Fenofibrate

Apotex Corp.
Apotex Inc.

HIGHLIGHTS OF PRESCRIBING INFORMATION INDICATIONS AND USAGEFenofibrate capsules, USP is a peroxisome proliferator receptor alpha (PPARα) activator indicated as an adjunct to diet: to  reduce  elevated  LDL-C,  Total-C,  triglycerides,  and  Apo  B,  and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia (1.1). to reduce  triglyceride (TG) levels in adult patients with severe hypertriglyceridemia (1.2). Important Limitations of Use: Fenofibrate was not shown to reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus (5.1).DOSAGE AND ADMINISTRATION Fenofibrate capsules can be taken without regard to meals (2.1). Primary hypercholesterolemia and mixed dyslipidemia: 130 mg per day (2.2). Severe Hypertriglyceridemia: 43 to 130 mg per day; the dose should be adjusted according to patient response (2.3). Renally impaired patients: Initial dose of 43 mg per day (2.4). Geriatric patients: Select the dose on the basis of renal function (2.5). DOSAGE FORMS AND STRENGTHS Oral capsules: 43 mg and 130 mg (3). CONTRAINDICATIONS Severe renal dysfunction, including patients receiving dialysis (4, 12.3) Active liver disease (4, 5.3) Gallbladder disease (4, 5.5) Nursing mothers (4, 8.3) Known hypersensitivity to fenofibrate (4, 5.9) WARNINGS AND PRECAUTIONS Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate. The risk for serious muscle toxicity appears to be increased when fenofibrate is co-administered with a statin (with a significantly higher rate observed with gemfibrozil), particularly in elderly patients and in patients with diabetes, renal failure, or hypothyroidism (5.2). Fenofibrate can increase  serum transaminases. Monitor liver tests, including ALT. periodically during therapy (5.3). Fenofibrate can reversibly increase serum creatinine levels. Monitor renal function periodically in patients with renal impairment (5.4). Fenofibrate increases cholesterol excretion into the bile, leading to risk of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated (5.5). Exercise caution in concomitant treatment with coumarin anticoagulants. Reduce the dosage of coumarin to maintain the PT/INR at the desired level to prevent bleeding complications (5.6). Side EffectsMost common adverse reactions (> 2% and greater than 1% in placebo) are abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis (6.1). To report SUSPECTED ADVERSE REACTIONS, contact Apotex Corp. at 1-800-706-5575 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . DRUG INTERACTIONS Coumarin Anticoagulants (7.1) Immunosuppressants (7.2) Bile-Acid Binding Resins (7.3) USE IN SPECIFIC POPULATIONS Geriatric use: Determine dose selection based on renal function (8.5). Renal impairment: Avoid in patients with severe renal impairment; dose reduction required in patients with mild to moderate renal impairment (8.6).

FULL PRESCRIBING INFORMATION: CONTENTS*

• 1 FENOFIBRATE INDICATIONS AND USAGE
  • 1.1 Primary Hypercholesterolemia and Mixed Dyslipidemia
  • 1.2 Hypertriglyceridemia
  • 1.3 Important Limitations of Use
• 2 FENOFIBRATE DOSAGE AND ADMINISTRATION
  • 2.1 General Considerations
  • 2.2 Primary Hypercholesterolemia and Mixed Dyslipidemia
  • 2.3 Severe Hypertriglyceridemia
  • 2.4 Impaired Renal Function
  • 2.5 Geriatric Patients
• 3 DOSAGE FORMS AND STRENGTHS
• 4 FENOFIBRATE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Mortality and Coronary Heart Disease Morbidity
  • 5.2 Skeletal Muscle
  • 5.3 Liver Function
  • 5.4 Serum Creatinine
  • 5.5 Cholelithiasis
  • 5.6 Coumarin Anticoagulants
  • 5.7 Pancreatitis
  • 5.8 Hematologic Changes
  • 5.9 Hypersensitivity Reactions
  • 5.10 Venothromboembolic Disease
  • 5.11 Paradoxical Decreases in HDL Cholesterol Levels
• 6 FENOFIBRATE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Coumarin Anticoagulants
  • 7.2 Immunosuppressants
  • 7.3 Bile-Acid Binding Resins
  • 7.4 Colchicine
• 8 USE IN SPECIFIC POPULATIONS
  • 8.1 Pregnancy
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic Impairment
• 10 OVERDOSAGE
• 11 FENOFIBRATE DESCRIPTION
• 12 CLINICAL PHARMACOLOGY
  • 12.1 Mechanism of Action
  • 12.2 Pharmacodynamics
  • 12.3 Pharmacokinetics
• 13 NONCLINICAL TOXICOLOGY
  • 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
• 14 CLINICAL STUDIES
  • 14.1 Primary Hypercholesterolemia (Heterozygous Familial and Non Familial) and Mixed Dyslipidemia
  • 14.2 Severe Hypertriglyceridemia
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Primary Hypercholesterolemia and Mixed Dyslipidemia

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

1.2 Hypertriglyceridemia

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

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

1.3 Important Limitations of Use

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

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, and should continue this diet during treatment with fenofibrate capsules. Fenofibrate capsules can be given without regard to meals.

Patients should be advised to swallow fenofibrate capsules whole. Do not open, crush, dissolve or chew capsules.

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 capsules 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 130 mg once daily.

2.2 Primary Hypercholesterolemia and Mixed Dyslipidemia

The initial dose of fenofibrate capsules is 130 mg per day.

2.3 Severe Hypertriglyceridemia

The initial dose is 43 to 130 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 130 mg per day.

2.4 Impaired Renal Function

Treatment with fenofibrate capsules should be initiated at a dose of 43 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 capsules 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 (8.6) and Clinical Pharmacology (12.3) ].

3 DOSAGE FORMS AND STRENGTHS

• 43 mg hard gelatin capsules with off-white opaque body and light green opaque cap, imprinted “APO F43” in black ink, filled with white to off-white granules/slugs.
• 130 mg hard gelatin capsules with white, opaque body and dark green opaque cap, imprinted “APO F130” in black ink, filled with white to off-white granules/slugs.

4 CONTRAINDICATIONS

Fenofibrate 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 (5.3) ].

• patients with pre-existing gallbladder disease [see Warnings and Precautions (5.5) ].

• nursing mothers [see Use in Specific Populations (8.3) ].

• patients  with known hypersensitivity  to  fenofibric  acid or fenofibrate [see Warnings and Precautions (5.9) ].

5 WARNINGS AND PRECAUTIONS

5.1 Mortality and Coronary Heart Disease Morbidity

The effects of fenofibrate on coronary heart disease morbidity and mortality and non-cardiovascular mortality have 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, nonfatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79 to 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 to 0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98 to 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 to 1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80 to 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, clofibrate, and gemfibrozil, the adverse findings in 4 large randomized, placebo-controlled clinical studies with these other fibrate drugs may also apply to fenofibrate capsules.}

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=0.91 to 1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from the WHO study (RR=1.29).

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

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 failure, or hypothyroidism.

Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates, in particularly 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) ].

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 therapy should be discontinued if markedly elevated CPK levels occur or myopathy/myositis is suspected or diagnosed.

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 87 mg to 130 mg fenofibrate capsules 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 levels related to fenofibrate therapy appears to be dose related.

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, and therapy discontinued if enzyme levels persist above 3 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. Renal monitoring should also be considered for patients taking fenofibrate 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 therapy should be discontinued if gallstones are found.

5.6 Coumarin Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with fenofibrate because of the potentiation of coumarin-type anti-coagulants in prolonging the prothrombin time/International Normalized Ratio (INR/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 administration.

5.9 Hypersensitivity Reactions

Acute hypersensitivity reactions such as Stevens-Johnson syndrome and toxic 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  9795 patients enrolled in FIELD, there were 4900 in the placebo group and 4895 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.

6 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 rates observed in clinical practice.

Adverse events reported by 2% or more of patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials, regardless of causality, are listed in Table 1. Adverse reactions led to discontinuation of treatment in 5.0% of patients treated with fenofibrate and in 3.0% treated with placebo. Increases   in   liver   function   tests   were   the   most   frequent   events,   causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.

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

^* Dosage equivalent to 130 mg fenofibrate 

^**Significantly different from placebo 

6.2 Postmarketing Experience

The following adverse reactions have been identified during post approval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, arthralgia, 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.

7 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. 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

Immunosuppressants such  as  cyclosporine  and  tacrolimus  can  produce nephrotoxicity with decreases in creatinine clearance and because renal excretion is the primary elimination route of fibrate drugs including fenofibrate, there is a risk that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibrate  with  immunosuppressants  and  other  potentially  nephrotoxic  agents should be carefully considered, and the lowest effective dose employed.

7.3 Bile-Acid Binding Resins

Since bile acid binding resins may bind other drugs given concurrently, patients should take fenofibrate 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.

8 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 maximum recommended human dose (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 to 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 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.

8.6 Renal Impairment

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

8.7 Hepatic Impairment

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

10 OVERDOSAGE

There is no specific treatment for overdose with fenofibrate. 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.

11 DESCRIPTION

Fenofibrate Capsules, USP is a lipid regulating agent available as capsules for oral administration. Each capsule contains 43 mg or 130 mg of micronized fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-­2-methyl-propanoic acid, l-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° to 82°C. Fenofibrate is a white crystalline powder which is stable under ordinary conditions.

Fenofibrate capsules, USP for oral administration contain 43 mg or 130 mg of fenofibrate and the following inactive ingredients: colloidal silicon dioxide, crospovidone and sodium lauryl sulfate. The capsule shell contains gelatin, titanium dioxide, D&C Yellow #10, FD&C Blue #2.  The capsule imprinting ink contains shellac, ethyl alcohol, isopropyl alcohol, butyl alcohol, black iron oxide, propylene glycol and ammonium hydroxide.

Meets USP Dissolution Test 3

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

The lipid-lowering effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor 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 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.

12.2 Pharmacodynamics

A variety of clinical studies have demonstrated that elevated levels of total-C, DL-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 All) 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 triglycerides, and inversely with the level of HDL-C. The independent effect of raising HDL-C or lowering TG on the risk of cardiovascular morbidity and mortality has not been determined.

Fenofibric acid, the active metabolite of fenofibrate, produces reductions in total cholesterol, LDL cholesterol, apolipoprotein B, total triglycerides, and triglyceride-rich lipoprotein in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins Apo AI and Apo AII.

12.3 Pharmacokinetics

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 radio-labeled 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 from fenofibrate occur within 4 to 8 hours after administration. There was less than dose-proportional increase in the systemic exposure of fenofibric acid from 43 mg and 130 mg of fenofibrate under fasting conditions.

Doses of three-capsules of 43 mg fenofibrate given concurrently were dose equivalent to single-capsule doses of 130 mg.

The extent of absorption of fenofibric acid was unaffected when fenofibrate was taken either in fasted state or with a low-fat meal. However, the C_max of fenofibrate increased in the presence of a low-fat meal. T_max was unaffected in the presence of a low-fat meal. In the presence of a high-fat meal, there was a 26% increase in AUC and 108% increase in C_max of fenofibric acid from fenofibrate relative to fasting state.

• Distribution: In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within a week 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.

• 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 the feces.

Fenofibrate acid from fenofibrate capsules is eliminated with a half-life of 23 hours, allowing once daily dosing.

• 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 with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration (2.4) and Use in Special Populations(8.5)].

• Pediatrics: The pharmacokinetics of fenofibrate 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 (creatinine clearance [CrCl] ≤ 30 mL/min or 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 (CrCl 30-80 mL/min or eGFR 30-59 mL/min/1.73m²) renal impairment 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 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 having 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 fenofibric acid on exposure to other drugs.

Table  2  Effects  of  Co-Administered  Drugs  on  Fenofibric  Acid  Systemic Exposure from Fenofibrate or Fenofibrate Administration  

¹ Fenofibrate oral tablet

² Fenofibrate oral micronized capsule 

Table  3  Effects  of Fenofibrate or Fenofibrate  Co-Administration  on  Systemic Exposure of Other Drugs 

¹ Fenofibrate oral tablet

² Fenofibrate oral micronized capsule

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), 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. 

I m pairment 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).

14 CLINICAL STUDIES

14.1 Primary Hypercholesterolemia (Heterozygous Familial and Non Familial) and Mixed Dyslipidemia

The effects of fenofibrate at a dose equivalent to 130 mg fenofibrate per day were assessed from four randomized, placebo-controlled, double-blind, parallel group studies including patients with the following mean baseline lipid values: total-C   306.9   mg/dL;   LDL-C   213.8   mg/dL;   HDL-C   52.3   mg/dL;   and triglycerides 191.0 mg/dL. Fenofibrate therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. Fenofibrate therapy also lowered triglycerides and raised HDL-C (See Table 4).

Table 4 Mean Percent Change in Lipid Parameters at End of Treatment ^†

^† Duration of study treatment was 3 to 6 months.

^* p=<0.05 vs. placebo

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 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 130 mg fenofibrate per day decreased primarily very low density   lipoprotein (VLDL) triglycerides and VLDL cholesterol treatment of patients with elevated triglycerides often results in an increase of LDL-C (See Table 5).

Table 5 Effects of Fenofibrate in Patients with Hypertriglyceridemia

^* p < 0.05 vs. placebo

The effect of fenofibrate on serum triglycerides was studied in a double-blind, randomized, 3 arm parallel-group trial of 146. The study population was comprised of 61 % male and 39% female patients. Approximately 70% of patients had hypertension and 32% had diabetes. Patients were treated for eight weeks with either fenofibrate 130 mg taken once daily with meals, fenofibrate 130 mg taken once daily between meals, or placebo. Fenofibrate 130 mg, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6).

Table 6 Fenofibrate Treatment in Patients with Hypertriglyceridemia

^{* p <  0.05 vs placebo}

^** p <  0.05 vs placebo (log transformed data)

The effect of fenofibrate on cardiovascular morbidity and mortality has not been determined.

16 HOW SUPPLIED/STORAGE AND HANDLING

Fenofibrate capsules, USP (micronized) are available in two strengths.

Fenofibrate Capsules, USP 43 mg are hard gelatin capsules with off-white opaque body and light green opaque cap, imprinted “APO F43” in black ink, filled with white to off-white granules/slugs. They are supplied as follows:  

Bottles of 30s (NDC 60505-3120-3)

Bottles of 100s (NDC 60505-3120-1)  

Fenofibrate Capsules, USP 130 mg are hard gelatin capsules with white, opaque body and dark green opaque cap, imprinted “APO F130” in black ink, filled with white to off-white granules/slugs. They are supplied as follows: 

Bottles of 30s (NDC 60505-3121-3)

Bottles of 90s (NDC 60505-3121-9)

Bottles of 100s (NDC 60505-3121-1) 

Bottles of 500s (NDC 60505-3121-5)

Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

Patients should be advised:

• of the potential benefits and risks of fenofibrate capsules.
• not to use fenofibrate capsules if there is a known hypersensitivity to fenofibrate or fenofibric acid.
• that if they are taking coumarin anticoagulants, fenofibrate capsules may increase their anticoagulant effect, and increased monitoring may be necessary.
• of medications that should not be taken in combination with fenofibrate capsules.
• to continue to follow an appropriate lipid-modifying diet while taking fenofibrate capsules.
• to take fenofibrate capsules once daily, without regard to food, at the prescribed dose, swallowing each capsule whole.
• 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 capsules.
• to inform their physician of any muscle pain, tenderness or weakness; onset of abdominal pain; or any other new symptoms.
• to return to their physician's office for routine monitoring.

All registered trademarks are the property of their respective owners. 

APOTEX INC.

FENOFIBRATE CAPSULES, USP

43 mg and 130 mg  

Revised:  September 2013

Rev. 5

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 43 mg

APOTEX CORP. NDC 60505-3120-3

Fenofibrate Capsules

43 mg

Rx

30 count

Representative sample of labeling (see HOW SUPPLIED section for complete listing):

PRINCIPAL DISPLAY PANEL - 130 mg

APOTEX CORP. NDC 60505-3121-3

Fenofibrate Capsules

130 mg

Rx

30 count