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These highlights do not include all the information needed to use Fenofibrate Tablets safely and effectively. See full prescribing information for Fenofibrate Tablets. Fenofibrate Tablets, for oral useInitial U.S. Approval: 1993 | Fenofibrate [Impax Generics] | BioPortfolio

13:05 EST 27th January 2019 | BioPortfolio

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Fenofibrate Tablets are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.

Fenofibrate Tablets is also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention.

Markedly elevated levels of serum triglycerides (e.g., >2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of Fenofibrate Tablets therapy on reducing this risk has not been adequately studied.

Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1) ].

Fenofibrate Tablets should be given with food to optimize the absorption of the medicine. Patients should be advised to swallow Fenofibrate Tablets whole. Do not crush, dissolve or chew tablets.

The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.

Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of Fenofibrate Tablets if lipid levels fall significantly below the targeted range.

Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 120 mg once daily.

The initial dose of Fenofibrate Tablets is 120 mg per day.

The initial dose is 40 to 120 mg per day. 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 maximum dose is 120 mg per day.

Treatment with Fenofibrate Tablets should be initiated at a dose of 40 mg per day in patients with mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of Fenofibrate Tablets should be avoided in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5) ].

Fenofibrate Tablets is contraindicated in:

The effect of Fenofibrate Tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.

The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p=0.32) as compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9,795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.

Because of chemical, pharmacological, and clinical similarities between fenofibrate, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to Fenofibrate Tablets.

In the Coronary Drug Project, a large study of post myocardial infarction of patients treated for 5 years with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo group. There was however, a difference in the rate of cholelithiasis and cholecystitis requiring surgery between the two groups (3.0% vs. 1.8%).

In a study conducted by the World Health Organization (WHO), 5000 subjects 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. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (n=4,081) study 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 higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from the WHO study (RR=1.29).

A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).

Fibrates increase the risk for myopathy and have been associated with rhabdomyolysis. The risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes, renal insufficiency, or hypothyroidism.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase (CPK) levels.

Patients should be advised to report promptly unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be assessed in patients reporting these symptoms, and Fenofibrate Tablets therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed.

Data from observational studies indicate that the risk for rhabdomyolysis is increased when fibrates, in particular gemfibrozil, are co-administered with an HMG-CoA reductase inhibitor (statin). The combination should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination [see Clinical Pharmacology (12.3)].

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine. [see Drug Interactions (7.4) ]

Fenofibrate at doses equivalent to 87 mg to 130 mg fenofibrate per day [at the highest dose, comparable to Fenofibrate Tablets, 120 mg] has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)].

In a pooled analysis of 10 placebo-controlled trials, increases to >3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminases related to fenofibrate therapy appears to be dose related. In an 8-week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 87 mg to 130 mg fenofibrate per day and was 0% in those receiving dosages equivalent to 43 mg or less fenofibrate per day, or placebo.

Hepatocellular, chronic active and cholestatic hepatitis have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

Baseline and regular periodic monitoring of liver tests, including serum ALT (SGPT) should be performed for the duration of therapy with Fenofibrate Tablets, and therapy discontinued if enzyme levels persist above three times the normal limit.

Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking Fenofibrate Tablets. Renal monitoring should also be considered for patients taking Fenofibrate Tablets at risk for renal insufficiency such as the elderly and patients with diabetes.

Fenofibrate, like clofibrate and gemfibrozil, 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.

Caution should be exercised when anticoagulants are given in conjunction with Fenofibrate Tablets because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7.1)].

Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. 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 fenofibrate therapy. 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 are recommended during the first 12 months of Fenofibrate Tablets administration.

Acute Hypersensitivity

Anaphylaxis and angioedema have been reported postmarketing with fenofibrate. 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.

Delayed Hypersensitivity

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 postmarketing, occurring days to weeks after initiation of fenofibrate. 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 and treat patients appropriately if SCAR is suspected.

In the 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%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (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).

There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in diabetic and non-diabetic patients 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. It is recommended that HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect rates observed in clinical practice.

Adverse reactions reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% 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.

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.

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
BODY SYSTEM
Adverse Reaction
Fenofibrate Dosage equivalent to 130 mg fenofibrate
(N=439)
Placebo
(N=365)
BODY AS A WHOLE
Abdominal Pain 4.6% 4.4%
Back Pain 3.4% 2.5%
Headache 3.2% 2.7%
DIGESTIVE
Nausea 2.3% 1.9%
Constipation 2.1% 1.4%
METABOLIC AND NUTRITIONAL DISORDERS
Abnormal Liver Tests 7.5% 1.4%
Increased AST 3.4% 0.5%
Increased ALT 3.0% 1.6%
Increased Creatine Phosphokinase 3.0% 1.4%
RESPIRATORY
Respiratory Disorder 6.2% 5.5%
Rhinitis 2.3% 1.1%

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:

myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasms, hepatitis, cirrhosis, anemia, arthralgia, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL cholesterol levels. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.

Caution should be exercised when coumarin anticoagulants are given in conjunction with Fenofibrate Tablets. 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 prothrombin time/INR has stabilized [see Warnings and Precautions (5.6) ].

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 Fenofibrate Tablets, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Fenofibrate Tablets with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored.

Since bile acid resins may bind other drugs given concurrently, patients should take Fenofibrate Tablets at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption.

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.

Pregnancy Category C. Safety in pregnant women has not been established. There are no adequate and well controlled studies of fenofibrate in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m.

In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6-15 during the period of organogenesis, adverse developmental findings were not observed at 14 mg/kg/day (less than 1 times the MRHD, based on body surface area comparisons; mg/m). At higher multiples of human doses evidence of maternal toxicity was observed.

In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, aborted litters were observed at 150 mg/kg/day (10 times the MRHD, based on body surface area comparisons: mg/m). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m).

In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), maternal toxicity was observed at less than 1 times the MRHD, based on body surface area comparisons; mg/m.

Fenofibrate should not be used in nursing mothers. A decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and efficacy have not been established in pediatric patients.

Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. Since elderly patients have a higher incidence of renal impairment, dose selection for the elderly should be made on the basis of renal function [see Dosage and Administration (2.5) and Clinical Pharmacology (12.3) ]. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking Fenofibrate Tablets.

The use of Fenofibrate Tablets should be avoided in patients with severe renal impairment [see Contraindications (4) ]. Dose reduction is required in patients with mild to moderate renal impairment [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) ]. Monitoring renal function in patients with renal impairment is recommended.

The use of Fenofibrate Tablets has not been evaluated in subjects with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].

There is no specific treatment for overdose with Fenofibrate Tablets. 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 fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.

Fenofibrate Tablets is a lipid regulating agent available as tablets for oral administration. Each tablet contains 40 mg or 120 mg fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:

The empirical formula is CHOCl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79° to 82°C. Fenofibrate is a white solid which is stable under ordinary conditions.

Inactive ingredients: Each tablet contains lactose monohydrate, NF; Polyethylene Glycol 6000, NF; Poloxamer 188, NF; and magnesium stearate, NF.

The active moiety of Fenofibrate Tablets is fenofibric acid. The pharmacological effects of fenofibric acid in both animals and humans have been extensively studied through oral administration of fenofibrate.

The lipid-lowering 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 alpha (PPARα). 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 decrease in TG 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 PPARα also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.

Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

A variety of clinical studies have demonstrated that elevated levels of total -C, LDL-C, and apo B, an LDL membrane complex, are risk factors for human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are risk factors for the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and TG, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined.

Fenofibric acid, the active metabolite of fenofibrate, produces reductions in TC, LDL-C, apo B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in HDL and apoproteins apo AI and apo AII.

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.

Plasma concentrations of fenofibric acid after single-dose administration of Fenofibrate Tablets,120 mg are equivalent to those of Fenofibrate 130 mg capsules under high-fat conditions.

A high-fat meal did not affect the fenofibric acid AUC after Fenofibrate Tablets administration but did increase the mean C by 44% compared to fasting conditions.

Drug-Drug Interactions: 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 2. 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 agents
Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mgTriCor (fenofibrate) oral tablet once daily for 10 days ↓2% ↓4%
Pravastatin 40 mg as a single dose Fenofibrate 3 × 67 mgTriCor (fenofibrate) oral micronized capsule as a single dose ↓1% ↓2%
Fluvastatin 40 mg as a single dose Fenofibrate 160 mg as a single dose ↓2% ↓10%
Anti-diabetic agents
Glimepiride 1 mg as a single dose Fenofibrate 145 mg once daily for 10 days ↑1% ↓1%
Metformin 850 mg three times daily for 10 days Fenofibrate 54 mg three times daily for 10 days ↓9% ↓6%
Rosiglitazone 8 mg once daily for 5 days Fenofibrate 145 mg once daily for 14 days ↑10% ↑3%
Table 3. 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 agents
Fenofibrate 160 mgTriCor (fenofibrate ) oral tablet once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0%
Fenofibrate 3 × 67 mgTriCor (fenofibrate ) oral micronized capsule as a single dose Pravastatin, 40 mg as a single dose Pravastatin ↑13% ↑13%
3α-Hydroxyl-iso-pravastatin ↑26% ↑29%
Fenofibrate 160 mg as a single dose Fluvastatin, 40 mg as a single dose (+)-3R, 5S-Fluvastatin ↑15% ↑16%
Anti-diabetic agents
Fenofibrate 145 mg once daily for 10 days Glimepiride, 1 mg as a single dose Glimepiride ↑35% ↑18%
Fenofibrate 54 mg three times daily for 10 days Metformin, 850 mg three times daily for 10 days Metformin ↑3% ↑6%
Fenofibrate 145 mg once daily for 14 days Rosiglitazone, 8 mg once daily for 5 days Rosiglitazone ↑6% ↓1%

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, 45, and 200 mg/kg/day, approximately 0.3, 1, and 6 times the maximum recommended human dose (MRHD), based on body surface area comparisons (mg/m). 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 rat carcinogenicity study in a different strain of rats (Sprague-Dawley), doses of 10 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 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/m 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, 45, and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18-month study at 10, 60, 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 (~10 times the MRHD, based on mg/m surface area comparisons).

The effects of fenofibrate at a dose equivalent to 120 mg Fenofibrate Tablets per day were assessed from four randomized, placebo-controlled, double-blind, parallel-group studies including patients with the following mean baseline lipid values: total-C 306.9 mg/dL; LDL-C 213.8 mg/dL; HDL-C 52.3 mg/dL; and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (see Table 4).

In a subset of the subjects, measurements of apo B were conducted. Fenofibrate treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p<0.0001, n=213 and 143 respectively).

Table 4. Mean Percent Change in Lipid Parameters at End of TreatmentDuration of study treatment was 3 to 6 months.
Treatment Group Total-C LDL-C HDL-C TG
Pooled Cohort
  Mean baseline lipid values (n=646) 306.9 mg/dL 213.8 mg/dL 52.3 mg/dL 191.0 mg/dL
  All FEN (n=361) -18.7%p=<0.05 vs. placebo -20.6% +11.0% -28.9%
  Placebo (n=285) -0.4% -2.2% +0.7% +7.7%
Baseline LDL-C >160 mg/dL and TG <150 mg/dL (Type IIa)
  Mean baseline lipid values (n=334) 307.7 mg/dL 227.7 mg/dL 58.1 mg/dL 101.7 mg/dL
  All FEN (n=193) -22.4% -31.4% +9.8% -23.5%
  Placebo (n=141) +0.2% -2.2% +2.6% +11.7%
Baseline LDL-C >160 mg/dL and TG ≥150 mg/dL (Type IIb)
  Mean baseline lipid values (n=242) 312.8 mg/dL 219.8 mg/dL 46.7 mg/dL 231.9 mg/dL
  All FEN (n=126) -16.8% -20.1% +14.6% -35.9%
  Placebo (n=116) -3.0% -6.6% +2.3% +0.9%

The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials of 147 hypertriglyceridemic patients. Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 120 mg Fenofibrate Tablets per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with elevated triglycerides often results in an increase of LDL-C (see Table 5).

Table 5. Effects of Fenofibrate in Patients With Severe Hypertriglyceridemia
Study 1 Placebo Fenofibrate
Baseline TG levels 350 to 499 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean)
Triglycerides 28 449 450 -0.5 27 432 223 -46.2=p<0.05 vs. placebo
VLDL Triglycerides 19 367 350 2.7 19 350 178 -44.1
Total Cholesterol 28 255 261 2.8 27 252 227 -9.1
HDL Cholesterol 28 35 36 4 27 34 40 19.6
LDL Cholesterol 28 120 129 12 27 128 137 14.5
VLDL Cholesterol 27 99 99 5.8 27 92 46 -44.7
Study 2 Placebo Fenofibrate
Baseline TG levels 500 to 1500 mg/dL N Baseline (Mean) Endpoint (Mean) % Change (Mean) N Baseline (Mean) Endpoint (Mean) % Change (Mean)
Triglycerides 44 710 750 7.2 48 726 308 -54.5
VLDL Triglycerides 29 537 571 18.7 33 543 205 -50.6
Total Cholesterol 44 272 271 0.4 48 261 223 -13.8
HDL Cholesterol 44 27 28 5.0 48 30 36 22.9
LDL Cholesterol 42 100 90 -4.2 45 103 131 45.0
VLDL Cholesterol 42 137 142 11.0 45 126 54 -49.4

Fenofibrate Tablets 40 mg, are white to off-white oval tablets debossed "FLO" on one side and blank on the other side.

Bottle of 90 tablets, NDC 0115-1522-10.

Fenofibrate Tablets 120 mg are white to off-white oval tablets debossed "FHI" on one side and blank on the other side.

Bottle of 90 tablets, NDC 0115-1523-10

Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

Patients should be advised:

Distributed by:

Impax Generics

Hayward, CA 94544 USA

© Valeant Pharmaceuticals North America LLC

U.S. Patent Numbers: 7,658,944, 8,124,125, 8,481,078, and 9,173,847

9543302 - 70013759

Revised: 06/2018

NDC 0115-1522-10

Fenofibrate Tablets

40 mg

Rx only 90 Tablets

Impax

NDC 0115-1523-10

Fenofibrate Tablets

120 mg

Rx only 90 Tablets

Impax

Manufacturer

Impax Generics

Active Ingredients

Source

Drugs and Medications [172 Associated Drugs and Medications listed on BioPortfolio]

Fenofibrate [directrx]

FENOFIBRATE

Fenofibrate [unit dose services]

FENOFIBRATE CAPSULES, MICRONIZED

Fenofibrate [unit dose services]

FENOFIBRATE CAPSULES, MICRONIZED

Fenofibrate [physicians total care, inc.]

FENOFIBRATE CAPSULES, MICRONIZED

Fenofibrate [ncs healthcare of ky, inc dba vangard labs]

FENOFIBRATE CAPSULES, MICRONIZED

Clinical Trials [93 Associated Clinical Trials listed on BioPortfolio]

A Randomized, Double-Blind Trial Comparing the Efficacy and Safety of Fenofibrate, Metformin, Their Combination and Placebo in Patients With Metabolic Syndrome.

The purpose of this study was to study the effect of different combinations of fenofibrate and metformin on the cluster of metabolic syndrome (MetS) biochemical abnormalities, and to deter...

Predictors of Response to Fenofibrate

Fenofibrate is one of the best options for treating hypertriglyceridemia. In the majority of patients, fenofibrate lowers triglycerides (TG) by 24-55% and improves HDL- and LDL-cholesterol...

The Fenofibrate and Metformin for Atherogenic Dyslipidemia (FAMA) Study

Patients with metabolic syndrome, insulin resistance, and elevated triglycerides of 150 mg/dl or higher will be randomized to one of four groups: 1) placebo; 2) metformin; 3) fenofibrate; ...

Use of Fenofibrate for Primary Biliary Cirrhosis

This is a pilot study to evaluate the safety and efficacy of fenofibrate on patients with primary biliary cirrhosis who have an incomplete response to ursodeoxycholic acid.

Effects of Fenofibrate on Adipocytokine Levels In Hypertriglyceridemic Patients

Fenofibrate increases adiponectin levels, but reduces leptin levels

PubMed Articles [23 Associated PubMed Articles listed on BioPortfolio]

Fenofibrate improves vascular endothelial function and contractility in diabetic mice.

Fenofibrate, a peroxisome proliferator-activated receptors α (PPARα) agonist, reduces vascular complications of diabetic patients but its protective mechanisms are not fully understood. Here we test...

Fenofibrate therapy to lower serum triglyceride concentrations in persons with spinal cord injury: A preliminary analysis of its safety profile.

Fenofibrate is used to treat elevated serum triglyceride (TG) concentrations (e.g. ≥150 mg/dl). The lipoprotein profile of most individuals with spinal cord injury (SCI) would not satisfy conventi...

Salutary effect of fenofibrate on type 1 diabetic retinopathy via inhibiting oxidative stress-mediated Wnt/β-catenin pathway activation.

Fenofibrate has been shown to have therapeutic effects on diabetic retinopathy (DR). Our previous studies demonstrated that the oxidative stress-activated Wnt/β-catenin pathway plays a pathogenic rol...

Polyurethane nanoparticles loaded fenofibrate exerts inhibitory effects on nonalcoholic fatty liver disease in mice.

Polyurethane (PU) nanoparticles are potential drug carriers. We aimed to study the in vitro and in vivo efficacy of biodegradable PU nanoparticles loaded with fenofibrate on nonalcoholic fatty liver d...

Effect of fenofibrate in 1113 patients at low-density lipoprotein cholesterol goal but high triglyceride levels: Real-world results and factors associated with triglyceride reduction.

Fibrates are used in patients with dyslipidemia and high cardiovascular risk. However, information regarding drug response to fibrate has been highly limited. We investigated treatment results and fac...

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