Patients Should Be Advised:
of the potential benefits and risks of Fenofibrate tablets for oral use.
not to use Fenofibrate tablets for oral use if there is a known hypersensitivity to fenofibrate or fenofibric acid.
of medications that should not be taken in combination with Fenofibrate tablets for oral use.
that if they are taking coumarin anticoagulants, Fenofibrate tablets for oral use may increase their anti-coagulant effect, and increased monitoring may be necessary.
to continue to follow an appropriate lipid-modifying diet while taking Fenofibrate tablets for oral use.
to take Fenofibrate tablets for oral use once daily, without regard to food, at the prescribed dose, swallowing each tablet whole.
to return for routine monitoring.
to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition. Patients should also be advised to inform their physicians prescribing a new medication that they are taking Fenofibrate tablets for oral use.
to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.Manufactured by:
Fournier Laboratories Ireland Limited, Anngrove, Carrigtwohill Co. Cork, IrelandDistributed by:
Zydus Pharmaceuticals USA Inc.
Pennington, NJ 0853403 A888 November, 2013
Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
- No Title 1572547434
- No Title 1572550651
- No Title 1572553540
- Indications And Usage
- Dosage And Administration
- Dosage Forms And Strengths
- Contraindications
- Warnings And Precautions
- Adverse Reactions
- Drug Interactions
- Use In Specific Populations
- Overdosage
- Description
- Clinical Pharmacology
- Nonclinical Toxicology
- Clinical Studies
- How Supplied/storage And Handling
- Package Label
- Fenofibrate Tablets, 54 Mg And 160 Mg
- No Title 1572453074
- Description
- Clinical Pharmacology
- Indications And Usage
- Contraindications
- Warnings
- Precautions
- Adverse Reactions
- Overdosage
- Dosage And Administration
- How Supplied
- References
- Principal Display Panel - 54 Mg Tablet Bottle Label
- Principal Display Panel - 160 Mg Tablet Bottle Label
No Title 1572547434 ⮝
Dist. by:
Global Pharmaceuticals
Division of IMPAX Laboratories, Inc.
Philadelphia, PA 19124 USARepackaged By :
Aidarex Pharmaceuticals LLC,
Corona, CA 92880Rev. 03/11
295-08
No Title 1572550651 ⮝
FENOFIBRATE
fenofibrate tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51655-010(NDC:0093-2060) Route of Administration oral
Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRATE - UNII:U202363UOS) FENOFIBRATE 145 mg in 30
Product Characteristics Color white Score no score Shape OVAL Size 18mm Flavor Imprint Code FO Contains
Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:51655-010-52 30 in 1 BOTTLE, DISPENSING
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021656 05/20/2014
Labeler - Northwind Pharmaceuticals (036986393)
Registrant - Northwind Pharmaceuticals (036986393)
Establishment Name Address ID/FEI Business Operations Northwind Pharmaceuticals 036986393 repack(51655-010) Revised: 5/2014 Document Id: fcef12aa-ba34-4a2c-abdd-9447cc18f3ac 34391-3 Set id: dbc61583-082b-4e69-8147-0de0ae72016f Version: 1 Effective Time: 20140520 Northwind Pharmaceuticals
No Title 1572553540 ⮝
FENOFIBRATE
fenofibrate tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51655-009(NDC:0115-5522) Route of Administration oral
Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRATE - UNII:U202363UOS) FENOFIBRATE 160 mg in 30
Product Characteristics Color white Score no score Shape OVAL Size 15mm Flavor Imprint Code G;352 Contains
Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:51655-009-52 30 in 1 BOTTLE, DISPENSING
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076509 05/07/2014
Labeler - Northwind Pharmaceuticals (036986393)
Registrant - Northwind Pharmaceuticals (036986393)
Establishment Name Address ID/FEI Business Operations Northwind Pharmaceuticals 036986393 repack(51655-009) Revised: 5/2014 Document Id: 7e1779df-a430-4654-80fc-95cf391c279d 34391-3 Set id: 4b4447a1-8136-4258-b2c8-c5f9c1bcec92 Version: 1 Effective Time: 20140507 Northwind Pharmaceuticals
Indications And Usage ⮝
1.1 Primary Hypercholesterolemia or Mixed Dyslipidemia
Fenofibrate tablets for oral use are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), Triglycerides and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in adult patients with primary hypercholesterolemia or mixed dyslipidemia.
1.2 Severe Hypertriglyceridemia
Fenofibrate tablets for oral use are 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 obviate 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 therapy on reducing this risk has not been adequately studied.
1.3 Important Limitations of Use
Fenofibrate at a dose equivalent to 145 mg of Fenofibrate tablets for oral use was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1)].
Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
Dosage And Administration ⮝
2.1 General Considerations
Patients should be placed on an appropriate lipid-lowering diet before receiving Fenofibrate tablets for oral use, and should continue this diet during treatment with Fenofibrate tablets for oral use. Fenofibrate tablets for oral use can be given without regard to meals.
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 for oral use 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 145 mg once daily.
2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia
The initial dose of Fenofibrate tablets for oral use is 145 mg once daily.
2.3 Severe Hypertriglyceridemia
The initial dose is 48 to 145 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 145 mg once daily.
2.4 Impaired Renal Function
Treatment with Fenofibrate tablets for oral use should be initiated at a dose of 48 mg per day in patients having 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 for oral use should be avoided in patients with severe renal impairment [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
2.5 Geriatric Patients
Dose selection for the elderly should be made on the basis of renal function [see Use in Specific Populations (8.5)].
Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
Dosage Forms And Strengths ⮝
48 mg yellow tablets, imprinted with the a logo and the code identification letters "FI".
145 mg white tablets, imprinted with a logo and the code identification letters "FO".Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
Contraindications ⮝
Fenofibrate tablets for oral use are contraindicated in:
patients with severe renal impairment, including those receiving dialysis [see Clinical Pharmacology (12.3)].
patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions (5.3)].
patients with preexisting gallbladder disease [see Warnings and Precautions (5.5)].
nursing mothers [see Use in Specific Populations (8.3)].
patients with known hypersensitivity to fenofibrate or fenofibric acid [see Warnings and Precautions (5.9)].Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
Warnings And Precautions ⮝
5.1 Mortality and Coronary Heart Disease Morbidity
The effect of Fenofibrate tablets for oral use 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 9795 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 tablets for oral use, 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 for oral use.
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=4081) 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 = .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 World Health Organization 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). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, p = 0.07).
5.2 Skeletal Muscle
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 for oral use 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)].
5.3 Liver Function
Fenofibrate at doses equivalent to 96 mg to 145 mg Fenofibrate tablets for oral use per day 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 appear 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 96 mg to 145 mg Fenofibrate tablets for oral use per day and was 0% in those receiving dosages equivalent to 48 mg or less Fenofibrate tablets for oral use per day, or placebo. Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy 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 function, including serum ALT (SGPT) should be performed for the duration of therapy with Fenofibrate tablets for oral use, and therapy discontinued if enzyme levels persist above three times the normal limit.
5.4 Serum Creatinine
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 for oral use. Renal monitoring should also be considered for patients taking Fenofibrate tablets for oral use at risk for renal insufficiency such as the elderly and patients with diabetes.
5.5 Cholelithiasis
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 for oral use therapy should be discontinued if gallstones are found.
5.6 Coumarin Anticoagulants
Caution should be exercised when coumarin anticoagulants are given in conjunction with Fenofibrate tablets for oral use because of the potentiation of coumarin-type anticoagulant effects 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)].
5.7 Pancreatitis
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.
5.8 Hematologic Changes
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 for oral use administration.
5.9 Hypersensitivity Reactions
Acute hypersensitivity reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrates. 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.
5.10 Venothromboembolic Disease
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).
5.11 Paradoxical Decreases in HDL Cholesterol Levels
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.
Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
Adverse Reactions ⮝
6.1 Clinical Trials Experience
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 the rates observed in practice.
Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1 below. Adverse events 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.
* Dosage equivalent to 145 mg Fenofibrate tablets for oral use.
** Significantly different from Placebo.
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 Fenofibrate* Placebo
Adverse Reaction (N=439) (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 Function Tests 7.5%** 1.4%
Increased ALT 3.0% 1.6%
Increased CPK 3.0% 1.4%
Increased AST 3.4%** 0.5%
RESPIRATORY
Respiratory Disorder 6.2% 5.5%
Rhinitis 2.3% 1.1%6.2 Postmarketing Experience
The following adverse reactions have been identified during postapproval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL-cholesterol levels. 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.
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Drug Interactions ⮝
7.1 Coumarin Anticoagulants
Potentiation of coumarin-type anticoagulant effects has been observed with prolongation of the PT/INR.
Caution should be exercised when coumarin anticoagulants are given in conjunction with Fenofibrate tablets for oral use. 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 [see Warnings and Precautions (5.6)].
7.2 Immunosuppressants
Immunosuppessants 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 for oral use, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using Fenofibrate tablets for oral use with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed and renal function monitored.
7.3 Bile Acid Binding Resins
Since bile acid binding resins may bind other drugs given concurrently, patients should take Fenofibrate tablets for oral use at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption.
7.4 Colchicine
Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.
Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
Use In Specific Populations ⮝
8.1 Pregnancy
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 MRHD, based on body surface area comparisons; mg/m2.
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/m2). 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/m2). No developmental findings were observed at 15 mg/kg/day (at less than 1 times the MRHD, based on body surface area comparisons; mg/m2).
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 maximum recommended human dose (MRHD), based on body surface area comparisons; mg/m2.
8.3 Nursing Mothers
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.
8.4 Pediatric Use
Safety and effectiveness have not been established in pediatric patients.
8.5 Geriatric Use
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 for oral use.
8.6 Renal Impairment
The use of Fenofibrate tablets for oral use should be avoided in patients who have 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.
8.7 Hepatic Impairment
The use of Fenofibrate tablets for oral use has not been evaluated in subjects with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3)].
Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
Overdosage ⮝
There is no specific treatment for overdose with Fenofibrate tablets for oral use. 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.
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Description ⮝
Fenofibrate tablets for oral use are a lipid regulating agent available as tablets for oral administration. Each tablet contains 48 mg or 145 mg of fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:
Tricor structureThe empirical formula is C20H21O4Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79-82 C. Fenofibrate is a white solid which is stable under ordinary conditions.
Inactive Ingredients
Each tablet contains hypromellose 2910 (3 cps), docusate sodium, sucrose, sodium lauryl sulfate, lactose monohydrate, silicified microcrystalline cellulose, crospovidone, and magnesium stearate.
In addition, individual tablets contain:
48 mg tablets
polyvinyl alcohol, titanium dioxide, talc, soybean lecithin, xanthan gum, D&C Yellow #10 aluminum lake, FD&C Yellow #6 /sunset yellow FCF aluminum lake, FD&C Blue #2 /indigo carmine aluminum lake.
145 mg tablets
polyvinyl alcohol, titanium dioxide, talc, soybean lecithin, xanthan gum.
Please see full information on Fenofibrate 145mg Zydus Pharmaceuticals at Permanent Link: http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=1c3696b1-23c1-2992-86a0-c0882b81048d
Clinical Pharmacology ⮝
12.1 Mechanism of Action
The active moiety of Fenofibrate tablets for oral use 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-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 peroxisome proliferator activated receptor (PPAR ). 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 PPAR also induces an increase in the synthesis of apolipoproteins 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.
12.2 Pharmacodynamics
A variety of clinical studies have demonstrated that elevated levels of total-C, LDL-C, and apo B, an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with 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 triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined.
Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apolipoproteins apoAI and apoAII.
12.3 Pharmacokinetics
Plasma concentrations of fenofibric acid after administration of three 48 mg or one 145 mg tablets are equivalent under fed conditions to one 200 mg micronized fenofibrate capsule.
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.
Absorption
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.
Exposure to fenofibric acid in plasma, as measured by Cmax and AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.
Distribution
Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady state are approximately double of those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
Metabolism
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.
Elimination
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.
Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily dosing.
Special Populations
Geriatrics
In elderly 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 elderly with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.5) and Use in Specific Populations (8.5)].
Pediatrics
The pharmacokinetics of Fenofibrate tablets for oral use has not been studied in pediatric populations.
Gender
No pharmacokinetic difference between males and females has been observed for fenofibrate.
Race
The influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability.
Renal Impairment
The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate, and severe renal impairment. Patients with severe renal impairment (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73m2) showed 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 (eGFR 30-59 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 Fenofibrate tablets for oral use should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment [see Dosage and Administration (2.4)].
Hepatic Impairment
No pharmacokinetic studies have been conducted in patients with hepatic impairment.
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 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibrate or fenofibric acid on other drugs.
Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration
Co-AdministeredDrug 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 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 agents
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 Fenofibrate tablets for oral use
2 Fenofibrate oral micronized capsule
1 Fenofibrate tablets for oral use
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Nonclinical Toxicology ⮝
13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility
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/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 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/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, 45, and 200 mg/kg/day (approximately 0.2, 1, 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, 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/m2 surface area comparisons).
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Clinical Studies ⮝
14.1 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia
The effects of fenofibrate at a dose equivalent to 145 mg Fenofibrate tablets for oral use 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 tablets for oral use therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate tablets for oral use therapy also lowered triglycerides and raised HDL-C (see Table 4).
Duration of study treatment was 3 to 6 months.
* p = < 0.05 vs. Placebo
Table 4. Mean Percent Change in Lipid Parameters at End of Treatment
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%* -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
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
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%In a subset of the subjects, measurements of apo B were conducted. Fenofibrate tablets for oral use 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).
14.2 Severe Hypertriglyceridemia
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 Fenofibrate tablets for oral use 145 mg 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).
* =p < 0.05 vs. Placebo
Table 5. Effects of Fenofibrate tablets for oral use in Patients With Severe Hypertriglyceridemia
Study 1 Placebo Fenofibrate tablets for oral use
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*
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 tablets for oral use
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*The effect of Fenofibrate tablets for oral use on cardiovascular morbidity and mortality has not been determined.
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How Supplied/storage And Handling ⮝
Fenofibrate tablets for oral use are available in two strengths:
48 mg yellow tablets, imprinted with the a logo and the code identification letters "FI", available in bottles of 90 (NDC 68382-228-16).
145 mg white tablets, imprinted with the a logo and the code identification letters "FO", available in bottles of 90 (NDC 68382-230-16).
Storage
Store at 25 C (77 F); excursions permitted to 15-30 C (59-86 F).
[See USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture.
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Package Label ⮝
NDC: 51655-902-52
MFG: 68382-230-16
Fenofibrate 145mg
30 Tablets
Rx Only
Lot #:
Exp. Date:
Each tablet contains: 145mg of fenofibrate
Dosage: See package insert
Store at 77 degrees F. Excursions permitted to 59-86 F. Protect from moisture.
Store in a USP tight container. Keep out of the reach of children.
Medication guide is found at www.fda.gov/drugs/drugsafety/ucm085729
Mfg by: Fournier Laboratories Ireland Limited Anngrove, Carrigtowhill Co, Cork, Ireland
Dist by: Zydus Pharmaceuticals USA Inc Pennington, NJ 08534
Lot: 04-B351-R1 (List 6123)
Repackaged by: Northwind Pharmaceuticals, Indianapolis, IN 46256
FENOFIBRATE
fenofibrate tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:51655-902(NDC:68382-230) Route of Administration ORAL
Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRATE - UNII:U202363UOS) FENOFIBRATE 145 mg
Inactive Ingredients Ingredient Name Strength TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TALC (UNII: 7SEV7J4R1U) XANTHAN GUM (UNII: TTV12P4NEE) DOCUSATE SODIUM (UNII: F05Q2T2JA0) SUCROSE (UNII: C151H8M554) SODIUM LAURYL SULFATE (UNII: 368GB5141J) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) CROSPOVIDONE (UNII: 68401960MK) MAGNESIUM STEARATE (UNII: 70097M6I30) HYPROMELLOSES (UNII: 3NXW29V3WO) POLYVINYL ALCOHOL (UNII: 532B59J990) LECITHIN, SOYBEAN (UNII: 1DI56QDM62)
Product Characteristics Color white Score no score Shape OVAL Size 18mm Flavor Imprint Code FO Contains
Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:51655-902-52 30 in 1 BOTTLE, DISPENSING; Type 0: Not a Combination Product
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021656 04/28/2015
Labeler - NORTHWIND PHARMACEUTICALS (036986393)
Registrant - NORTHWIND PHARMACEUTICALS (036986393)
Establishment Name Address ID/FEI Business Operations NORTHWIND PHARMACEUTICALS 036986393 repack(51655-902) Revised: 4/2015 Document Id: d7f3051c-ff67-40ab-962a-6f03e8d3a4a1 34391-3 Set id: 5b988a9b-04a0-4be7-8936-70edba261bf8 Version: 1 Effective Time: 20150430 NORTHWIND PHARMACEUTICALS
Fenofibrate Tablets, 54 Mg And 160 Mg ⮝
Rx only
No Title 1572453074 ⮝
Rx only
Description ⮝
Fenofibrate tablets is a lipid regulating agent available as tablets for oral administration. Each tablet contains 54 mg or 160 mg of fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methylpropanoic acid, 1-methylethyl ester with the following structural formula:
The molecular formula is C20H21O4Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79-82 C. Fenofibrate is a white solid which is stable under ordinary conditions.
Each tablet also contains the following inactive ingredients: croscarmellose sodium, NF; hypromellose type 2208/100,000 cP, USP; magnesium sulfate, NF; and microcrystalline cellulose, NF. The film-coating material contains hypromellose type 2910/ 3 cP, 6 cP and 50 cP, macrogol, polydextrose, titanium dioxide and triacetin.
Clinical Pharmacology ⮝
A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with level of total-C, LDL-C, and triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering triglycerides (TG) on the risk of cardiovascular morbidity and mortality has not been determined.
Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides and triglyceride rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins apoAI and apoAII.
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 (PPAR ). 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 PPAR 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.
Pharmacokinetics/Metabolism
Plasma concentrations of fenofibric acid after administration of 160 mg tablets are equivalent under fed conditions to 200 mg tablets, respectively.
Absorption
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.
The absorption of fenofibrate is increased when administered with food. With fenofibrate, the absorption is increased by approximately 35% under fed as compared to fasting conditions.
Distribution
In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of dosing and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.
Metabolism
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.
Excretion
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.
Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration in a clinical setting.
Special Populations
Geriatrics
In elderly 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 the elderly, without increasing accumulation of the drug or metabolites.
Pediatrics
Fenofibrate tablets have not been investigated in adequate and well-controlled trials in pediatric patients.
Gender
No pharmacokinetic difference between males and females has been observed for fenofibrate.
Race
The influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. Therefore, inter-ethnic pharmacokinetic differences are very unlikely.
Renal Insufficiency
In a study in patients with severe renal impairment (creatinine clearance <50 mL/min), the rate of clearance of fenofibric acid was greatly reduced, and the compound accumulated during chronic dosage. However, in patients having moderate renal impairment (creatinine clearance of 50 to 90 mL/min), the oral clearance and the oral volume of distribution of fenofibric acid are increased compared to healthy adults (2.1 L/h and 95 L versus 1.1 L/h and 30 L, respectively). Therefore, the dosage of fenofibrate tablets should be minimized in patients who have severe renal impairment, while no modification of dosage is required in patients having moderate renal impairment.
Hepatic Insufficiency
No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.
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 CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
Potentiation of coumarin-type anticoagulants has been observed with prolongation of the prothrombin time/INR.
Bile acid sequestrants have been shown to bind other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption (see WARNINGS and PRECAUTIONS).
Clinical Trials
Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
The effects of fenofibrate at a dose equivalent to 160 mg fenofibrate tablet 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 tablets therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate tablets therapy also lowered triglycerides and raised HDL-C (see Table 1).
Table 1 Mean Percent Change in Lipid Parameters at End of Treatment* Treatment Group Total-C LDL-C HDL-C TG
- *
- Duration of study treatment was 3 to 6 months
- p=<0.05 vs. Placebo
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% -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% In a subset of the subjects, measurements of apo B were conducted.
Fenofibrate tablets 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).
Hypertriglyceridemia (Fredrickson Type IV and V)
The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials1 of 147 hypertriglyceridemic patients (Fredrickson Types IV and V). Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline triglyceride (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 (Type IV/V hyperlipidemia), treatment with fenofibrate at dosages equivalent to 160 mg fenofibrate tablet per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2).
Table 2 Effects of Fenofibrate Tablets in Patients With Fredrickson Type IV/V Hyperlipidemia
- *
- = p<0.05 vs. Placebo
Study 1 Placebo Fenofibrate Tablets 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* 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 Tablets 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* The effect of fenofibrate tablets on cardiovascular morbidity and mortality has not been determined.
Indications And Usage ⮝
Treatment of Hypercholesterolemia
Fenofibrate tablets are indicated as adjunctive therapy to diet for the reduction of LDL-C, Total-C, Triglycerides and Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb). Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate (see National Cholesterol Education Program [NCEP] Treatment Guidelines, below).
Treatment of Hypertriglyceridemia
Fenofibrate tablets are also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia). 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.
Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV and V hyperlipoproteinemia2.
The initial treatment of 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, like thiazide diuretics and beta-blockers, is 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.
The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet (see WARNINGS and PRECAUTIONS).
Fredrickson Classification of Hyperlipoproteinemias Type Lipoprotein Elevated Lipid Elevation Major Minor C = cholesterol
TG = triglycerides
LDL = low density lipoprotein
VLDL = very low density lipoprotein
IDL = intermediate density lipoproteinI (rare) chylomicrons TG C IIa LDL C - IIb LDL, VLDL C TG III (rare) IDL C, TG - IV VLDL TG C V (rare) chylomicrons TG
The NCEP Treatment Guidelines: LDL-C Goals and Cutpoints for Therapeutic Lifestyle Changes and Drug Therapy in Different Risk Categories LDL Level at Which to Initiate which to Consider Therapeutic Lifestyle
(mg/ dL)LDL Level at Which to Initiate which to Consider Drug Therapy
(mg/ dL)Risk Category LDL Goal
(mg/dL)
- *
- CHD = coronary heart disease
- Some authorities recommend use of LDL-lowering drugs in this category if an LDL-C level of < 100 mg/dL cannot be achieved by therapeutic lifestyle changes. Others prefer use of drugs that primarily modify triglycerides and HDL-C, e.g., nicotinic acid or fibrate. Clinical judgment also may call for deferring drug therapy in this subcategory.
- Almost all people with 0 to 1 risk factor have 10 year risk < 10 %; thus 10 year risk assessment in people with 0 to 1 risk factor is not necessary. After the LDL-C goal has been achieved, if the TG is still > 200 mg/dL, non HDL-C (Total-C minus HDL-C) becomes a secondary target of therapy. Non-HDL-C goals are set 30 mg/dL higher than LDL-C goals for each risk category.
CHD* or CHD risk equivalents (10-years risk > 20%) < 100 100 130
(100-129:drug optional)2+ Risk Factors (10-year risk 20%) < 130 130 10-year risk
10%- 20%: 130
10-year risk
< 10%: 1600 to 1 Risk Factor < 160 160 190
(160-189: LDL-lowering drug optional)
Contraindications ⮝
Fenofibrate tablets are contraindicated in patients who exhibit hypersensitivity to fenofibrate.
Fenofibrate tablets are contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality.
Fenofibrate tablets are contraindicated in patients with preexisting gallbladder disease (see WARNINGS).
Warnings ⮝
Liver Function
Fenofibrate at doses equivalent to 107 mg to 160 mg fenofibrate tablets per day 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 transaminase related to fenofibrate therapy appear 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 107 mg to 160 mg fenofibrate tablets per day. Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.
Regular periodic monitoring of liver function, 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.
Cholelithiasis
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.
Concomitant Oral Anticoagulants
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/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.
Concomitant HMG-CoA reductase inhibitors
The combined use of fenofibrate tablets and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination.
In a single-dose drug interaction study in 23 healthy adults the concomitant administration of fenofibrate tablets and pravastatin resulted in no clinically important difference in the pharmacokinetics of fenofibric acid, pravastatin or its active metabolite 3a-hydroxy iso-pravastatin when compared to either drug given alone.
The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absence of a marked pharmacokinetic interaction, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure.
The use of fibrates alone, including fenofibrate tablets, may occasionally be associated with myositis, myopathy, or rhabdomyolysis. Patients receiving fenofibrate tablets and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination. If myopathy/myositis is suspected or diagnosed, fenofibrate tablets therapy should be stopped.
Mortality
The effect of fenofibrate tablets on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.
Other Considerations
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%).
Because of chemical, pharmacological, and clinical similarities between fenofibrate tablets, Atromid-S (clofibrate), and Lopid (gemfibrozil), the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate tablets.
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=4081) 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 World Health Organization study (RR=1.29). Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study.
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). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, p=0.07). There was a statistically significant difference in the number of appendectomies in the gemfibrozil group (6/311 vs. 0/317, p=0.029).
Precautions ⮝
General
Initial Therapy
Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate tablets therapy. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy.
Continued therapy
Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of fenofibrate tablets. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 160 mg per day.
Pancreatitis
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.
Hypersensitivity Reactions
Acute hypersensitivity reactions including severe skin rashes requiring patient hospitalization and treatment with steroids have occurred very rarely during treatment with fenofibrate, including rare spontaneous reports of Stevens-Johnson syndrome, and toxic epidermal necrolysis. 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.
Hematologic Changes
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. Extremely rare spontaneous reports of thrombocytopenia and agranulocytosis have been received during post-marketing surveillance outside of the U.S. Periodic blood counts are recommended during the first 12 months of fenofibrate tablets administration.
Skeletal muscle
The use of fibrates alone, including fenofibrate tablets, may occasionally be associated with myopathy. Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase 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 therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed.
Drug Interactions
Oral Anticoagulants
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 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 LEVEL HAS STABILIZED.
HMG-CoA reductase inhibitors
The combined use of fenofibrate tablets and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination (see WARNINGS).
Resins
Since bile acid sequestrants 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.
Cyclosporine
Because cyclosporine 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.
The benefits and risks of using fenofibrate tablets with immunosuppresants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a 24-month study in rats (10, 45, and 200 mg/kg; 0.3, 1, and 6 times the maximum recommended human dose on the basis of mg/meter2 of surface area), the incidence of liver carcinoma was significantly increased at 6 times the maximum recommended human dose in males and females. A statistically significant increase in pancreatic carcinomas occurred in males at 1 and 6 times the maximum recommended human dose; there were also increases in pancreatic adenomas and benign testicular interstitial cell tumors at 6 times the maximum recommended human dose in males. In a second 24-month study in a different strain of rats (doses of 10 and 60 mg/kg; 0.3 and 2 times the maximum recommended human dose based on mg/meter2 surface area), there were significant increases in the incidence of pancreatic acinar adenomas in both sexes and increases in interstitial cell tumors of the testes at 2 times the maximum recommended human dose.
A comparative carcinogenicity study was done in rats comparing three drugs: fenofibrate (10 and 70 mg/kg; 0.3 and 1.6 times the maximum recommended human dose), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250 mg/kg; 1.7 times the human dose) (multiples based on mg/meter2 surface area). Pancreatic acinar adenomas were increased in males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar adenomas were increased in males and hepatic neoplastic nodules in females treated with clofibrate; hepatic neoplastic nodules were increased in males and females treated with gemfibrozil while testicular interstitial cell tumors were increased in males on all three drugs.
In a 21-month study in mice at doses of 10, 45, and 200 mg/kg (approximately 0.2, 0.7 and 3 times the maximum recommended human dose on the basis of mg/meter2 surface area), there were statistically significant increases in liver carcinoma at 3 times the maximum recommended human dose in both males and females. In a second 18-month study at the same doses, there was a significant increase in liver carcinoma in male mice and liver adenoma in female mice at 3 times the maximum recommended human dose.
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.
Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis.
Pregnancy
Teratogenic Effects
Pregnancy Category C
Fenofibrate has been shown to be embryocidal and teratogenic in rats when given in doses 7 to 10 times the maximum recommended human dose and embryocidal in rabbits when given at 9 times the maximum recommended human dose (on the basis of mg/meter2 surface area). There are no adequate and wellcontrolled studies in pregnant women. Fenofibrate should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Administration of 9 times the maximum recommended human dose of fenofibrate to female rats before and throughout gestation caused 100% of dams to delay delivery and resulted in a 60% increase in post-implantation loss, a decrease in litter size, a decrease in birth weight, a 40% survival of pups at birth, a 4% survival of pups as neonates, and a 0% survival of pups to weaning, and an increase in spina bifida.
Administration of 10 times the maximum recommended human dose to female rats on days 6 15 of gestation caused an increase in gross, visceral and skeletal findings in fetuses (domed head/hunched shoulders/rounded body/abnormal chest, kyphosis, stunted fetuses, elongated sternal ribs, malformed sternebrae, extra foramen in palatine, misshapen vertebrae, supernumerary ribs).
Administration of 7 times the maximum recommended human dose to female rats from day 15 of gestation through weaning caused a delay in delivery, a 40% decrease in live births, a 75% decrease in neonatal survival, and decreases in pup weight, at birth as well as on days 4 and 21 post-partum.
Administration of 9 and 18 times the maximum recommended human dose to female rabbits caused abortions in 10% of dams at 9 times and 25% of dams at 18 times the maximum recommended human dose and death of 7% of fetuses at 18 times the maximum recommended human dose.
Nursing mothers
Fenofibrate should not be used in nursing mothers. Because of the potential for tumorigenicity seen in animal studies, a decision should be made whether to discontinue nursing or to discontinue the drug.
Pediatric Use
Safety and efficacy in pediatric patients have not been established.
Geriatric Use
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. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection.
Adverse Reactions ⮝
CLINICAL
Adverse events reported by 2% or more of patients treated with fenofibrate during the double-blind, placebo-controlled trials, regardless of causality, are listed in the table below. Adverse events led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases in liver function test were the most frequent events, causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.
BODY SYSTEM Fenofibrate* PLACEBO Adverse Event (N=439) (N=365)
- *
- Dosage equivalent to 200 mg fenofibrate tablets.
- Significantly different from Placebo
BODY AS A WHOLE Abdominal Pain 4.6% 4.4% Back Pain 3.4% 2.5% Headache 3.2% 2.7% Asthenia 2.1% 3.0% Flu Syndrome 2.1% 2.7% DIGESTIVE Liver Function Test Abnormal 7.5% 1.4% Diarrhea 2.3% 4.1% Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC AND NUTRITIONAL DISORDERS SGPT Increased 3.0% 1.6% Creatine Phophokinase
Increased3.0% 1.4% SGOT Increased 3.4% 0.5% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% Additional adverse events reported by three or more patients in placebo-controlled trials or reported in other controlled or open trials, regardless of causality are listed below.
BODY AS A WHOLE: Chest pain, pain (unspecified), infection, malaise, allergic reaction, cyst, hernia, fever, photosensitivity reaction, and accidental injury.
CARDIOVASCULAR SYSTEM: Angina pectoris, hypertension, vasodilatation, coronary artery disorder, electrocardiogram abnormal, ventricular extrasystoles, myocardial infarct, peripheral vascular disorder, migraine, varicose vein, cardiovascular disorder, hypotension, palpitation, vascular disorder, arrhythmia, phlebitis, tachycardia, extrasystoles, and atrial fibrillation.
DIGESTIVE SYSTEM: Dyspepsia, flatulence, nausea, increased appetite, gastroenteritis, cholelithiasis, rectal disorder, esophagitis, gastritis, colitis, tooth disorder, vomiting, anorexia, gastrointestinal disorder, duodenal ulcer, nausea and vomiting, peptic ulcer, rectal hemorrhage, liver fatty deposit, cholecystitis, eructation, gamma glutamyl transpeptidase, and diarrhea.
ENDOCRINE SYSTEM: Diabetes mellitus
HEMIC AND LYMPHATIC SYSTEM: Anemia, leukopenia, ecchymosis, eosinophilia, lymphadenopathy, and thrombocytopenia.
METABOLIC AND NUTRITIONAL DISORDERS: Creatinine increased, weight gain, hypoglycemia, gout, weight loss, edema, hyperuricemia, and peripheral edema.
MUSCULOSKELETAL SYSTEM: Myositis, myalgia, arthralgia, arthritis, tenosynovitis, joint disorder, arthrosis, leg cramps, bursitis, and myasthenia.
NERVOUS SYSTEM: Dizziness, insomnia, depression, vertigo, libido decreased, anxiety, paresthesia, dry mouth, hypertonia, nervousness, neuralgia, and somnolence.
RESPIRATORY SYSTEM: Pharyngitis, bronchitis, cough increased, dyspnea, asthma, pneumonia, laryngitis, and sinusitis.
SKIN AND APPENDAGES: Rash, pruritus, eczema, herpes zoster, urticaria, acne, sweating, fungal dermatitis, skin disorder, alopecia, contact dermatitis, herpes simplex, maculopapular rash, nail disorder, and skin ulcer.
SPECIAL SENSES: Conjunctivitis, eye disorder, amblyopia, ear pain, otitis media, abnormal vision, cataract specified, and refraction disorder.
UROGENITAL SYSTEM: Urinary frequency, prostatic disorder, dysuria, kidney function abnormal, urolithiasis, gynecomastia, unintended pregnancy, vaginal moniliasis, and cystitis.
Overdosage ⮝
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.
Dosage And Administration ⮝
Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate tablets, and should continue this diet during treatment with fenofibrate tablets. Fenofibrate tablets should be given with meals, thereby optimizing the bioavailability of the medication.
For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of fenofibrate tablets is 160 mg per day.
For adult patients with hypertriglyceridemia, the initial dose is 54 to 160 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 160 mg per day.
Treatment with fenofibrate tablets should be initiated at a dose of 54 mg/day in patients having impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. In the elderly, the initial dose should likewise be limited to 54 mg/day.
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.
How Supplied ⮝
Fenofibrate tablet, 54 mg are yellow, film-coated, oval shape tablets debossed with "G" on one side and "351" on the other side.
Bottles of 30
NDC 54868-5697-1
Bottles of 90
NDC 54868-5697-0
Fenofibrate tablet, 160 mg are white to off-white, film-coated, modified capsule shaped tablets, debossed with "G352" on one side and plain on the other side.
Bottles of 30
NDC 54868-5660-0
Bottles of 90
NDC 54868-5660-1
Store at 20 to 25 C (68 to 77 F) (see USP Controlled Room Temperature).
Keep out of reach of children. Protect from moisture.
Dispense in tightly-closed, light-resistant container as defined in the USP, with a child-resistant closure, as required.
References ⮝
- GOLDBERG AC, et al. Fenofibrate for the Treatment of Type IV and V Hyperlipoproteinemias: A Double-Blind, Placebo-Controlled Multicenter US Study. Clinical Therapeutics, 11, pp. 69 83, 1989.
- NIKKILA EA, Familial Lipoprotein Lipase Deficiency and Related Disorders of Chylomicron Metabolism. In Stanbury J.B., et al. (eds.): The Metabolic Basis of Inherited Disease, 5th edition, McGraw-Hill, 1983, Chap. 30, pp. 622 642.
- BROWN WV, et al. Effects of Fenofibrate on Plasma Lipids: Double-Blind, Multicenter Study In Patients with Type IIA or IIB Hyperlipidemia. Arteriosclerosis. 6, pp.670 678, 1986.
Dist. by:
Global Pharmaceuticals
Division of IMPAX Laboratories, Inc.
Philadelphia, PA 19124Rev. 10/09
295-05
Relabeling and Repackaging by:
Physicians Total Care, Inc.
Tulsa, OK 74146
Principal Display Panel - 54 Mg Tablet Bottle Label ⮝
FenofibrateTablets
54 mg*
Rx only
Principal Display Panel - 160 Mg Tablet Bottle Label ⮝
FenofibrateTablets
160 mg*
Rx only
FENOFIBRATE
fenofibrate tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-5697(NDC:0115-5511) Route of Administration ORAL
Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRATE - UNII:U202363UOS) FENOFIBRATE 54 mg
Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSES (UNII: 3NXW29V3WO) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) HYPROMELLOSE 2910 (3 MPA.S) (UNII: 0VUT3PMY82) HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6) HYPROMELLOSE 2910 (50 MPA.S) (UNII: 1IVH67816N) POLYETHYLENE GLYCOL (UNII: 3WJQ0SDW1A) POLYDEXTROSE (UNII: VH2XOU12IE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)
Product Characteristics Color yellow Score score with uneven pieces Shape OVAL Size 9mm Flavor Imprint Code G;351 Contains
Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-5697-0 90 in 1 BOTTLE, PLASTIC 2 NDC:54868-5697-1 30 in 1 BOTTLE, PLASTIC
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076509 11/15/2006
FENOFIBRATE
fenofibrate tablet
Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:54868-5660(NDC:0115-5522) Route of Administration ORAL
Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRATE - UNII:U202363UOS) FENOFIBRATE 160 mg
Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSES (UNII: 3NXW29V3WO) MAGNESIUM STEARATE (UNII: 70097M6I30) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) HYPROMELLOSE 2910 (3 MPA.S) (UNII: 0VUT3PMY82) HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6) HYPROMELLOSE 2910 (50 MPA.S) (UNII: 1IVH67816N) POLYETHYLENE GLYCOL (UNII: 3WJQ0SDW1A) POLYDEXTROSE (UNII: VH2XOU12IE) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) TRIACETIN (UNII: XHX3C3X673)
Product Characteristics Color white Score score with uneven pieces Shape OVAL Size 15mm Flavor Imprint Code G;352 Contains
Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:54868-5660-0 30 in 1 BOTTLE, PLASTIC 2 NDC:54868-5660-1 90 in 1 BOTTLE, PLASTIC
Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA076509 08/23/2006
Labeler - Physicians Total Care, Inc. (194123980)
Establishment Name Address ID/FEI Business Operations Physicians Total Care, Inc. 194123980 relabel, repack Revised: 5/2010 Document Id: 80ae2eaf-98af-4ca0-b6f8-d4ceb2c01e2b 34391-3 Set id: 2e51aa89-684d-451e-b513-12b00bf9aea0 Version: 2 Effective Time: 20100525 Physicians Total Care, Inc.
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