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FDA Drug information

Lipofen

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Marketing start date: 22 Jul 2024

Summary of product characteristics


Adverse Reactions

6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Mortality and coronary heart disease morbidity [see Warnings and Precautions (5.1) ] Hepatoxicity [see Warnings and Precautions (5.2) ] Pancreatitis [see Warnings and Precautions (5.7) ] Hypersensitivity reactions [see Warnings and Precautions (5.9) ] Venothromboembolic disease [see Warnings and Precautions (5.10) ] The most common adverse reactions (incidence of > 2% and at least 1% greater than placebo) are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis ( 6 ). To report SUSPECTED ADVERSE REACTIONS, contact ANI Pharmaceuticals, Inc. at 1-800-308-6755 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rate observed in clinical practice. Adverse reactions 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. 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 Event Fenofibrate Dosage equivalent to 150 mg LIPOFEN (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 Abnormal Liver Function Tests 7.5% Significantly different from placebo 1.4% Nausea 2.3% 1.9% Constipation 2.1% 1.4% METABOLIC AND NUTRITIONAL DISORDERS Increased ALT 3.0% 1.6% Creatine Phosphokinase Increased 3.0% 1.4% Increased AST 3.4% 0.5% RESPIRATORY Respiratory Disorder 6.2% 5.5% Rhinitis 2.3% 1.1% Urticaria was seen in 1.1 vs. 0% and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials. Increases in Liver Enzymes In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate at doses equivalent to 100 mg to 150 mg LIPOFEN daily versus 1.1% of patients treated with placebo. 6.2 Postmarketing Experience 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 spasm, hepatitis, cirrhosis, increased total bilirubin, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, severely depressed HDL-cholesterol levels, and interstitial lung disease. Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.

Contraindications

4 CONTRAINDICATIONS LIPOFEN is 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 (5.2) ] . Patients with preexisting gallbladder disease [see Warnings and Precautions (5.5) ] . Patients with known hypersensitivity to fenofibrate or fenofibric acid [see Warnings and Precautions (5.9) ] . Nursing mothers [see Use in Specific Populations (8.2) ] . Severe renal impairment, including patients receiving dialysis ( 4 , 8.6 , 12.3 ) Active liver disease ( 4 , 5.3 ) Gallbladder disease ( 4 , 5.5 ) Known hypersensitivity to fenofibrate or fenofibric acid ( 4 ) Nursing mothers ( 4 , 8.2 )

Description

11 DESCRIPTION LIPOFEN ® (fenofibrate capsules, USP), is a lipid regulating agent available as hard gelatin capsules for oral administration. Each hard gelatin capsule contains 50 or 150 mg of fenofibrate USP. 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 C 20 H 21 O 4 Cl 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. LIPOFEN (fenofibrate capsules, USP) meets USP Dissolution Test 2. Inactive Ingredients: Each hard gelatin capsule contains Gelucire 44/14 (lauroyl macrogol glyceride type 1500), polyethylene glycol 20,000, polyethylene glycol 8000, hydroxypropylcellulose, sodium starch glycolate, gelatin, titanium dioxide, shellac, propylene glycol, may also contain black iron oxide, FD&C Blue #1, FD&C Blue #2, FD&C Red #40, D&C Yellow #10. Chemical Structure

Dosage And Administration

2 DOSAGE AND ADMINISTRATION Primary hypercholesterolemia or mixed dyslipidemia: 150 mg per day ( 2.2 ) Severe Hypertriglyceridemia: 50 to 150 mg per day; adjust the dose according to patient response ( 2.3 ) Renally impaired patients: 50 mg per day; increase the dose according to the effect on renal function and lipid levels ( 2.4 ) Geriatric patients: select the dose based on renal function ( 2.5 ) The maximum daily dose is 150 mg per day ( 2.3 ) 2.1 General Considerations LIPOFEN capsules should be given with meals thereby optimizing the absorption of the medication. Patients should be advised to swallow LIPOFEN capsules whole. Do not open, crush, dissolve or chew capsules. Patients should be placed on an appropriate lipid-lowering diet before receiving LIPOFEN, and should continue this diet during treatment with LIPOFEN. 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. Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of LIPOFEN. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 150 mg per day. Consideration should be given to reducing the dosage of LIPOFEN if lipid levels fall significantly below the targeted range. 2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia The dose of LIPOFEN is 150 mg once daily. 2.3 Severe Hypertriglyceridemia The initial dose is 50 to 150 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determination at 4 to 8 week intervals. The maximum dose of LIPOFEN is 150 mg once daily. 2.4 Impaired Renal Function In patients with mild-to-moderate renal impairment, treatment with LIPOFEN should be initiated at a dose of 50 mg per day, and increased only after evaluation of the effects on renal function and lipid levels at this dose. The use of LIPOFEN 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) and Clinical Pharmacology (12.3) ] .

Indications And Usage

1 INDICATIONS AND USAGE LIPOFEN is a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as an adjunct to diet: To reduce elevated LDL-C, total-c, TG and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia ( 1.1 ) To reduce triglycerides in adult patients with severe hypertriglyceridemia ( 1.2 ) Important Limitations of Use: Fenofibrate at a dose equivalent to 150 mg of LIPOFEN was not shown to reduce coronary heart disease morbidity and mortality in a large, randomized controlled trial of patients with type 2 diabetes mellitus ( 5.1 ) 1.1 Primary Hypercholesterolemia or Mixed Dyslipidemia LIPOFEN is indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (total-c), Triglycerides (TG) and apolopoprotein 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 LIPOFEN 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 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 150 mg of LIPOFEN was not shown to reduce coronary heart disease morbidity and mortality in 2 large, randomized controlled trials of patients with type 2 diabetes mellitus [see Warnings and Precautions (5.1) ] .

Overdosage

10 OVERDOSAGE There is no specific treatment for overdose with LIPOFEN. 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. The usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.

Adverse Reactions Table

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 EventFenofibrateDosage equivalent to 150 mg LIPOFEN (N=439)Placebo (N=365)
BODY AS A WHOLE
Abdominal Pain4.6%4.4%
Back Pain3.4%2.5%
Headache3.2%2.7%
DIGESTIVE
Abnormal Liver Function Tests 7.5%Significantly different from placebo1.4%
Nausea2.3%1.9%
Constipation2.1%1.4%
METABOLIC AND NUTRITIONAL DISORDERS
Increased ALT3.0%1.6%
Creatine Phosphokinase Increased3.0%1.4%
Increased AST3.4%0.5%
RESPIRATORY
Respiratory Disorder6.2%5.5%
Rhinitis2.3%1.1%

Drug Interactions

7 DRUG INTERACTIONS Coumarin-type anticoagulants ( 7.1 ) Immunosuppressants ( 7.2 ) Bile acid binding resins ( 7.3 ) Colchicine ( 7.4 ) 7.1 Coumarin Anticoagulants Potentiation of coumarin-type anticoagulant effect has been observed with prolongation of the PT/INR. Caution should be exercised when LIPOFEN is given in conjunction with coumarin anticoagulants. LIPOFEN may potentiate the anticoagulant effect of these agents resulting in prolongation of the PT/INR. To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the oral anticoagulant as recommended until the PT/INR has stabilized [see Warnings and Precautions (5.6) ] . 7.2 Immunosuppressants Immunosuppressant agents such as cyclosporine and tacrolimus can impair renal function and because renal excretion is the primary elimination route of fibrate drugs including LIPOFEN, there is a risk that an interaction will lead to deterioration of renal function. When immunosuppressants and other potentially nephrotoxic agents are co-administered with LIPOFEN, the lowest effective dose of LIPOFEN should be employed and renal function should be monitored. 7.3 Bile-Acid Binding Resins Since bile-acid binding resins may bind other drugs given concurrently, patients should take LIPOFEN 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.

Clinical Pharmacology

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action The active moiety of LIPOFEN 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 α (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 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 PPARα also induces an increase in the synthesis of apolipoproteins AI, AII 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 Elevated levels of total-c, LDL-C, and apo B and decreased levels of HDL-C and its transport complex, Apo AI and Apo AII, are risk factors for atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the 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 apolipoproteins AI and AII. 12.3 Pharmacokinetics The extent and rate of absorption of fenofibric acid after administration of 150 mg LIPOFEN capsules are equivalent under low-fat and high-fat fed conditions to 160 mg TriCor ® tablets. 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. In a bioavailability study with LIPOFEN capsules 200 mg, following single-dose administration, the plasma concentration (AUC) for the parent compound fenofibrate was approximately 40 µg/mL compared to 204 µg/mL for the metabolite, fenofibric acid. In the same study, the half-life was observed to be 0.91 hrs for the parent compound versus 16.76 hrs for the metabolite. 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 radiolabeled 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 approximately 5 hours after oral administration. The absorption of fenofibrate is increased when administered with food. With LIPOFEN, the extent of absorption is increased by approximately 58% and 25% under high-fat fed and low-fat fed conditions as compared to fasting conditions, respectively. In a single dose and multiple dose bioavailability study with LIPOFEN capsules 200 mg, the extent of absorption (AUC) of fenofibric acid, the principal metabolite of fenofibrate, was 42% larger at steady state compared to single-dose administration. The rate of absorption (C max ) of fenofibric acid was 73% greater after multiple-dose than after single-dose administration. The extent of absorption of LIPOFEN in terms of AUC value of fenofibric acid increased in a less than proportional manner while the rate of absorption in terms of C max value of fenofibric acid increased proportionally related to dose. Distribution: Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved after 5 days. Plasma concentrations of fenofibric acid at steady state are slightly more than double 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; unchanged fenofibrate is detected at low concentrations in plasma compared to fenofibric acid over most of the single dose and multiple dosing periods. 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 vitro and 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 radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in feces. Fenofibric acid is eliminated with a half-life of approximately 20 hours allowing once daily dosing. Geriatrics: In elderly volunteers 77 to 87 years of age, the apparent 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 an equivalent dose of LIPOFEN can be used in elderly subjects 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: Pharmacokinetics of LIPOFEN has not been studied 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. Renal Impairment: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate and severe renal impairment. Patients with mild (estimated glomerular filtration rate eGFR 60-89 ml/min/1.73m 2 ) to moderate (eGFR 30-59 mL/min/1.73m 2 ) renal impairment had similar exposure but an increase in the half-life for fenofibric acid was observed as compared to that of healthy subjects. Patients with severe renal impairment (eGFR <30 mL/min/1.73m 2 ) showed a 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. In patients with mild to moderate renal impairment, treatment with LIPOFEN should be initiated at a dose of 50 mg per day and increased only after evaluation of the effects on renal function and lipid levels at this dose. Based on these findings, the use of LIPOFEN should be avoided in patients who have severe renal impairment. Hepatic Impairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment. Drug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome P450 (CYP) 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 fenofibrate on co-administered drugs. 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 C max Lipid-lowering agents Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg TriCor (fenofibrate) oral tablet once daily for 10 days ↓2% ↓4% Pravastatin 40 mg as a single dose Fenofibrate 3 × 67 mg TriCor (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 on Systemic Exposure of Co-Administered Drugs Dosage Regimen of Fenofibrate Dosage Regimen of Co-Administered Drug Change in Co-Administered Drug Exposure Analyte AUC C max Lipid-lowering agents Fenofibrate 160 mg TriCor (fenofibrate) oral tablet once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0% Fenofibrate 3 × 67 mg TriCor (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%

Clinical Pharmacology Table

Table 2: Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration
Co-Administered DrugDosage Regimen of Co-Administered DrugDosage Regimen of FenofibrateChanges in Fenofibric Acid Exposure
AUCCmax
Lipid-lowering agents
Atorvastatin20 mg once daily for 10 daysFenofibrate 160 mgTriCor (fenofibrate) oral tablet once daily for 10 days↓2%↓4%
Pravastatin40 mg as a single doseFenofibrate 3 × 67 mgTriCor (fenofibrate) oral micronized capsule as a single dose↓1%↓2%
Fluvastatin40 mg as a single doseFenofibrate 160 mg as a single dose↓2%↓10%
Anti-diabetic agents
Glimepiride1 mg as a single doseFenofibrate 145 mg once daily for 10 days↑1%↓1%
Metformin850 mg three times daily for 10 daysFenofibrate 54 mg three times daily for 10 days↓9%↓6%
Rosiglitazone8 mg once daily for 5 daysFenofibrate 145 mg once daily for 14 days↑10%↑3%

Mechanism Of Action

12.1 Mechanism of Action The active moiety of LIPOFEN 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 α (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 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 PPARα also induces an increase in the synthesis of apolipoproteins AI, AII and HDL cholesterol. Fenofibrate also reduces serum uric acid levels in hyperuricemic and normal individuals by increasing the urinary excretion of uric acid.

Pharmacodynamics

12.2 Pharmacodynamics Elevated levels of total-c, LDL-C, and apo B and decreased levels of HDL-C and its transport complex, Apo AI and Apo AII, are risk factors for atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the 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 apolipoproteins AI and AII.

Pharmacokinetics

12.3 Pharmacokinetics The extent and rate of absorption of fenofibric acid after administration of 150 mg LIPOFEN capsules are equivalent under low-fat and high-fat fed conditions to 160 mg TriCor ® tablets. 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. In a bioavailability study with LIPOFEN capsules 200 mg, following single-dose administration, the plasma concentration (AUC) for the parent compound fenofibrate was approximately 40 µg/mL compared to 204 µg/mL for the metabolite, fenofibric acid. In the same study, the half-life was observed to be 0.91 hrs for the parent compound versus 16.76 hrs for the metabolite. 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 radiolabeled 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 approximately 5 hours after oral administration. The absorption of fenofibrate is increased when administered with food. With LIPOFEN, the extent of absorption is increased by approximately 58% and 25% under high-fat fed and low-fat fed conditions as compared to fasting conditions, respectively. In a single dose and multiple dose bioavailability study with LIPOFEN capsules 200 mg, the extent of absorption (AUC) of fenofibric acid, the principal metabolite of fenofibrate, was 42% larger at steady state compared to single-dose administration. The rate of absorption (C max ) of fenofibric acid was 73% greater after multiple-dose than after single-dose administration. The extent of absorption of LIPOFEN in terms of AUC value of fenofibric acid increased in a less than proportional manner while the rate of absorption in terms of C max value of fenofibric acid increased proportionally related to dose. Distribution: Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved after 5 days. Plasma concentrations of fenofibric acid at steady state are slightly more than double 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; unchanged fenofibrate is detected at low concentrations in plasma compared to fenofibric acid over most of the single dose and multiple dosing periods. 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 vitro and 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 radiolabeled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in feces. Fenofibric acid is eliminated with a half-life of approximately 20 hours allowing once daily dosing. Geriatrics: In elderly volunteers 77 to 87 years of age, the apparent 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 an equivalent dose of LIPOFEN can be used in elderly subjects 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: Pharmacokinetics of LIPOFEN has not been studied 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. Renal Impairment: The pharmacokinetics of fenofibric acid was examined in patients with mild, moderate and severe renal impairment. Patients with mild (estimated glomerular filtration rate eGFR 60-89 ml/min/1.73m 2 ) to moderate (eGFR 30-59 mL/min/1.73m 2 ) renal impairment had similar exposure but an increase in the half-life for fenofibric acid was observed as compared to that of healthy subjects. Patients with severe renal impairment (eGFR <30 mL/min/1.73m 2 ) showed a 2.7-fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. In patients with mild to moderate renal impairment, treatment with LIPOFEN should be initiated at a dose of 50 mg per day and increased only after evaluation of the effects on renal function and lipid levels at this dose. Based on these findings, the use of LIPOFEN should be avoided in patients who have severe renal impairment. Hepatic Impairment: No pharmacokinetic studies have been conducted in patients having hepatic impairment. Drug-Drug Interactions: In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome P450 (CYP) 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 fenofibrate on co-administered drugs. 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 C max Lipid-lowering agents Atorvastatin 20 mg once daily for 10 days Fenofibrate 160 mg TriCor (fenofibrate) oral tablet once daily for 10 days ↓2% ↓4% Pravastatin 40 mg as a single dose Fenofibrate 3 × 67 mg TriCor (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 on Systemic Exposure of Co-Administered Drugs Dosage Regimen of Fenofibrate Dosage Regimen of Co-Administered Drug Change in Co-Administered Drug Exposure Analyte AUC C max Lipid-lowering agents Fenofibrate 160 mg TriCor (fenofibrate) oral tablet once daily for 10 days Atorvastatin, 20 mg once daily for 10 days Atorvastatin ↓17% 0% Fenofibrate 3 × 67 mg TriCor (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%

Pharmacokinetics Table

Table 2: Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration
Co-Administered DrugDosage Regimen of Co-Administered DrugDosage Regimen of FenofibrateChanges in Fenofibric Acid Exposure
AUCCmax
Lipid-lowering agents
Atorvastatin20 mg once daily for 10 daysFenofibrate 160 mgTriCor (fenofibrate) oral tablet once daily for 10 days↓2%↓4%
Pravastatin40 mg as a single doseFenofibrate 3 × 67 mgTriCor (fenofibrate) oral micronized capsule as a single dose↓1%↓2%
Fluvastatin40 mg as a single doseFenofibrate 160 mg as a single dose↓2%↓10%
Anti-diabetic agents
Glimepiride1 mg as a single doseFenofibrate 145 mg once daily for 10 days↑1%↓1%
Metformin850 mg three times daily for 10 daysFenofibrate 54 mg three times daily for 10 days↓9%↓6%
Rosiglitazone8 mg once daily for 5 daysFenofibrate 145 mg once daily for 14 days↑10%↑3%

Effective Time

20210921

Version

1

Dosage Forms And Strengths

3 DOSAGE FORMS AND STRENGTHS 50 mg: Size 3 white opaque gelatin capsule imprinted "G 246" and "50" in black ink. 150 mg: Size 1 white opaque gelatin capsule imprinted "G 248" and "150" in green ink. Oral capsules: 50 mg and 150 mg ( 3 )

Spl Product Data Elements

Lipofen fenofibrate FENOFIBRATE FENOFIBRIC ACID LAUROYL PEG-32 GLYCERIDES POLYETHYLENE GLYCOL 20000 POLYETHYLENE GLYCOL 8000 HYDROXYPROPYL CELLULOSE (160000 WAMW) SODIUM STARCH GLYCOLATE TYPE A GELATIN, UNSPECIFIED TITANIUM DIOXIDE SHELLAC PROPYLENE GLYCOL FERROSOFERRIC OXIDE FD&C BLUE NO. 1 FD&C BLUE NO. 2 FD&C RED NO. 40 D&C YELLOW NO. 10 G;246;50 Lipofen fenofibrate FENOFIBRATE FENOFIBRIC ACID LAUROYL PEG-32 GLYCERIDES POLYETHYLENE GLYCOL 20000 POLYETHYLENE GLYCOL 8000 HYDROXYPROPYL CELLULOSE (160000 WAMW) SODIUM STARCH GLYCOLATE TYPE A GELATIN, UNSPECIFIED TITANIUM DIOXIDE SHELLAC PROPYLENE GLYCOL FERROSOFERRIC OXIDE FD&C BLUE NO. 1 D&C YELLOW NO. 10 G;248;150

Carcinogenesis And Mutagenesis And Impairment Of Fertility

13.1 Carcinogenesis, Mutagenesis, 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) of 300 mg fenofibrate daily, equivalent to 150 mg LIPOFEN daily, based on body surface area comparisons. 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, based on body surface area comparisons), 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 2 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, based on body surface area comparisons) 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. 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. 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 body surface area comparisons).

Nonclinical Toxicology

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, 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) of 300 mg fenofibrate daily, equivalent to 150 mg LIPOFEN daily, based on body surface area comparisons. 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, based on body surface area comparisons), 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 2 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, based on body surface area comparisons) 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. 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. 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 body surface area comparisons).

Application Number

NDA021612

Brand Name

Lipofen

Generic Name

fenofibrate

Product Ndc

62559-305

Product Type

HUMAN PRESCRIPTION DRUG

Route

ORAL

Package Label Principal Display Panel

PRINCIPAL DISPLAY PANEL - 50 mg Capsule Bottle Label NDC 62559-305-90 Lipofen ® (fenofibrate capsules, USP) 50 mg Rx Only ani Pharmaceuticals, Inc. 90 Capsules PRINCIPAL DISPLAY PANEL - 50 mg Capsule Bottle Label

Recent Major Changes

Warnings and Precautions, Hepatotoxicity ( 5.2 ) 06/2021

Recent Major Changes Table

Warnings and Precautions, Hepatotoxicity (5.2)06/2021

Information For Patients

17 PATIENT COUNSELING INFORMATION Patients should be advised: of the potential benefits and risks of LIPOFEN. not to use LIPOFEN if there is a known hypersensitivity to fenofibrate or fenofibric acid. of medications that should not be taken in combination with LIPOFEN. that if they are taking coumarin anticoagulants, LIPOFEN may increase their anti-coagulant effect, and increased monitoring may be necessary. to inform their physician of all medications, supplements, and herbal preparations they are taking and any change in their medical condition. to inform a physician prescribing a new medication, that they are taking LIPOFEN. to continue to follow an appropriate lipid-modifying diet while taking LIPOFEN. to take LIPOFEN once daily at the prescribed dose, swallowing each capsule whole. to inform their physician of symptoms of liver injury (e.g., jaundice, abnormal pain, nausea, malaise, dark urine, abnormal stool, pruritus); any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms. not to breastfeed during treatment with LIPOFEN and for 5 days after the final dose. to return to their physician's office for routine monitoring. Product of Israel Distributed by: ANI Pharmaceuticals, Inc. Baudette, MN 56623

Clinical Studies

14 CLINICAL STUDIES Clinical trials have not been conducted with LIPOFEN. 14.1 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia The effects of fenofibrate at a dose equivalent to 150 mg per day of LIPOFEN 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 ). Table 4: Mean Percent Change in Lipid Parameters at End of Treatment Duration 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 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 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 150 mg LIPOFEN per day decreased primarily very low density lipoprotein (VLDL), triglycerides and VLDL cholesterol. Treatment of some with elevated triglycerides often results in an increase of LDL-C (see Table 5 ). Table 5: Effects 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 The effect of LIPOFEN on cardiovascular morbidity and mortality has not been determined.

Clinical Studies Table

Table 4: Mean Percent Change in Lipid Parameters at End of TreatmentDuration of study treatment was 3 to 6 months.
Treatment GroupTotal-CLDL-CHDL-CTG
Pooled Cohort
Mean baseline lipid values (n=646)306.9 mg/dL213.8 mg/dL52.3 mg/dL191.0 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
Mean baseline lipid values (n=334)307.7 mg/dL227.7 mg/dL58.1 mg/dL101.7 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/dL219.8 mg/dL46.7 mg/dL231.9 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%

Geriatric Use

8.5 Geriatric Use Fenofibrate is substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Since elderly patients have a higher incidence of renal impairment, the 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) ] . Fenofibrate exposure is not influenced by age. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking LIPOFEN.

Pediatric Use

8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients.

Pregnancy

8.1 Pregnancy Risk Summary Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 150 mg daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data ). LIPOFEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data 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, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, equivalent to 150 mg LIPOFEN daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain. In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.

Use In Specific Populations

8 USE IN SPECIFIC POPULATIONS Geriatric Use: Determine dose selection based on renal function ( 8.5 ) Renal Impairment: Avoid use in patients with severe renal impairment. Dose reduction is required in patients with mild to moderate renal impairment ( 8.6 , 12.3 ) 8.1 Pregnancy Risk Summary Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum recommended clinical dose of 150 mg daily, based on body surface area (mg/m 2 ). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data ). LIPOFEN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data 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, no adverse developmental findings were observed at 14 mg/kg/day (less than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate daily, equivalent to 150 mg LIPOFEN daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain. In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6-18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain. In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect. 8.2 Lactation Risk Summary There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with LIPOFEN and for 5 days after the final dose [see Contraindications (4) ] . 8.3 Females and Males of Reproductive Potential Infertility In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (approximately 10 times the MRHD, based on mg/m 2 surface area comparisons) [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1) ] . 8.4 Pediatric Use Safety and effectiveness have not been established in pediatric patients. 8.5 Geriatric Use Fenofibrate is substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Since elderly patients have a higher incidence of renal impairment, the 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) ] . Fenofibrate exposure is not influenced by age. Elderly patients with normal renal function should require no dose modifications. Consider monitoring renal function in elderly patients taking LIPOFEN. 8.6 Renal Impairment The use of LIPOFEN should be avoided in patients who have severe renal impairment [see Contraindication (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 LIPOFEN has not been evaluated in patients with hepatic impairment [see Contraindications (4) and Clinical Pharmacology (12.3) ].

How Supplied

16 HOW SUPPLIED/STORAGE AND HANDLING LIPOFEN ® (fenofibrate capsules, USP) is available in two strengths: 50 mg: Size 3 white opaque/white opaque gelatin capsule, imprinted in black ink with "50" between lines on the body, "G 246" on the cap and containing a white to almost white paste, available in bottles of 90 (NDC 62559-305-90). 150 mg: Size 1 white opaque/white opaque gelatin capsule, imprinted in green ink with "150" between lines on the body, "G 248" on the cap and containing a white to almost white paste, available in bottles of 90 (NDC 62559-306-90). Store at 25°C; Excursions permitted to 15°C - 30°C (59°F - 86°F). [See USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture and light.

Storage And Handling

Store at 25°C; Excursions permitted to 15°C - 30°C (59°F - 86°F). [See USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture and light.

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