fenofibric acid 135 MG Delayed Release Oral Capsule

DRUG INTERACTIONS

7 • Coumarin Anticoagulants: ( 7.1 ).

• Bile Acid Binding Resins: ( 7.2 ).

• Immunosuppressants: ( 7.3 ).

7.1 Coumarin Anticoagulants Potentiation of coumarin-type anticoagulant effect has been observed with prolongation of the PT/INR.

Caution should be exercised when oral coumarin anticoagulants are given in conjunction with fenofibric acid delayed-release capsules.

The dosage of the anticoagulant 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 Bile Acid Binding Resins Since bile acid binding resins may bind other drugs given concurrently, patients should take fenofibric acid delayed-release capsules at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid impeding its absorption.

7.3 Immunosuppressants Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination route of drugs of the fibrate class including fenofibric acid delayed-release capsules, there is a risk that an interaction will lead to deterioration of renal function.

The benefits and risks of using fenofibric acid delayed-release capsules with immunosuppressants and other potentially nephrotoxic agents should be carefully considered, and the lowest effective dose employed.

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.

OVERDOSAGE

10 There is no specific treatment for overdose with fenofibric acid delayed-release capsules.

General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur.

If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway.

Because fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered.

DESCRIPTION

11 Fenofibric acid is a lipid regulating agent available as delayed-release capsules for oral administration.

Each delayed-release capsule contains choline fenofibrate, equivalent to 45 mg or 135 mg of fenofibric acid.

The chemical name for choline fenofibrate is 2-Hydroxy- N,N,N -trimethylethanaminium 2-[4-(4-chlorobenzoyl)phenoxy]-2-methylpropanoate with the following structural formula: The molecular formula is C 22 H 28 ClNO 5 and the molecular weight is 421.91.

Choline fenofibrate is freely soluble in water.

The melting point is approximately 210°C.

Choline fenofibrate is a white to off-white crystalline powder, which is stable under ordinary conditions.

Each delayed-release capsule contains enteric coated pellets comprised of choline fenofibrate and the following inactive ingredients: colloidal silicon dioxide, gelatin, hydroxypropyl cellulose, hypromellose, methacrylic acid copolymer type C, polysorbate 80, povidone, sodium lauryl sulfate, sodium stearyl fumarate, talc, titanium dioxide, triethyl citrate and yellow iron oxide.

The 45 mg capsules also contain red iron oxide.

The 135 mg capsules also contain FD&C Blue No.

2.

In addition, the black imprinting ink contains ammonium hydroxide, black iron oxide, propylene glycol and shellac glaze.

Choline Fenofibrate Structural Formula

CLINICAL STUDIES

14 14.1 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 135 mg once daily of fenofibric acid delayed-release capsules decreased primarily VLDL-TG and VLDL-C.

Treatment of patients with elevated TG often results in an increase of LDL-C (Table 4).

Table 4.

Effects of Fenofibrate in Patients With Severe Hypertriglyceridemia Study 1 Placebo Fenofibrate Baseline TG levels 350 to 499 mg/dL N Baseline Mean (mg/dL) Endpoint Mean (mg/dL) Mean % Change N Baseline Mean (mg/dL) Endpoint Mean (mg/dL) Mean % Change 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 (mg/dL) Endpoint Mean (mg/dL) Mean % Change N Baseline Mean (mg/dL) Endpoint Mean (mg/dL) Mean % Change 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 14.2 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia The effects of fenofibrate at a dose equivalent to fenofibric acid delayed-release capsules 135 mg once daily 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 (Table 5).

Table 5.

Mean Percent Change in Lipid Parameters at End of Treatment Duration of study treatment was 3 to 6 months Treatment Group Total-C (mg/dL) LDL-C (mg/dL) HDL-C (mg/dL) TG (mg/dL) Pooled Cohort Mean baseline lipid values (n = 646) 306.9 213.8 52.3 191.0 All Fenofibrate (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 160 mg/dL and TG ≥ 150 mg/dL Mean baseline lipid values (n = 242) 312.8 219.8 46.7 231.9 All Fenofibrate (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).

HOW SUPPLIED

16 /STORAGE AND HANDLING Fenofibric Acid Delayed-Release Capsules are available containing choline fenofibrate equivalent to 45 mg or 135 mg of fenofibric acid.

The 45 mg capsules are hard-shell gelatin capsules with a brown-pink opaque cap and light yellow opaque body filled with white to off-white enteric coated pellets.

The capsules are axially printed with MYLAN over CF 45 in black ink on the cap and body.

They are available as follows: NDC 0378-2589-77 bottles of 90 capsules The 135 mg capsules are hard-shell gelatin capsules with a powder blue opaque cap and light yellow opaque body filled with white to off-white enteric coated pellets.

The capsules are axially printed with MYLAN over CF 135 in black ink on the cap and body.

They are available as follows: NDC 0378-2590-77 bottles of 90 capsules Store at 20° to 25°C (68° to 77°F).

[See USP Controlled Room Temperature.] Protect from moisture.

Keep out of the reach of children.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

RECENT MAJOR CHANGES

Warnings and Precautions, Hypersensitivity Reactions ( 5.9 ) 05/2018

GERIATRIC USE

8.5 Geriatric Use Fenofibric acid delayed-release capsules are substantially excreted by the kidney as fenofibric acid and fenofibric acid glucuronide, 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 fenofibric acid delayed-release capsules.

DOSAGE FORMS AND STRENGTHS

3 Fenofibric Acid Delayed-Release Capsules are available containing choline fenofibrate equivalent to 45 mg or 135 mg of fenofibric acid.

• The 45 mg capsules are hard-shell gelatin capsules with a brown-pink opaque cap and light yellow opaque body filled with white to off-white enteric coated pellets.

The capsules are axially printed with MYLAN over CF 45 in black ink on the cap and body.

• The 135 mg capsules are hard-shell gelatin capsules with a powder blue opaque cap and light yellow opaque body filled with white to off-white enteric coated pellets.

The capsules are axially printed with MYLAN over CF 135 in black ink on the cap and body.

Oral Delayed-Release Capsules: 45 mg and 135 mg ( 3 ).

MECHANISM OF ACTION

12.1 Mechanism of Action The active moiety of fenofibric acid delayed-release capsules 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, fenofibric acid increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of Apo CIII (an inhibitor of lipoprotein lipase activity).

Activation of PPARα also induces an increase in the synthesis of HDL-C and Apo AI and AII.

INDICATIONS AND USAGE

1 Fenofibric acid delayed-release capsules are a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated as adjunctive therapy to diet to: • Reduce TG in patients with severe hypertriglyceridemia ( 1.1 ).

• Reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDL-C in patients with primary hypercholesterolemia or mixed dyslipidemia ( 1.2 ).

Limitations of Use: Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsules did not reduce coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus ( 5.1 ).

1.1 Treatment of Severe Hypertriglyceridemia Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce triglycerides (TG) in patients with severe hypertriglyceridemia.

Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacological intervention.

Markedly elevated levels of serum triglycerides (e.g., > 2,000 mg/dL) may increase the risk of developing pancreatitis.

The effect of fenofibric acid delayed-release capsules therapy on reducing this risk has not been adequately studied.

1.2 Treatment of Primary Hypercholesterolemia or Mixed Dyslipidemia Fenofibric acid delayed-release capsules 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 patients with primary hypercholesterolemia or mixed dyslipidemia.

1.3 Limitations of Use Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsules did not 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) ] .

1.4 General Considerations for Treatment Laboratory studies should be performed to establish that lipid levels are abnormal before instituting fenofibric acid delayed-release capsules therapy.

Every reasonable attempt should be made to control serum lipids with non-drug methods including appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that may be contributing to the lipid abnormalities.

Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible, and excessive alcohol intake should be addressed before triglyceride-lowering drug therapy is considered.

If the decision is made to use lipid-altering drugs, the patient should be instructed that this does not reduce the importance of adhering to diet.

Drug therapy is not indicated for patients who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of VLDL.

PEDIATRIC USE

8.4 Pediatric Use The safety and effectiveness of fenofibric acid delayed-release capsules in pediatric patients have not been established.

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 135 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 ).

Fenofibric acid delayed-release capsules 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 135 mg fenofibric acid delayed-release capsules 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.

WARNING AND CAUTIONS

5 WARNINGS AND PRECAUTIONS • Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate.

Risks are increased in elderly patients and patients with diabetes, renal failure, hypothyroidism, or statin co-administration ( 5.2 ).

• Fenofibric acid delayed-release capsules can increase serum transaminases.

Liver tests should be monitored periodically ( 5.3 ).

• Fenofibric acid delayed-release capsules can reversibly increase serum creatinine levels ( 5.4 ).

Monitor renal function periodically in patients with renal insufficiency ( 8.6 ).

• Fenofibric acid delayed-release capsules increase cholesterol excretion into the bile, leading to risk of cholelithiasis.

If suspected, gallbladder studies are indicated ( 5.5 ).

• Use caution in concomitant treatment with oral coumarin anticoagulants.

Adjust the dosage of coumarin anticoagulant to maintain the prothrombin time/INR at the desired level to prevent bleeding complications ( 5.6 ).

• Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions, including severe cutaneous adverse drug reactions have been reported postmarketing.

Some cases were life-threatening and required emergency treatment.

Discontinue fenofibrate and treat patients appropriately if reactions occur ( 5.9 ).

5.1 Mortality and Coronary Heart Disease Morbidity The effect of fenofibric acid delayed-release capsules on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.

Because of similarities between fenofibric acid delayed-release capsules and fenofibrate, clofibrate, and gemfibrozil, the findings in the following large randomized, placebo-controlled clinical studies with these fibrate drugs may also apply to fenofibric acid delayed-release capsules.

The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy treated with fenofibrate.

The mean duration of follow-up was 4.7 years.

Fenofibrate plus statin combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p = 0.32) as compared to statin monotherapy.

In a gender subgroup analysis, the hazard ratio for MACE in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction p = 0.01).

The clinical significance of this subgroup finding is unclear.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate.

Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p = 0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p = 0.04).

There was a non-significant 11% (HR 1.11 [0.95, 1.29], p = 0.18) and 19% (HR 1.19 [0.90, 1.57], p = 0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.

In the Coronary Drug Project, a large study of post-myocardial infarction 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 = 0.91-1.64).

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 WHO study (RR = 1.29).

A secondary prevention component of the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because of known or suspected coronary heart disease.

Subjects received gemfibrozil or placebo for 5 years.

Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05).

5.2 Skeletal Muscle Fibrates increase the risk of myositis or 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.

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

Patients should promptly report unexplained muscle pain, tenderness or weakness, particularly if accompanied by malaise or fever.

CPK levels should be assessed in patients reporting these symptoms, and fenofibric acid delayed-release capsules should be discontinued if markedly elevated CPK levels occur or myopathy or myositis is suspected or diagnosed.

Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates are co-administered with a statin.

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

5.3 Liver Function Fenofibric acid delayed-release capsules at a dose of 135 mg once daily have been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)].

In a pooled analysis of three 12-week, double-blind, controlled studies of fenofibric acid delayed-release capsules, increases in ALT and AST to > 3 times the upper limit of normal on two consecutive occasions occurred in 1.9% and 0.2%, respectively, of patients receiving fenofibric acid delayed-release capsules without other lipid-altering drugs.

Increases in ALT and/or AST were not accompanied by increases in bilirubin or clinically significant increases in alkaline phosphatase.

In a pooled analysis of 10 placebo-controlled trials of fenofibrate, increases to > 3 times the upper limit of normal in ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo.

The incidence of increases in transaminases observed with fenofibrate therapy may be dose related.

In an 8-week dose-ranging study of fenofibrate in hypertriglyceridemia, the incidence of ALT or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages equivalent to 90 mg to 135 mg fenofibric acid delayed-release capsules once daily and was 0% in those receiving dosages equivalent to 45 mg fenofibric acid delayed-release capsules once daily or less, or placebo.

Hepatocellular, chronic active, and cholestatic hepatitis observed 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 monitoring of liver function, including serum ALT (SGPT) should be performed for the duration of therapy with fenofibric acid delayed-release capsules, and therapy discontinued if enzyme levels persist above 3 times the upper limit of normal.

5.4 Serum Creatinine Reversible elevations in serum creatinine have been reported in patients receiving fenofibric acid delayed-release capsules as well as patients receiving fenofibrate.

In the pooled analysis of three 12-week, double-blind, controlled studies of fenofibric acid delayed-release capsules, increases in creatinine to > 2 mg/dL occurred in 0.8% of patients treated with fenofibric acid delayed-release capsules without other lipid-altering drugs.

Elevations in serum creatinine were generally stable over time with no evidence for continued increases in serum creatinine with long-term therapy and tended to return to baseline following discontinuation of treatment.

The clinical significance of these observations is unknown.

Monitoring renal function in patients with renal impairment taking fenofibric acid delayed-release capsules is suggested.

Renal monitoring should be considered for patients at risk for renal insufficiency, such as the elderly and those with diabetes.

5.5 Cholelithiasis Fenofibric acid delayed-release capsules, like fenofibrate, clofibrate, and gemfibrozil, may increase cholesterol excretion into the bile, potentially leading to cholelithiasis.

If cholelithiasis is suspected, gallbladder studies are indicated.

Fenofibric acid delayed-release capsules therapy should be discontinued if gallstones are found.

5.6 Coumarin Anticoagulants Caution should be exercised when fenofibric acid delayed-release capsules are given in conjunction with oral coumarin anticoagulants.

Fenofibric acid delayed-release capsules may potentiate the anticoagulant effects of these agents resulting in prolongation of the prothrombin time/International Normalized Ratio (PT/INR).

Frequent monitoring of PT/INR and dose adjustment of the oral anticoagulant are recommended until the PT/INR has stabilized in order to prevent bleeding complications [see Drug Interactions (7.1) ] .

5.7 Pancreatitis Pancreatitis has been reported in patients taking drugs of the fibrate class, including fenofibric acid delayed-release capsules.

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 Hematological Changes Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibric acid delayed-release capsules and fenofibrate therapy.

However, these levels stabilize during long-term administration.

Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrates.

Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of fenofibric acid delayed-release capsules administration.

5.9 Hypersensitivity Reactions Acute Hypersensitivity Anaphylaxis and angioedema have been reported postmarketing with fenofibrate.

In some cases, reactions were life-threatening and required emergency treatment.

If a patient develops signs or symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and discontinue fenofibrate.

Delayed Hypersensitivity Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing, occurring days to weeks after initiation of fenofibrate.

The cases of DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory).

Discontinue fenofibrate and treat patients appropriately if SCAR is suspected.

5.10 Venothromboembolic Disease In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group.

Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group.

For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal PE 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.

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION Patient Counseling Patients should be advised: • of the potential benefits and risks of fenofibric acid delayed-release capsules.

• not to use fenofibric acid delayed-release capsules if there is a known hypersensitivity to fenofibrate or fenofibric acid.

• of medications that should not be taken in combination with fenofibric acid delayed-release capsules.

• that if they are taking coumarin anticoagulants, fenofibric acid delayed-release capsules may increase their anti-coagulant effect, and increased monitoring may be necessary.

• to continue to follow an appropriate lipid-modifying diet while taking fenofibric acid delayed-release capsules.

• to take fenofibric acid delayed-release capsules once daily, without regard to food, at the prescribed dose, swallowing each capsule whole.

• to return to their physician’s office for routine monitoring.

• to inform their physician of all medications, supplements, and herbal preparations they are taking and any change to their medical condition.

Patients should also be advised to inform their physicians prescribing a new medication that they are taking fenofibric acid delayed-release capsules.

• to inform their physician of any muscle pain, tenderness, or weakness; onset of abdominal pain; or any other new symptoms.

• not to breastfeed during treatment with fenofibric acid delayed-release capsules and for 5 days after the final dose.

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

Revised: 4/2019 FENC:R6

DOSAGE AND ADMINISTRATION

2 • Hypertriglyceridemia: 45 to 135 mg once daily ( 2.2 ).

• Primary hypercholesterolemia or mixed dyslipidemia: 135 mg once daily ( 2.3 ).

• Renally impaired patients: 45 mg once daily ( 2.4 ).

• Maximum dose: 135 mg once daily ( 2.1 ).

• May be taken without regard to food ( 2.1 ).

2.1 General Considerations Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibric acid delayed-release capsules and should continue this diet during treatment.

Fenofibric acid delayed-release capsules can be taken without regard to meals.

Patients should be advised to swallow fenofibric acid delayed-release capsules whole.

Do not open, crush, dissolve, or chew capsules.

Serum lipids should be monitored periodically.

2.2 Severe Hypertriglyceridemia The initial dose of fenofibric acid delayed-release capsules is 45 to 135 mg once daily.

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 135 mg once daily.

2.3 Primary Hypercholesterolemia or Mixed Dyslipidemia The dose of fenofibric acid delayed-release capsules is 135 mg once daily.

2.4 Impaired Renal Function Treatment with fenofibric acid delayed-release capsules should be initiated at a dose of 45 mg once daily in patients with mild to moderate renal impairment and should only be increased after evaluation of the effects on renal function and lipid levels at this dose.

The use of fenofibric acid delayed-release capsules should be avoided in patients with severely impaired renal function [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) ] .