorvastatin | ↓ 17% | 0% |
| Fenofibrate 3 x 67 mg2 as a single dose | Pravastatin, 40 mg as a single dose | Pravastatin | ↑ 13% | ↑ 13% |
| 3α-hydroxyl-iso- pravastatin | ↑ 26% | ↑ 29% | ||
| Fenofibrate 160 mg1 once daily for 10 days | Pravastatin, 40 mg once daily for 10 days | Pravastatin | ↑ 28% | ↑ 36% |
| 3α-hydroxyl- iso-pravastatin | ↑ 39% | ↑ 55% | ||
| Fenofibrate 160 mg1 as a single dose | Fluvastatin, 40 mg as a single dose | (+)-3R, 5S- Fluvastatin | ↑ 15% | ↑ 16% |
| Anti-diabetic medications | ||||
| Fenofibrate 145 mg1 once daily for 10 days | Glimepiride, 1 mg as a single dose | Glimepiride | ↑ 35% | ↑ 18% |
| Fenofibrate 54 mg1 three times daily for 10 days | Metformin, 850 mg three times daily for 10 days | Metformin | ↑ 3% | ↑ 6% |
| Fenofibrate 145 mg1 once daily for 14 days | Rosiglitazone, 8 mg once daily for 5 days | Rosiglitazone | ↑ 6% | ↓ 1% |
| Anti-viral medications | ||||
| FIBRICOR 105 mg once daily for 10 days | Efavirenz, 600 mg as a single dose | Efavirenz | ↓ 8% | ↑ 1% |
|
1 TriCor® (fenofibrate) oral tablet |
||||
Inform patients that FIBRICOR may cause liver enzyme elevations and possibly liver failure. Advise patients to promptly report fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice [see Contraindications (4), Warnings and Precautions (5.2)].
Advise patients that FIBRICOR may cause myopathy and rhabdomyolysis. Inform patients that the risk is also increased when taking certain types of medication and they should discuss all medication, both prescription and over the counter, with their healthcare provider. Instruct patients to inform other healthcare providers prescribing a new medication or increasing the dosage of an existing medication that they are taking FIBRICOR. Instruct patients to promptly report any unexplained muscle pain, tenderness, or weakness particularly if accompanied by malaise or fever [see Warnings and Precautions (5.3) and Drug Interactions (7)].
Inform patients that the concomitant use of FIBRICOR with coumarin-type anticoagulants may increase the risk of bleeding. Advise patients if they are taking or planning to take coumarin-type anticoagulants to inform their healthcare providers and that increased monitoring may be necessary [see Warnings and Precautions (5.6) and Drug Interactions (7)].
Inform patients that serious hypersensitivity reactions, such as anaphylaxis and angioedema, have been reported with fenofibrates, including FIBRICOR . Advise patients to report immediately any signs or symptoms suggesting allergic reaction, and to discontinue drug until they have consulted prescribing physicians [see Warnings and Precautions (5.9)].
Advise patients to inform their healthcare provider of a known or suspected pregnancy to discuss if FIBRICOR should be discontinued [see Use in Specific Populations (8.1)].
Advise patients that breastfeeding during treatment with FIBRICOR is not recommended [see Use in Specific Populations (8.2)].
If a dose is missed, advise patients not take an extra dose and to resume treatment with the next dose.
TriCor® is a registered trademark of Abbott Laboratories. FIBRICOR® is a registered U.S. trademark of Athena Bioscience LLC
