FENOFIBRATE capsule
For Healthcare Providers >

1. Patients Should Be Advised:
2. Revised: 5/2014document Id:
3. Manufactured For:

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.
• of medications that should not be taken in combination with fenofibrate capsules.
• that if they are taking coumarin anticoagulants, fenofibrate capsules 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 fenofibrate capsules.
• to continue to follow an appropriate lipid-modifying diet while taking fenofibrate capsules.
• to take fenofibrate capsules once daily at the prescribed dose, swallowing each capsule whole.
• 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.

Product of Israel

Manufactured into capsules by:
Galephar Pharmaceutical Research Inc.
Humacao, PR 00792

Manufactured for:
H2-Pharma, LLC
Montgomery, AL 36117

H2pharma

Principal Display Panel 50 mg Bottle Label

NDC 61269-210-90

Fenofibrate Capsules, USP

50 mg

Rx Only

H2-Pharma

90 Capsules

Principal Display Panel 150 mg Bottle Label

NDC 61269-212-90

Fenofibrate Capsules, USP

150 mg

Rx Only

H2-Pharma

90 Capsules

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:61269-210 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE(UNII: U202363UOS) (FENOFIBRATE - UNII:U202363UOS) FENOFIBRATE 50 mg

Inactive Ingredients Ingredient Name Strength POLYETHYLENE GLYCOL 8000(UNII: Q662QK8M3B) HYDROXYPROPYL CELLULOSE(UNII: RFW2ET671P) GELATIN(UNII: 2G86QN327L) TITANIUM DIOXIDE(UNII: 15FIX9V2JP) SHELLAC(UNII: 46N107B71O) PROPYLENE GLYCOL(UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE(UNII: XM0M87F357) FD&C BLUE NO. 1(UNII: H3R47K3TBD) FD&C BLUE NO. 2(UNII: L06K8R7DQK) FD&C RED NO. 40(UNII: WZB9127XOA) D&C YELLOW NO. 10(UNII: 35SW5USQ3G)

Product Characteristics Color white (white) Score no score Shape CAPSULE (CAPSULE) Size 16mm Flavor Imprint Code G;246;50 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:61269-210-90 90 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021612 05/05/2014

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:61269-212 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE(UNII: U202363UOS) (FENOFIBRATE - UNII:U202363UOS) FENOFIBRATE 150 mg

Inactive Ingredients Ingredient Name Strength POLYETHYLENE GLYCOL 8000(UNII: Q662QK8M3B) HYDROXYPROPYL CELLULOSE(UNII: RFW2ET671P) GELATIN(UNII: 2G86QN327L) TITANIUM DIOXIDE(UNII: 15FIX9V2JP) SHELLAC(UNII: 46N107B71O) PROPYLENE GLYCOL(UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE(UNII: XM0M87F357) FD&C BLUE NO. 1(UNII: H3R47K3TBD) D&C YELLOW NO. 10(UNII: 35SW5USQ3G)

Product Characteristics Color white (white) Score no score Shape CAPSULE (CAPSULE) Size 19mm Flavor Imprint Code G;248;150 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:61269-212-90 90 in 1 BOTTLE, PLASTIC

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA NDA021612 05/05/2014

Labeler -H2-Pharma, LLC (028473634)

Registrant -Galephar Pharmaceutical Research Inc. (968996160)

Establishment
Name	Address	ID/FEI	Business Operations
Chemagis Ltd.		600077101	API MANUFACTURE(61269-210, 61269-212)

Establishment
Name	Address	ID/FEI	Business Operations
Galephar Pharmaceutical Research Inc.		003551624	MANUFACTURE(61269-210, 61269-212) , ANALYSIS(61269-210, 61269-212) , PACK(61269-210, 61269-212)

Establishment
Name	Address	ID/FEI	Business Operations
Galephar Pharmaceutical Research Inc.		968996160	MANUFACTURE(61269-210, 61269-212) , ANALYSIS(61269-210, 61269-212) , PACK(61269-210, 61269-212) , LABEL(61269-210, 61269-212)

Revised: 5/2014document Id: ⮝

8da243b2-fa62-4e6f-a064-12d15e0eda2934391-3Set id: 6d8a9e4f-8d3b-48f2-8379-361db685e1d3Version: 1Effective Time: 20140501H2-Pharma, LLC

Manufactured For: ⮝

Apotex Inc.Apotex Corp.Toronto, ONWeston, FloridaCanada, M9L 1T933326

Revised: October 2019

Rev. 9

1. No Title 1572548229
2. No Title 1572555402
3. No Title 1572450578
4. Clinical
5. Description
6. Clinical Pharmacology
7. Indications And Usage
8. Contraindications
9. Warnings
10. Precautions
11. Adverse Reactions
12. Overdosage
13. Dosage And Administration
14. How Supplied
15. Storage
16. References
17. Package/label Principal Display Panel
18. Storage
19. Fenofibrate
20. Highlights Of Prescribing Information
21. Recent Major Changes
22. Dosage Forms And Strengths
23. Warnings And Precautions
24. Drug Interactions
25. Use In Specific Populations
26. 1 Indications And Usage
27. 2 Dosage And Administration
28. 3 Dosage Forms And Strengths
29. 4 Contraindications
30. 5 Warnings And Precautions
31. 6 Adverse Reactions
32. 7 Drug Interactions
33. 8 Use In Specific Populations
34. 10 Overdosage
35. 11 Description
36. 12 Clinical Pharmacology
37. 13 Nonclinical Toxicology
38. 14 Clinical Studies
39. 16 How Supplied/storage And Handling
40. Principal Display Panel - 43 Mg
41. Principal Display Panel - 130 Mg
42. 1 Indications And Usage
43. 2 Dosage And Administration
44. 3. Dosage Forms And Strengths
45. 4 Contraindications
46. 5 Warnings And Precautions
47. 6 Adverse Reactions
48. 7 Drug Interactions
49. 8 Use In Specific Populations
50. 10 Overdosage
51. 11 Description
52. 12 Clinical Pharmacology
53. 13 Non-clinical Toxicology
54. 14 Clinical Studies
55. 16 How Supplied/storage And Handling
56. 3 Dosage Forms And Strengths
57. 13 Nonclinical Toxicology
58. Package/label Display Panel
59. Indications And Usage
60. Dosage And Administration
61. Package Label.principal Display Panel
62. Packaging Information
63. Package/label Display Panel Carton 134 Mg
64. Package/label Display Panel Blister 134 Mg
65. Package/label Display Panel Carton 200 Mg
66. Package/label Display Panel Blister 200 Mg
67. Fenofibrate Capsules, Micronized
68. No Title 1572448705
69. Description
70. Clinical Pharmacology
71. Indications And Usage
72. Contraindications
73. Warnings
74. Precautions
75. Adverse Reactions
76. Overdosage
77. Dosage And Administration
78. How Supplied
79. References
80. Principal Display Panel - 200 Mg Capsule Bottle Label

No Title 1572548229 ⮝

Dist. by:
Global Pharmaceuticals
Division of IMPAX Laboratories, Inc.
Philadelphia, PA 19124

184-07
Rev. 10/09

No Title 1572555402 ⮝

Manufactured by:
Bora Pharmaceutical Laboratories Inc.
Jhunan, Taiwan

Distributed by:
Amneal Pharmaceuticals LLC
Bridgewater, NJ 08807

184-12

Rev. 11-2018-00

No Title 1572450578 ⮝

Rx only

Clinical ⮝

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

BODY SYSTEM Adverse Event	Fenofibrate* (N=439)	PLACEBO (N=365)
BODY AS A WHOLE
Abdominal Pain	4.6%	4.4%
Back Pain	3.4%	2.5%
Headache	3.2%	2.7%
Asthenia	2.1%	3.0%
Flu Syndrome	2.1%	2.7%
DIGESTIVE
Liver Function Tests Abnormal	7.5%	1.4%
Diarrhea	2.3%	4.1%
Nausea	2.3%	1.9%
Constipation	2.1%	1.4%
METABOLIC AND NUTRITIONAL DISORDERS
SGPT Increased	3.0%	1.6%
Creatine Phosphokinase Increased	3.0%	1.4%
SGOT Increased	3.4%	0.5%
RESPIRATORY
Respiratory Disorder	6.2%	5.5%
Rhinitis	2.3%	1.1%
* Dosage equivalent to 200 mg fenofibrate capsules Significantly different from Placebo

Additional adverse events reported by three or more patients in placebo-controlled trials or reported in other controlled or open trials, regardless of causality are listed below.

BODY AS A WHOLE: Chest pain, pain (unspecified), infection, malaise, allergic reaction, cyst, hernia, fever, photosensitivity reaction, and accidental injury.

CARDIOVASCULAR SYSTEM: Angina pectoris, hypertension, vasodilatation, coronary artery disorder, electrocardiogram abnormal, ventricular extrasystoles, myocardial infarct, peripheral vascular disorder, migraine, varicose vein, cardiovascular disorder, hypotension, palpitation, vascular disorder, arrhythmia, phlebitis, tachycardia, extrasystoles, and atrial fibrillation.

DIGESTIVE SYSTEM: Dyspepsia, flatulence, nausea, increased appetite, gastroenteritis, cholelithiasis, rectal disorder, esophagitis, gastritis, colitis, tooth disorder, vomiting, anorexia, gastrointestinal disorder, duodenal ulcer, nausea and vomiting, peptic ulcer, rectal hemorrhage, liver fatty deposit, cholecystitis, eructation, gamma glutamyl transpeptidase, and diarrhea.

ENDOCRINE SYSTEM: Diabetes mellitus

HEMIC AND LYMPHATIC SYSTEM: Anemia, leukopenia, ecchymosis, eosinophilia, lymphadenopathy, and thrombocytopenia.

METABOLIC AND NUTRITIONAL DISORDERS: Creatinine increased, weight gain, hypoglycemia, gout, weight loss, edema, hyperuricemia, and peripheral edema.

MUSCULOSKELETAL SYSTEM: Myositis, myalgia, arthralgia, arthritis, tenosynovitis, joint disorder, arthrosis, leg cramps, bursitis, and myasthenia.

NERVOUS SYSTEM: Dizziness, insomnia, depression, vertigo, libido decreased, anxiety, paresthesia, dry mouth, hypertonia, nervousness, neuralgia, and somnolence.

RESPIRATORY SYSTEM: Pharyngitis, bronchitis, cough increased, dyspnea, asthma, pneumonia, laryngitis, and sinusitis.

SKIN AND APPENDAGES: Rash, pruritus, eczema, herpes zoster, urticaria, acne, sweating, fungal dermatitis, skin disorder, alopecia, contact dermatitis, herpes simplex, maculopapular rash, nail disorder, and skin ulcer.

SPECIAL SENSES: Conjunctivitis, eye disorder, amblyopia, ear pain, otitis media, abnormal vision, cataract specified, and refraction disorder.

UROGENITAL SYSTEM: Urinary frequency, prostatic disorder, dysuria, kidney function abnormal, urolithiasis, gynecomastia, unintended pregnancy, vaginal moniliasis, and cystitis.

Description  ⮝

Fenofibrate Capsules, USP (Micronized) are lipid regulating agent available as capsules for oral administration. 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 C20H21O4Cl and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79 to 82 C. Fenofibrate, USP is a white solid which is stable under ordinary conditions.

Each 67 mg Fenofibrate Capsules (Micronized) contain the following inactive ingredients: colloidal silicone dioxide, croscarmellose sodium, crospovidone, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, sodium lauryl sulfate, talc, FD&C Blue 1, FD&C Red 33, D&C Yellow 10, titanium dioxide and gelatin. Imprinting ink contains shellac, potassium hydroxide, propylene glycol and black iron oxide.

Each 134 mg Fenofibrate Capsules (Micronized) contain the following inactive ingredients: colloidal silicone dioxide, croscarmellose sodium, crospovidone, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, sodium lauryl sulfate, talc, FD&C Blue 1, D&C Red 3, titanium dioxide and gelatin. Imprinting ink contains shellac, potassium hydroxide and propylene glycol.

Each 200 mg Fenofibrate Capsules (Micronized) contain the following inactive ingredients: colloidal silicone dioxide, croscarmellose sodium, crospovidone, lactose monohydrate, magnesium stearate, povidone, pregelatinized starch, sodium lauryl sulfate, talc, iron oxide red, iron oxide yellow, titanium dioxide and gelatin. Imprinting ink contains shellac, potassium hydroxide, propylene glycol and black iron oxide.

Clinical Pharmacology  ⮝

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with 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 apoproteins apo AI and apo AII.

The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor (PPAR ). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride- rich particles from plasma by activating lipoprotein lipase and reducing production of apoproteins C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.

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

Pharmacokinetics/Metabolism

Clinical experience has been obtained with two different formulations of fenofibrate: a micronized and non-micronized formulation, which have been demonstrated to be bioequivalent. Comparisons of blood levels following oral administration of both formulations in healthy volunteers demonstrate that a single capsule containing 67 mg of the micronized formulation is bioequivalent to 100 mg of the non-micronized formulation. Three capsules containing 67 mg Fenofibrate Capsules are bioequivalent to a single 200 mg Fenofibrate Capsules.

Absorption

The absolute bioavailability of fenofibrate cannot be determined as the compound is virtually insoluble in aqueous media suitable for injection. However, fenofibrate is well absorbed from the gastrointestinal tract. Following oral administration in healthy volunteers, approximately 60% of a single dose of radiolabelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.

The absorption of fenofibrate is increased when administered with food. With micronized fenofibrate, the absorption is increased by approximately 35% under fed as compared to fasting conditions.

Distribution

In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of dosing with single oral doses equivalent to 67 mg fenofibrate and did not demonstrate accumulation across time following multiple dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

Metabolism

Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.

Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.

In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.

Excretion

After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.

Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration in a clinical setting.

Special Populations

Geriatrics

In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites.

Pediatrics

Fenofibrate has not been investigated in adequate and well-controlled trials in pediatric patients.

Gender

No pharmacokinetic difference between males and females has been observed for fenofibrate.

Race

The influence of race on the pharmacokinetics of fenofibrate has not been studied however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. Therefore, inter-ethnic pharmacokinetic differences are very unlikely.

Renal Insufficiency

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) showed 2.7 fold increase in exposure for fenofibric acid and increased accumulation of fenofibric acid during chronic dosing compared to that of healthy subjects. Patients with mild to moderate renal impairment (CrCl 30 to 80 mL/min) 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.

Hepatic Insufficiency

No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.

Drug-drug Interactions

In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C8, CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Potentiation of coumarin-type anticoagulants has been observed with prolongation of the prothrombin time/INR.

Bile acid sequestrants have been shown to bind other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption. (See WARNINGS and PRECAUTIONS).

Concomitant administration of a single dose of fenofibrate (administered as 3 X 67 mg fenofibrate micronized capsules) with a single dose of pravastatin (40 mg) in 23 healthy subjects increased the mean Cmax and mean AUC for pravastatin by 13%. The Cmax and AUC of fenofibrate decreased by 2% and 1%, respectively, after concomitant administration of fenofibrate and pravastatin. The mean Cmax and AUC for 3 -hydroxy-iso-pravastatin increased by 29% and 26%, respectively.

Concomitant administration of a single dose of fenofibrate (equivalent to 145 mg fenofibrate) and a single dose of fluvastatin (40 mg) resulted in a small increase (approximately 15 to 16%) in exposure to (+)3R,5S-fluvastatin, the active enantiomer of fluvastatin.

A single dose of either pravastatin or fluvastatin had no clinically important effect on the pharmacokinetics of fenofibric acid.

Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) with atorvastatin (20 mg) once daily for 10 days resulted in approximately 17% decrease (range from 67% decrease to 44% increase) in atorvastatin AUC values in 22 healthy males. The atorvastatin Cmax values were not significantly affected by fenofibrate. The pharmacokinetics of fenofibric acid were not significantly affected by atorvastatin.

Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) once daily for 10 days with glimepiride (1 mg tablet) single dose simultaneously with the last dose of fenofibrate resulted in a 35% increase in mean AUC of glimepiride in healthy subjects. Glimepiride Cmax was not significantly affected by fenofibrate coadministration. There was no statistically significant effect of multiple doses of fenofibrate on glucose nadir or AUC with the baseline glucose concentration as the covariate after glimepiride administration in healthy volunteers. However, glucose concentrations at 24 hours remained statistically significantly lower after pretreatment with fenofibrate than with glimepiride alone.

Glimepiride had no significant effect on the pharmacokinetics of fenofibric acid.

Concomitant administration of fenofibrate (54 mg) and metformin (850 mg) three times a day for 10 days resulted in no significant changes in the pharmacokinetics of fenofibric acid and metformin when compared with the two drugs administered alone in healthy subjects.

Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) once daily for 14 days with rosiglitazone tablet (rosiglitazone maleate) (8 mg) once daily for 5 days, Day 10 through Day 14, resulted in no significant changes in the pharmacokinetics of fenofibric acid and rosiglitazone when compared with the two drugs administered alone in healthy subjects.

Clinical Trials

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)

The effects of fenofibrate at a dose equivalent to 200 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 1).

Table 1: Mean Percent Change in Lipid Parameters at End of Treatment*

Treatment Group	Total-C	LDL-C	HDL-C	TG
Pooled Cohort
Mean baseline lipid values (n=646)	306.9 mg/dL	213.8 mg/dL	52.3 mg/dL	191.0 mg/dL
All FEN (n=361)	-18.7%	-20.6%	+11.0%	-28.9%
Placebo (n=285)	-0.4%	-2.2%	+0.7%	+7.7%
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL (Type IIa)
Mean baseline lipid values (n=334)	307.7 mg/dL	227.7 mg/dL	58.1 mg/dL	101.7 mg/dL
All FEN (n=193)	-22.4%	-31.4%	+9.8%	-23.5%
Placebo (n=141)	+0.2%	-2.2%	+2.6%	+11.7%
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL (Type IIb)
Mean baseline lipid values (n=242)	312.8 mg/dL	219.8 mg/dL	46.7 mg/dL	231.9 mg/dL
All FEN (n=126)	-16.8%	-20.1%	+14.6%	-35.9%
Placebo (n=116)	-3.0%	-6.6%	+2.3%	+0.9%
* 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).

Hypertriglyceridemia (Fredrickson Type IV and V)

The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials1 of 147 hypertriglyceridemia patients (Fredrickson Type IV and V). Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline triglyceride (TG) levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia (Type IV/V hyperlipidemia), treatment with fenofibrate at dosages equivalent to 200 mg fenofibrate per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2).

Table 2: Effects of Fenofibrate Capsules in Patients With Fredrickson Type IV/V Hyperlipidemia

Study 1	Placebo				Fenofibrate Capsules
Baseline TG levels 350 to 499 mg/dL	N	Baseline (Mean)	Endpoint (Mean)	% Change (Mean)	N	Baseline (Mean)	Endpoint (Mean)	% Change (Mean)
Triglycerides	28	449	450	-0.5	27	432	223	-46.2*
VLDL Triglycerides	19	367	350	2.7	19	350	178	-44.1*
Total Cholesterol	28	255	261	2.8	27	252	227	-9.1*
HDL Cholesterol	28	35	36	4	27	34	40	19.6*
LDL Cholesterol	28	120	129	12	27	128	137	14.5
VLDL Cholesterol	27	99	99	5.8	27	92	46	-44.7*
Study 2	Placebo				Fenofibrate Capsules
Baseline TG levels 350 to 499 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*
* = p<0.05 vs. Placebo

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

Indications And Usage  ⮝

Treatment of Hypercholesterolemia

Fenofibrate capsules are indicated as adjunctive therapy to diet for the reduction of LDL-C, total-C, Triglycerides and apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb. Lipid altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate (see National Cholesterol Education Program [NCEP] Treatment Guidelines, below).

Treatment of Hypertriglyceridemia

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

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

Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV and V hyperlipoproteinemia2.

The initial treatment 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, like thiazide diuretics and beta-blockers, is sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.

The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet (See WARNINGSand PRECAUTIONS).

Fredrickson Classification of Hyperlipoproteinemias

		Lipid Elevation
Type	Lipoprotein	Major	Minor
I (rare)	Chylomicrons	TG	C
IIa	LDL	C	-
IIb	LDL, VLDL	C	TG
III (rare)	IDL	C, TG	-
IV	VLDL	TG	C
V (rare)	Chylomicrons, VLDL	TG

C = cholesterol

TG = triglycerides

LDL = low density lipoprotein

VLDL = very low density lipoprotein

IDL = intermediate density lipoprotein

The NCEP Treatment Guidelines

Definite Atherosclerotic Disease	Two or More Other Risk Factors	LDL-Cholesterol mg/dL (mmol/L)
		Initiation Level	Goal
NO NO YES	NO YES YES or NO	190 ( 4.9) 160 ( 4.1) 130c ( 3.4)	<160 (<4.1) <130 (<3.4) <100 (<2.6)

( a ) Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease).

( b ) Other risk factors for coronary heart disease (CHD) include: age (males: 45 years; females 55 years or premature menopause without estrogen replacement therapy); family history of premature CHD; current cigarette smoking; hypertension; confirmed HDL-C < 35 mg/dL (< 0.91 mmol/L); and diabetes mellitus. Subtract I risk factor if HDL-C is 60 mg/dL ( 1.6 mmol/L).

( c ) In CHD patients with LDL-C levels 100 to 129 mg/dL, the physician should exercise clinical judgement in deciding whether to initiate drug treatment.

Contraindications  ⮝

Fenofibrate Capsules are contraindicated in patients who exhibit hypersensitivity to fenofibrate.

Fenofibrate Capsules are contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality.

Fenofibrate Capsules are contraindicated in patients with preexisting gallbladder disease (see WARNINGS).

Warnings  ⮝

Liver Function

Fenofibrate Capsules at doses equivalent to 134 mg to 200 mg fenofibrate per day has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In a pooled analysis of 10 placebo-controlled trials, increases to > 3 times the upper limit of normal occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with placebo.

When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed. The incidence of increases in transaminase related to fenofibrate therapy appear to be dose related. In an 8 week dose-ranging study, the incidence of ALT or AST elevations to at least three times the upper limit of normal was 13% in patients receiving dosages equivalent to 134 mg to 200 mg fenofibrate per day and was 0% in those receiving dosages equivalent to 34 mg or 67 mg of fenofibrate per day or placebo. Hepatocellular, chronic active and cholestatic hepatitis associated with fenofibrate therapy have been reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been reported in association with chronic active hepatitis.

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 three times the normal limit.

Cholelithiasis

Fenofibrate, like clofibrate and gemfibrozil, may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated. Fenofibrate therapy should be discontinued if gallstones are found.

Concomitant Oral Anticoagulants

Caution should be exercised when anticoagulants are given in conjunction with fenofibrate because of the potentiation of coumarin-type anticoagulants in prolonging the prothrombin time/INR. The dosage of the anticoagulant should be reduced to maintain the prothrombin time/lNR at the desired level to prevent bleeding complications. Frequent prothrombin time/INR determinations are advisable until it has been definitely determined that the prothrombin time/INR has stabilized.

Concomitant HMG-CoA Reductase Inhibitors

The combined use of fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination.

Concomitant administration of fenofibrate (equivalent to fenofibrate 200 mg) and pravastatin (40 mg) once daily for 10 days increased the mean Cmax and AUC values for pravastatin by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and for 3 -hydroxy-iso-pravastatin by 55% (range from 32% decrease to 314% increase) and 39% (range from 24% decrease to 261% increase), respectively. (See also CLINICAL PHARMACOLOGY, Drug-drug interactions.)

The combined use of fibric acid derivatives and HMG-CoA reductase inhibitors has been associated, in the absences of a marked pharmacokinetic interaction, in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase (CK) levels and myoglobinuria, leading in a high proportion of cases to acute renal failure.

The use of fibrates alone, including fenofibrate capsules may occasionally be associated with myositis, myopathy, or rhabdomyolysis. Patients receiving fenofibrate and complaining of muscle pain, tenderness, or weakness should have prompt medical evaluation for myopathy, including serum creatine kinase level determination. If myopathy/myositis is suspected or diagnosed, fenofibrate therapy should be stopped.

Mortality

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

Other Considerations

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

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

In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate group compared with the placebo group (5.70% vs. 3.96%, p=<0.01). Excess mortality was due to a 33% increase in non-cardiovascular causes, including malignancy, post-cholecystectomy complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (n=4081) study of middle-aged men without a history of coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization group but did not achieve statistical significance (p=0.19, 95% confidence interval for relative risk G:P=0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the limited size of the study, the relative risk of death from any cause was not shown to be different than that seen in the 9 year follow-up data from World Health Organization study (RR=1.29). Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil group did not differ statistically from that observed in the WHO study.

A secondary prevention component of the Helsinki Heart Study enrolled middle aged men excluded from the primary prevention study because of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years. Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant (hazard ratio 2.2, 95% confidence interval: 0.94-5.05). The rate of gallbladder surgery was not statistically significant between study groups, but did trend higher in the gemfibrozil group, (1.9% vs. 0.3%, p=0.07).

There was a statistically significant difference in the number of appendectomies in the gemfibrozil group (6/311 vs. 0/317, p=0.029).

Precautions  ⮝

Initial Therapy

Laboratory studies should be done to ascertain that the lipid levels are consistently abnormal before instituting fenofibrate therapy. Every attempt should be made to control serum lipids with appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as diabetes mellitus and hypothyroidism that are contributing to the lipid abnormalities. Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued or changed if possible prior to consideration of triglyceride-lowering drug therapy.

Continued Therapy

Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of Fenofibrate Capsules. Therapy should be withdrawn in patients who do not have an adequate response after two months of treatment with the maximum recommended dose of 200 mg per day.

Pancreatitis

Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

Hypersensitivity Reactions

Acute Hypersensitivity: 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 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.

Hematologic Changes

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Extremely rare spontaneous reports of thrombocytopenia and agranulocytosis have been received during postmarketing surveillance outside of the U.S. Periodic blood counts are recommended during the first 12 months of fenofibrate administration.

Skeletal Muscle

The use of fibrates alone, including fenofibrate, may occasionally be associated with myopathy. Treatment with drugs of the fibrate class has been associated on rare occasions with rhabdomyolysis, usually in patients with impaired renal function. Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of creatine phosphokinase levels.

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

Venothromboembolic Disease

In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p < 0.01).

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.

Drug Interactions

Oral Anticoagulants

CAUTION SHOULD BE EXERCISED WHEN COUMARIN ANTICOAGULANTS ARE GIVEN IN CONJUNCTION WITH FENOFIBRATE CAPSULES. THE DOSAGE OF THE ANTICOAGULANTS SHOULD BE REDUCED TO MAINTAIN THE PROTHROMBIN TIME/INR AT THE DESIRED LEVEL TO PREVENT BLEEDING COMPLICATIONS. FREQUENT PROTHROMBIN TIME/INR DETERMINATIONS ARE ADVISABLE UNTIL IT HAS BEEN DEFINITELY DETERMINED THAT THE PROTHROMBIN TIME/INR HAS STABILIZED.

HMG-CoA Reductase Inhibitors

The combined use of fenofibrate and HMG-CoA reductase inhibitors should be avoided unless the benefit of further alterations in lipid levels is likely to outweigh the increased risk of this drug combination (see WARNINGS).

Resins

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

Cyclosporine

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

Two dietary carcinogenicity studies have been conducted in rats with fenofibrate. In the first 24 month study, 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, 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 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.

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 mg/m2 surface area comparisons).

Pregnancy

Teratogenic Effects

Pregnancy category C

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

In female rats given oral dietary doses of 15, 75, and 300 mg/kg/day of fenofibrate from 15 days prior to mating through weaning, maternal toxicity was observed at 0.3 times the MRHD, based on body surface area comparisons; mg/m2.

In pregnant rats given oral dietary doses of 14, 127, and 361 mg/kg/day from gestation day 6 to 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.

Nursing Mothers

It is not known whether fenofibrate is excreted into milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from fenofibrate, a decision should be made whether to discontinue nursing or administration of fenofibrate taking into account the importance of the drug to the lactating woman.

Pediatric Use

Safety and efficacy in pediatric patients have not been established.

Geriatric Use

Fenofibric acid is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Fenofibric acid exposure is not influenced by age. However, elderly patients have a higher incidence of renal impairment, such that dose selection for the elderly should be made on the basis of renal function (see CLINICAL PHARMACOLOGY, Special Populations, Renal Insufficiency). Elderly patients with normal renal function should require no dose modifications.

Adverse Reactions  ⮝

Photosensitivity reactions have occurred days to months after initiation; in some of these cases, patients reported a prior photosensitivity reaction to ketoprofen.

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

Adverse events reported by 2% or more of patients treated with fenofibrate (and greater than placebo) during the double-blind, placebo-controlled trials, regardless of causality, are listed in Table 3 below. Adverse events led to discontinuation of treatment in 5% of patients treated with fenofibrate and in 3% 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 3. Adverse Reactions Reported by 2% or More of Patients Treated with Fenofibrate and Greater than Placebo During the Double-Blind, Placebo-Controlled Trials

BODY SYSTEM	Fenofibrate*	PLACEBO
Adverse Reaction	(N=439)	(N=365)
BODY AS A WHOLE
Abdominal Pain	4.6%	4.4%
Back pain	3.4%	2.5%
Headache	3.2%	2.7%
DIGESTIVE
Abnormal Liver Function Tests	7.5%**	1.4%
Nausea	2.3%	1.9%
Constipation	2.1%	1.4%
METABOLIC AND NUTRITIONAL DISORDERS
Increased ALT	3.0%	1.6%
Increased CPK	3.0%	1.4%
Increased AST	3.4%**	0.5%
RESPIRATORY
Respiratory Disorder	6.2%	5.5%
Rhinitis	2.3%	1.1%
* Dosage equivalent to 145 mg fenofibrate ** Significantly different from Placebo

Post-Marketing Experience: The following adverse reactions have been identified during post-approval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia and interstitial lung disease. 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.

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.

Dosage And Administration  ⮝

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 should be given with meals, thereby optimizing the bioavailability of the medication.

For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of Fenofibrate Capsules is 200 mg per day.

For adult patients with hypertriglyceridemia, the initial dose is 67 to 200 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 200 mg per day.

Treatment with Fenofibrate Capsules should be initiated at a dose of 67 mg/day in patients having impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. In the elderly, the initial dose should likewise be limited to 67 mg/day.

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.

How Supplied  ⮝

Fenofibrate Capsules, USP (Micronized), 67 mg are opaque purple cap and body, hard gelatin capsules, imprinted AMG on the Cap and 444 on the body in black ink. They are supplied as follows:

NDC 43975-444-10 Bottles of 100 capsules

Fenofibrate Capsules, USP (Micronized), 134 mg are opaque blue cap and body, hard gelatin capsules, imprinted AMG on the Cap and 445 on the body in white ink. They are supplied as follows:

NDC 43975-305-10 Bottles of 100 capsules

NDC 43975-305-50 Bottles of 500 capsules

Fenofibrate Capsules, USP (Micronized), 200 mg are opaque orange cap and body, hard gelatin capsules, imprinted AMG on the Cap and 446 on the body in black ink. They are supplied as follows:

NDC 43975-306-10 Bottles of 100 capsules

NDC 43975-306-50 Bottles of 500 capsules

Storage  ⮝

Store at 20 to 25 C (68 to 77 F) [See USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture.

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

Manufactured By:
Inventia Healthcare Limited
Plot No. F1 & F-1/1, Additional Ambernath M.I.D.C.,
Ambernath (East)-421506,
Dist. Thane, Maharashtra, India

Distributed by:
Amerigen Pharmaceuticals, Inc.
Lyndhurst, NJ 07071 USA
1-877-220-3784

OS1028/04

Rev. 03/2019

References  ⮝

1. GOLDBERG AC, et al. Fenofibrate for the Treatment of Type IV and V Hyperlipoproteinemias: A Double-Blind, Placebo-Controlled Multicenter US Study. Clinical Therapeutics, 11, pp. 69-83, 1989.

2. NIKKILA EA. Familial Lipoprotein Lipase Deficiency and Related Disorders of Chylomicron Metabolism. In Stanbury J.B., et al. (eds.): The Metabolic Basis of Inherited Disease, 5th edition, McGraw-Hill, 1983, Chap. 30, pp. 622-642.

3. BROWN WV, et al. Effects of Fenofibrate on Plasma Lipids: Double-Blind, Multicenter Study In Patients with Type IIA or IIB Hyperlipidemia. Arteriosclerosis. 6, pp. 670-678, 1986.

Package/label Principal Display Panel  ⮝

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43975-444 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 67 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE K30 (UNII: U725QWY32X) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TALC (UNII: 7SEV7J4R1U) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN (UNII: 2G86QN327L) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) D&C RED NO. 33 (UNII: 9DBA0SBB0L) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) SHELLAC (UNII: 46N107B71O) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE (UNII: XM0M87F357) POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)

Product Characteristics Color PURPLE (Opaque Purple Cap and Body) Score no score Shape CAPSULE Size 14mm Flavor Imprint Code AMG;444 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:43975-444-10 100 in 1 BOTTLE; Type 0: Not a Combination Product 05/01/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA209504 05/01/2018

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43975-305 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 134 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE K30 (UNII: U725QWY32X) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TALC (UNII: 7SEV7J4R1U) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN (UNII: 2G86QN327L) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 3 (UNII: PN2ZH5LOQY) SHELLAC (UNII: 46N107B71O) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)

Product Characteristics Color BLUE (Opaque Blue Cap and Body) Score no score Shape CAPSULE Size 18mm Flavor Imprint Code AMG;445 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:43975-305-10 100 in 1 BOTTLE; Type 0: Not a Combination Product 05/01/2018 2 NDC:43975-305-50 500 in 1 BOTTLE; Type 0: Not a Combination Product 05/01/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA209504 05/01/2018

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:43975-306 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 200 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) CROSPOVIDONE (15 MPA.S AT 5%) (UNII: 68401960MK) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE K30 (UNII: U725QWY32X) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TALC (UNII: 7SEV7J4R1U) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN (UNII: 2G86QN327L) SHELLAC (UNII: 46N107B71O) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE (UNII: XM0M87F357) FERRIC OXIDE RED (UNII: 1K09F3G675) FERRIC OXIDE YELLOW (UNII: EX438O2MRT) POTASSIUM HYDROXIDE (UNII: WZH3C48M4T)

Product Characteristics Color ORANGE (Opaque Orange Cap and Body) Score no score Shape CAPSULE Size 19mm Flavor Imprint Code AMG;446 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:43975-306-10 100 in 1 BOTTLE; Type 0: Not a Combination Product 05/01/2018 2 NDC:43975-306-50 500 in 1 BOTTLE; Type 0: Not a Combination Product 05/01/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA209504 05/01/2018

Labeler - Amerigen Pharmaceuticals Inc. (828949136)

Registrant - Amerigen Pharmaceuticald Ltd. (864406702)

Revised: 3/2019 Document Id: ab581ce4-6b13-4449-a695-5f7743af4bf3 34391-3 Set id: c740f57c-cac5-4526-a5a9-aaab65b1caf6 Version: 3 Effective Time: 20190331 Amerigen Pharmaceuticals Inc.

Storage ⮝

Store at 20 to 25 C (68 to 77 F) [see USP Controlled Room Temperature]. Keep out of the reach of children. Protect from moisture.

Fenofibrate ⮝

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:50090-4121(NDC:42858-134) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 134 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) POVIDONE K25 (UNII: K0KQV10C35) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) TALC (UNII: 7SEV7J4R1U) D&C RED NO. 28 (UNII: 767IP0Y5NH) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) GELATIN, UNSPECIFIED (UNII: 2G86QN327L)

Product Characteristics Color BLUE (light blue Opaque Cap and Body) Score no score Shape CAPSULE Size 18mm Flavor Imprint Code RP;134 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:50090-4121-0 90 in 1 BOTTLE; Type 0: Not a Combination Product 02/02/2019

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075753 06/01/2017

Labeler - A-S Medication Solutions (830016429)

Establishment
Name	Address	ID/FEI	Business Operations
A-S Medication Solutions		830016429	RELABEL(50090-4121) , REPACK(50090-4121)

Revised: 2/2019 Document Id: 6b567862-4123-4ced-a38f-97cdd7333a5f 34391-3 Set id: b614039a-b988-4c17-bbc5-edf041a23cb4 Version: 2 Effective Time: 20190206 A-S Medication Solutions

Highlights Of Prescribing Information ⮝

These highlights do not include all the information needed to use Fenofibrate Capsules, USP safely and effectively. See full prescribing information for Fenofibrate Capsules, USP.
Fenofibrate Capsules, USP, for oral use
Initial U.S. Approval: 1993

Recent Major Changes ⮝

Warnings and Precautions (5.9) 11/2018

Dosage Forms And Strengths ⮝

• Oral capsules: 50 mg and 150 mg (3)

Warnings And Precautions ⮝

• Fibrates increase the risk of myopathy, and rhabdomyolysis has been reported in patients taking fibrates (with a significantly higher rate observed with gemfibrozil); rhabdomyolysis risk is increased in the elderly, patients with diabetes, renal insufficiency 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 (5.4). Monitor renal function periodically in patients with renal impairment (8.6)
• Fenofibrate may increase cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis is suspected, gallbladder studies are indicated (5.5)
• Exercise caution in concomitant treatment with coumarin-type anticoagulants. Adjust dosage of these anticoagulants to maintain the Prothrombin Time/International Normalized Ratio (PT/INR) at the desired level to prevent bleeding complications (5.6 , 7.1)

Drug Interactions ⮝

• Coumarin-type anticoagulants (7.1)
• Immunosuppressants (7.2)
• Bile acid binding resins (7.3)
• Colchicine (7.4)

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)

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 2/2014

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 hypercholesterolemia or mixed dyslipidemia.

1.2 Severe Hypertriglyceridemia

Fenofibrate capsules, USP are also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually 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 three times the normal limit.

5.4 Serum Creatinine

Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking fenofibrate. 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 (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7.1)].

5.7 Pancreatitis

Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

5.8 Hematologic Changes

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in patients following initiation of fenofibrate therapy. However, these levels stabilize during long-term administration. Thrombocytopenia and agranulocytosis have been reported in individuals treated with fenofibrate. Periodic monitoring of red and white blood cell counts are recommended during the first 12 months of fenofibrate 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 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

Body System Adverse Reaction	Fenofibrate* (N=439)	Placebo (N=365)
Body As A Whole
Abdominal Pain	4.6%	4.4%
Back Pain	3.4%	2.5%
Headache	3.2%	2.7%
Digestive
Abnormal Liver Function Tests	7.5%**	1.4%
Nausea	2.3%	1.9%
Constipation	2.1%	1.4%
Metabolic and Nutritional Disorders
Increased AST	3.4%**	0.5%
Increased ALT	3.0%	1.6%
Increased Creatine Phosphokinase	3.0%	1.4%
Respiratory
Respiratory Disorder	6.2%	5.5%
Rhinitis	2.3%	1.1%

* Dosage equivalent to 130 mg fenofibrate

**Significantly different from placebo

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.

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, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, arthralgia, 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.

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 decrease 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 to 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 g/mol; fenofibrate is insoluble in water. The melting point is 79 C to 82 C. Fenofibrate, USP 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 D & C Yellow #10, FD & C Blue #2, gelatin and titanium dioxide. The capsule imprinting ink contains ammonium hydroxide, iron oxide black, propylene glycol and shellac.

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 (PPAR ).

Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation) to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.

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

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 AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with the level of total-C, LDL-C, and 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 Cmax of fenofibrate increased in the presence of a low-fat meal. Tmax 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 Cmax 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 to 80 mL/min or eGFR 30 to 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 inhibitor 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

Co-Administered Drug	Dosage Regimen of Co-Administered Drug	Dosage Regimen of Fenofibrate	Changes in Fenofibric Acid Exposure
			AUC	Cmax
No dosing adjustments required for fenofibrate with the following co-administered drugs
Lipid-lowing agents
Atorvastatin	20 mg once daily for 10 days	Fenofibrate 160 mg1 once daily for 10 days	2%	4%
Pravastatin	40 mg as a single dose	Fenofibrate 3 x 67 mg2 as a single dose	1%	2%
Fluvastatin	40 mg as a single dose	Fenofibrate 160 mg1 as a single dose	2%	10%
Anti-diabetic agents
Glimepiride	1 mg once daily as a single dose	Fenofibrate 145 mg1 once daily for 10 days	1%	1%
Metformin	850 mg three times daily for 10 days	Fenofibrate 54 mg1 three times daily for 10 days	9%	6%
Rosiglitazone	8 mg once daily for 5 days	Fenofibrate 145 mg1 once daily for 14 days	10%	3%

1 Fenofibrate oral tablet

2 Fenofibrate oral micronized capsule

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

Dosage Regimen of Fenofibrate	Dosage Regimen of Co-Administered Drug	Changes in Co-Administered Drug Exposure
		Analyte	AUC	Cmax
No dosing adjustments required for these co-administered drugs with fenofibrate
Lipid-lowing agents
Fenofibrate 160 mg1 once daily for 10 days	Atorvastatin, 20 mg once daily for 10 days	Atorvastatin	17%	0%
Fenofibrate 3 x 67 mg2 as a single dose	Pravastatin, 40 mg as a single dose	Pravastatin	13%	13%
		3 -Hydroxyl-iso-pravastatin	26%	29%
Fenofibrate 160 mg1 once daily for 10 days	Pravastatin, 40 mg once daily for 10 days	Pravastatin	28%	36%
		3 -Hydroxyl-iso-pravastatin	39%	55%
Fenofibrate 160 mg1 as a single dose	Fluvastatin, 40 mg as a single dose	(+)-3R, 5S-Fluvastatin	15%	16%
Anti-diabetic agents
Fenofibrate 145 mg1 once daily for 10 days	Glimepiride, 1 mg once daily as a single dose	Glimepiride	35%	18%
Fenofibrate 54 mg1 three times daily for 10 days	Metformin, 850 mg three times daily for 10 days	Metformin	3%	6%
Fenofibrate 145 mg1 once daily for 14 days	Rosiglitazone, 8 mg once daily for 5 days	Rosiglitazone	6%	1%

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.

Impairment of Fertility: In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (~10 times the MRHD, based on mg/m2 surface area comparisons).

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

Treatment Group	Total-C	LDL-C	HDL-C	TG
Pooled Cohort
Mean baseline lipid values (N=646)	306.9 mg/dL	213.8 mg/dL	52.3 mg/dL		191.0 mg/dL
All FEN (n=361)	-18.7% *	-20.6% *	+11.0% *		-28.9% *
Placebo (n=285)	-0.4%	-2.2%	+0.7%		+7.7%
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL (Type IIa)
Mean baseline lipid values (N=334)	307.7 mg/dL	227.7 mg/dL	58.1 mg/dL	101.7 mg/dL
All FEN (n=193)	-22.4% *	-31.4% *	+9.8% *	-23.5% *
Placebo (n=141)	+0.2%	-2.2%	+2.6%	+11.7%
Baseline LDL-C > 160 mg/dL and TG 150 mg/dL (Type IIb)
Mean baseline lipid values (N=242)	312.8 mg/dL	219.8 mg/dL	46.7 mg/dL	231.9 mg/dL
All FEN (n=126)	-16.8% *	-20.1% *	+14.6% *	-35.9% *
Placebo (n=116)	-3.0%	-6.6%	+2.3%	+0.9%

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

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 *
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	1.2	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*

* 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

	Placebo (n =50)		Fenofibrate with meals (n=54)		Fenofibrate between meals (n=42)
	Baseline mg/dL (mean)	% Change at endpoint (mean)	Baseline mg/dL (mean)	% Change at endpoint (mean)	Baseline mg/dL (mean)	% Change at endpoint (mean)
Triglycerides	479	+0.7	475	-36.7 *	487	-36.6 *
Total Cholesterol	237	-0.8	248	-5.1	241	-3.4
HDL Cholesterol	35	+0.8	36	+13.7 *	36	+14.3 *
Non-HDL Cholesterol	202	-1.1	212	-8.2 **	205	-6.6 **
LDL Cholesterol	115	+3.2	120	+15.4 *	122	+14.5
VLDL Cholesterol	87	-1.6	92	-34.4 *	83	-30.4 *

*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)

Storage

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

Principal Display Panel - 43 Mg ⮝

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

PRINCIPAL DISPLAY PANEL - 43 mg

APOTEX CORP. NDC 60505-3120-3

Fenofibrate Capsules

43 mg

Rx

30 count

Principal Display Panel - 130 Mg ⮝

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

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-3120 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Fenofibrate (UNII: U202363UOS) (Fenofibric Acid - UNII:BGF9MN2HU1) Fenofibrate 43 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (UNII: 68401960MK) SODIUM LAURYL SULFATE (UNII: 368GB5141J) GELATIN (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) SHELLAC (UNII: 46N107B71O) FERROSOFERRIC OXIDE (UNII: XM0M87F357) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X)

Product Characteristics Color WHITE, GREEN (LIGHT GREEN) Score no score Shape CAPSULE Size 14mm Flavor Imprint Code APO;F43 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-3120-3 30 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2013 2 NDC:60505-3120-1 100 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2013

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202252 07/26/2013

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:60505-3121 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Fenofibrate (UNII: U202363UOS) (Fenofibric Acid - UNII:BGF9MN2HU1) Fenofibrate 130 mg

Inactive Ingredients Ingredient Name Strength SILICON DIOXIDE (UNII: ETJ7Z6XBU4) CROSPOVIDONE (UNII: 68401960MK) SODIUM LAURYL SULFATE (UNII: 368GB5141J) GELATIN (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) SHELLAC (UNII: 46N107B71O) FERROSOFERRIC OXIDE (UNII: XM0M87F357) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) AMMONIA (UNII: 5138Q19F1X)

Product Characteristics Color WHITE, GREEN (DARK GREEN) Score no score Shape CAPSULE Size 19mm Flavor Imprint Code APO;F130 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:60505-3121-3 30 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2013 2 NDC:60505-3121-1 100 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2013 3 NDC:60505-3121-5 500 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2013 4 NDC:60505-3121-9 90 in 1 BOTTLE; Type 0: Not a Combination Product 07/26/2013

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202252 07/26/2013

Labeler - Apotex Corp. (845263701)

Registrant - Apotex Inc. (209429182)

Establishment
Name	Address	ID/FEI	Business Operations
Apotex Inc.		209429182	manufacture(60505-3120, 60505-3121) , analysis(60505-3120, 60505-3121)

Establishment
Name	Address	ID/FEI	Business Operations
Apotex Inc.		205576023	manufacture(60505-3120, 60505-3121)

Revised: 11/2018 Document Id: b4926081-4113-5837-0632-e0b6bdd37af6 34391-3 Set id: 68024459-987a-9cf4-f539-4959093bc9f0 Version: 6 Effective Time: 20181111 Apotex Corp.

1 Indications And Usage  ⮝

1.1 Primary Hypercholesterolemia or Mixed Dyslipidemia

Fenofibrate capsules are 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

Fenofibrate capsules are also indicated as adjunctive therapy to diet for treatment of adult patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacologic intervention.

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

1.3 Important Limitations of Use

Fenofibrate at a dose equivalent to 150 mg 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)].

2 Dosage And Administration  ⮝

2.1 General Considerations

Fenofibrate capsules should be given with meals thereby optimizing the absorption of the medication.

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

Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, and should continue this diet during treatment with fenofibrate 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.

Periodic determination of serum lipids should be obtained during initial therapy in order to establish the lowest effective dose of fenofibrate. 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 fenofibrate if lipid levels fall significantly below the targeted range.

2.2 Primary Hypercholesterolemia or Mixed Dyslipidemia

The dose of fenofibrate capsules 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 fenofibrate capsules is 150 mg once daily.

2.4 Impaired Renal Function

In patients with mild-to-moderate renal impairment, treatment with fenofibrate capsules 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 fenofibrate 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)].

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.

4 Contraindications  ⮝

Fenofibrate capsules are contraindicated in:

• patients with severe renal impairment, including those receiving dialysis [see Clinical Pharmacology (12.3)].
• patients with active liver disease, including those with primary biliary cirrhosis and unexplained persistent liver function abnormalities [see Warnings and Precautions (5.3)].
• patients with preexisting gallbladder disease [see Warnings and Precautions (5.5)].
• patients with known hypersensitivity to fenofibrate or fenofibric acid [see Warnings and Precautions(5.9)].
• nursing mothers [see Use in Specific Populations (8.3)].

5 Warnings And Precautions  ⮝

5.1 Coronary Heart Disease Morbidity and Mortality

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

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

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16) and a significant 11% reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p=0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as compared to placebo.1

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

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 the WHO study (RR=1.29).

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

5.2 Skeletal Muscle

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

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

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. Creatine phosphokinase (CPK) levels should be assessed in patients reporting these symptoms, and fenofibrate therapy should be discontinued if markedly elevated CPK levels occur or myopathy is diagnosed.

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 100 mg to 150 mg fenofibrate per day has been associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In a pooled analysis of 10 placebo-controlled trials of fenofibrate, increases to > 3 times the upper limit of normal of 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. When transaminase determinations were followed either after discontinuation of treatment or during continued treatment, a return to normal limits was usually observed.

Chronic active hepatocellular 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 monitoring of liver tests, including ALT should be performed for the duration of therapy with fenofibrate, and therapy discontinued if enzyme levels persist above three times the normal limit.

5.4 Serum Creatinine

Elevations in serum creatinine have been reported in patients on fenofibrate. These elevations tend to return to baseline following discontinuation of fenofibrate. The clinical significance of these observations is unknown. Monitor renal function in patients with renal impairment taking fenofibrate. Renal monitoring should also be considered for patients taking fenofibrate and are 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 fenofibrate is given in conjunction with coumarin anticoagulants. Fenofibrate may potentiate the anticoagulant effects of these agents resulting in prolongation of the Prothrombin Time/International Normalized Ratio (PT/INR). To prevent bleeding complications, frequent monitoring of PT/INR and dose adjustment of the anticoagulant are recommended until PT/INR has stabilized [see Drug Interactions (7.1)].

5.7 Pancreatitis

Pancreatitis has been reported in patients taking fenofibrate, gemfibrozil, and clofibrate. This occurrence may represent a failure of efficacy in patients with severe hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract stone or sludge formation with obstruction of the common bile duct.

5.8 Hematologic Changes

Mild to moderate decreases in 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 is recommended during the first 12 months of fenofibrate administration.

5.9 Hypersensitivity Reactions

Acute hypersensitivity reactions including severe skin rashes such as Steven-Johnson syndrome and toxic epidermal necrolysis requiring patient hospitalization and treatment with steroids have been reported in individuals treated with fenofibrate. Urticaria was seen in 1.1 vs. 0% and rash in 1.4 vs. 0.8% of fenofibrate and placebo patients respectively in controlled trials.

5.10 Venothromboembolic Disease

In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher rates in the fenofibrate than the placebo-treated group. Of 9,795 patients enrolled in FIELD, 4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or suspected fatal or nonfatal pulmonary embolism or thrombophlebitis than the placebo group (5.2% vs. 3.3% at 5 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 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

* Dosage equivalent to 150 mg fenofibrate
** Significantly different from placebo
BODY SYSTEM Adverse Event	Fenofibrate* (N=439)	Placebo (N=365)
BODY AS A WHOLE
Abdominal Pain	4.6%	4.4%
Back Pain	3.4%	2.5%
Headache	3.2%	2.7%
DIGESTIVE
Abnormal Liver Function Tests	7.5%**	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%

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of fenofibrate: myalgia, rhabdomyolysis, pancreatitis, acute renal failure, muscle spasm, hepatitis, cirrhosis, anemia, arthralgia, decreases in hemoglobin, decreases in hematocrit, white blood cell decreases, asthenia, and severely depressed HDL cholesterol levels. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

7 Drug Interactions  ⮝

7.1 Coumarin Anticoagulants

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

Caution should be exercised when fenofibrate is given in conjunction with coumarin anticoagulants. Fenofibrate 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 fenofibrate capsules, 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 fenofibrate capsules, the lowest effective dose of fenofibrate capsules 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 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 6-18 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

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 fenofibrate.

8.6 Renal Impairment

The use of fenofibrate 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 fenofibrate has not been evaluated in patients 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. The 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 are 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 C20H21O4C1 and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79-82oC. Fenofibrate is a white solid which is stable under ordinary conditions.

Fenofibrate Capsules, USP meet 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.

12 Clinical Pharmacology  ⮝

12.1 Mechanism of Action

The active metabolite 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-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor (PPAR ). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR also induces an increase in the synthesis of 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 fenofibrate 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 fenofibrate capsules 200 mg, following single-dose administration, the plasma concentration (AUC) for the parent compound fenofibrate was approximately 40 g/mL compared to 204 g/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 fenofibrate, 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 fenofibrate 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 (Cmax) of fenofibric acid was 73% greater after multiple-dose than after single-dose administration.

The extent of absorption of fenofibrate capsules in terms of AUC value of fenofibric acid increased in a less than proportional manner while the rate of absorption in terms of Cmax 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 fenofibrate 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 fenofibrate 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/1.73m2) to moderate (eGFR 30-59 mL/min/1.73m2) 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/1.73m2) 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 fenofibrate 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 fenofibrate 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

1 TriCor (fenofibrate) oral tablet
2 TriCor (fenofibrate) oral micronized capsule
Co-Administered Drug	Dosage Regimen of Co-Administered Drug	Dosage Regimen of Fenofibrate	Changes in Fenofibric Acid Exposure
			AUC	Cmax
Lipid-lowering agents
Atorvastatin	20 mg once daily for 10 days	Fenofibrate 160 mg1 once daily for 10 days	2%	4%
Pravastatin	40 mg as a single dose	Fenofibrate 3 x 67 mg2 as a single dose	1%	2%
Fluvastatin	40 mg as a single dose	Fenofibrate 160 mg1 as a single dose	2%	10%
Anti-diabetic agents
Glimepiride	1 mg as a single dose	Fenofibrate 145 mg1 once daily for 10 days	1%	1%
Metformin	850 mg three times daily for 10 days	Fenofibrate 54 mg1 three times daily for 10 days	9%	6%
Rosiglitazone	8 mg once daily for 5 days	Fenofibrate 145 mg1 once daily for 14 days	10%	3%

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	Cmax
1 TriCor (fenofibrate) oral tablet
2 TriCor (fenofibrate) oral micronized capsule
Lipid-lowering agents
Fenofibrate 160 mg1 once daily for 10 days	Atorvastatin, 20 mg once daily for 10 days	Atorvastatin	17%	0%
Fenofibrate 3 x 67 mg2 as a single dose	Pravastatin, 40 mg as a single dose	Pravastatin	13%	13%
		3 -Hydroxyl-iso-pravastatin	26%	29%
Fenofibrate 160 mg1 as a single dose	Fluvastatin, 40 mg as a single dose	(+)-3R, 5S-Fluvastatin	15%	16%
Anti-diabetic agents
Fenofibrate 145 mg1 once daily for 10 days	Glimepiride, 1 mg as a single dose	Glimepiride	35%	18%
Fenofibrate 54 mg1 three times daily for 10 days	Metformin, 850 mg three times daily for 10 days	Metformin	3%	6%
Fenofibrate 145 mg1 once daily for 14 days	Rosiglitazone, 8 mg once daily for 5 days	Rosiglitazone	6%	1%

13 Non-clinical Toxicology  ⮝

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis: 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 are comparisons (mg/m2). At a dose of 200 mg/kg/day (at 6 times MRHD), the incidence of liver carcinoma 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 in males at 6 times the MRHD. In a second 24-month 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; 2 times the human dose), and gemfibrozil (250 mg/kg; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinomas in males and hepatic neoplastic nodules in females. Gemfibrozil increased hepatic neoplastic nodules in males and females, while all three drugs increased testicular interstitial cell tumors in males.

In a 21-month study in CF-1 mice, fenofibrate 10, 45 and 200 mg/kg/day (approximately 0.2, 1, and 3 times the MRHD on the basis of mg/m2 surface area) significantly increased the liver carcinomas in both sexes at 3 times the MRHD. In a second 18 month study at 10, 60 and 200 mg/kg/day, fenofibrate significantly increased the liver carcinomas in male mice and liver adenomas in female mice at 3 times the MRHD.

Electron microscopy studies have demonstrated peroxisomal proliferation following fenofibrate administration to the rat. An adequate study to test for peroxisome proliferation in humans has not been done, but changes in peroxisome morphology and numbers have been observed in humans after treatment with other members of the fibrate class when liver biopsies were compared before and after treatment in the same individual.

Mutagenesis: Fenofibrate has been demonstrated to be devoid of mutagenic potential in the following tests: Ames, mouse lymphoma, chromosomal aberration and unscheduled DNA synthesis in primary rat hepatocytes.

Impairment of Fertility: In fertility studies rats were given oral dietary doses of fenofibrate, males received 61 days prior to mating and females 15 days prior to mating through weaning which resulted in no adverse effect on fertility at doses up to 300 mg/kg/day (approximately 10 times the MRHD, based on mg/m2 surface area comparisons).

14 Clinical Studies  ⮝

Clinical trials have not been conducted with Fenofibrate Capsules, USP.

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 fenofibrate was 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
Treatment Group	Total-C	LDL-C	HDL-C	TG
Pooled Cohort
Mean baseline lipid values (n=646)	306.9 mg/dL	213.8 mg/dL	52.3 mg/dL	191.0 mg/dL
All FEN (n=361)	-18.7%*	-20.6%*	+11.0%*	* -28.9%*
Placebo (n=285)	-0.4%	-2.2%	+0.7%	+7.7%
Baseline LDL-C >160 mg/dL and TG <150 mg/dL
Mean baseline lipid values (n=334)	307.7 mg/dL	227.7 mg/dL	58.1 mg/dL	101.7 mg/dL
All FEN (n=193)	-22.4%*	-31.4%*	+9.8%	-23.5%*
Placebo (n=141)	+0.2%	-2.2%	+2.6%	+11.7%
Baseline LDL-C >160 mg/dL and TG 150 mg/dL
Mean baseline lipid values (n=242)	312.8 mg/dL	219.8 mg/dL	46.7 mg/dL	231.9 mg/dL
All FEN (n=126)	-16.8%*	-20.1%*	+14.6%*	-35.9%*
Placebo (n=116)	-3.0%	-6.6%	+2.3%	+0.9%

In a subset of the subjects, measurements of apo B were conducted. Fenofibrate 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 fenofibrate 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

* = P<0.05 vs. Placebo
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*
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 fenofibrate on cardiovascular morbidity and mortality has not been determined.

16 How Supplied/storage And Handling  ⮝

Fenofibrate Capsules, USP are 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 61269-210-90).

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 61269-212-90).

Store at Controlled Room Temperature, 15 C - 30 C (59 F - 86 F). Keep out of the reach of children. Protect from moisture and light.

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.

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 fenofibrate 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/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, 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).

Package/label Display Panel  ⮝

Fenofibrate Capsules USP, 150 mg
NDC 62559-461-90
Rx only
90 Capsules

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62559-460 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 50 mg

Inactive Ingredients Ingredient Name Strength LAUROYL PEG-32 GLYCERIDES (UNII: H5ZC52369M) POLYETHYLENE GLYCOL 20000 (UNII: 5WKN5KL2O8) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) SHELLAC (UNII: 46N107B71O) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE (UNII: XM0M87F357) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C RED NO. 40 (UNII: WZB9127XOA) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)

Product Characteristics Color white (white) Score no score Shape CAPSULE (CAPSULE) Size 16mm Flavor Imprint Code G;246;50 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:62559-460-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 04/13/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021612 04/13/2016

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62559-461 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 150 mg

Inactive Ingredients Ingredient Name Strength LAUROYL PEG-32 GLYCERIDES (UNII: H5ZC52369M) POLYETHYLENE GLYCOL 20000 (UNII: 5WKN5KL2O8) POLYETHYLENE GLYCOL 8000 (UNII: Q662QK8M3B) HYDROXYPROPYL CELLULOSE (1600000 WAMW) (UNII: RFW2ET671P) SODIUM STARCH GLYCOLATE TYPE A POTATO (UNII: 5856J3G2A2) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) SHELLAC (UNII: 46N107B71O) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE (UNII: XM0M87F357) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G)

Product Characteristics Color white (white) Score no score Shape CAPSULE (CAPSULE) Size 19mm Flavor Imprint Code G;248;150 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:62559-461-90 90 in 1 BOTTLE; Type 0: Not a Combination Product 04/13/2016

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date NDA authorized generic NDA021612 04/13/2016

Labeler - ANI Pharmaceuticals, Inc. (145588013)

Registrant - Cipher Pharmaceuticals Inc. (200224645)

Revised: 1/2019 Document Id: b5690adc-f97e-4861-a1fb-99634f8f523b 34391-3 Set id: 3a69e15a-eda6-4a6e-8934-6881e4370521 Version: 5 Effective Time: 20190115 ANI Pharmaceuticals, Inc.

Indications And Usage ⮝

Treatment of Hypercholesterolemia

Fenofibrate capsules, USP are indicated as adjunctive therapy to diet for the reduction of LDL-C, Total-C, Triglycerides and Apo B in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb). Lipid altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate (see National Cholesterol Education Program [NCEP] Treatment Guidelines, below).

Treatment of Hypertriglyceridemia

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

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

Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV and V hyperlipoproteinemia2.

The initial treatment 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, like thiazide diuretics and beta-blockers, is sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.

The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet (See WARNINGS and PRECAUTIONS).

Fredrickson Classification of Hyperlipoproteinemias

C = cholesterol TG = triglycerides LDL = low density lipoprotein VLDL = very low density lipoprotein IDL = intermediate density lipoprotein
Type	Lipoprotein Elevated	Lipid Elevation
		Major	Minor
I (rare)	chylomicrons	TG	C
IIa	LDL	C	--
IIb	LDL, VLDL	C	TG
III (rare)	IDL	C, TG	--
IV	VLDL	TG	C
V (rare)	chylomicrons, VLDL	TG

The NCEP Treatment Guidelines

(a) Coronary heart disease or peripheral vascular disease (including symptomatic carotid artery disease). (b) Other risk factors for coronary heart disease (CHD) include age (males: 45 years; females: 55 years or premature menopause without estrogen replacement therapy); family history of premature CHD; current cigarette smoking; hypertension; confirmed HDL-C < 35 mg/dL (< 0.91 mmoI/L); and diabetes mellitus. Subtract 1 risk factor if HDL-C is > 60 mg/dL ( 1.6 mmoI/L) (c) In CHD patients with LDL-C levels 100 mg/dL to 129 mg/dL, the physician should exercise clinical judgment in deciding whether to initiate drug treatment.
Definite Atherosclerotic Diseasea	Two or More Other Risk Factorsb	LDL-Cholesterol mg/dL (mmol/L)
		Initiation Level	Goal
No	No	190 ( 4.9)	< 160 (< 4.1)
No	Yes	160 ( 4.1)	< 130 (< 3.4)
Yes	Yes or No	130c ( 3.4)	< 100 (< 2.6)

Dosage And Administration ⮝

Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibrate capsules, USP and should continue this diet during treatment with fenofibrate capsules, USP. Fenofibrate capsules, USP should be given with meals, thereby optimizing the bioavailability of the medication.

For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of fenofibrate capsules, USP is 200 mg per day.

For adult patients with hypertriglyceridemia, the initial dose is 67 mg to 200 mg per day. Dosage should be individualized according to patient response, and should be adjusted if necessary following repeat lipid determinations at 4 week to 8 week intervals. The maximum dose is 200 mg per day.

Treatment with fenofibrate capsules, USP should be initiated at a dose of 67 mg/day in patients having impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. In the elderly, the initial dose should likewise be limited to 67 mg/day.

Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of fenofibrate capsules, USP if lipid levels fall significantly below the targeted range.

Package Label.principal Display Panel ⮝

NDC 27241-118-04
100 Capsules
Fenofibrate Capsules, USP
67 mg
Rx Only
ajanta

NDC 27241-119-04
100 Capsules
Fenofibrate Capsules, USP
134 mg
Rx Only
ajanta

NDC 27241-120-04
100 Capsules
Fenofibrate Capsules, USP
200 mg
Rx Only
ajanta

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:27241-118 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 67 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561) POVIDONE K25 (UNII: K0KQV10C35) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) TALC (UNII: 7SEV7J4R1U) SHELLAC (UNII: 46N107B71O) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE (UNII: XM0M87F357) POTASSIUM HYDROXIDE (UNII: WZH3C48M4T) D&C RED NO. 28 (UNII: 767IP0Y5NH) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) FD&C RED NO. 40 (UNII: WZB9127XOA) GELATIN (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color PINK Score no score Shape CAPSULE Size 14mm Flavor Imprint Code ap;FEN67 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:27241-118-04 100 in 1 BOTTLE; Type 0: Not a Combination Product 09/10/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA210705 09/10/2018

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:27241-119 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 134 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561) POVIDONE K25 (UNII: K0KQV10C35) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) TALC (UNII: 7SEV7J4R1U) SHELLAC (UNII: 46N107B71O) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE (UNII: XM0M87F357) POTASSIUM HYDROXIDE (UNII: WZH3C48M4T) D&C RED NO. 28 (UNII: 767IP0Y5NH) FD&C BLUE NO. 1 (UNII: H3R47K3TBD) GELATIN (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color BLUE Score no score Shape CAPSULE Size 18mm Flavor Imprint Code ap;FEN134 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:27241-119-04 100 in 1 BOTTLE; Type 0: Not a Combination Product 09/10/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA210705 09/10/2018

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:27241-120 Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 200 mg

Inactive Ingredients Ingredient Name Strength CROSPOVIDONE, UNSPECIFIED (UNII: 2S7830E561) POVIDONE K25 (UNII: K0KQV10C35) LACTOSE MONOHYDRATE (UNII: EWQ57Q8I5X) MAGNESIUM STEARATE (UNII: 70097M6I30) STARCH, CORN (UNII: O8232NY3SJ) SODIUM LAURYL SULFATE (UNII: 368GB5141J) CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) TALC (UNII: 7SEV7J4R1U) SHELLAC (UNII: 46N107B71O) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FERROSOFERRIC OXIDE (UNII: XM0M87F357) POTASSIUM HYDROXIDE (UNII: WZH3C48M4T) D&C RED NO. 28 (UNII: 767IP0Y5NH) FD&C RED NO. 40 (UNII: WZB9127XOA) FERRIC OXIDE YELLOW (UNII: EX438O2MRT) GELATIN (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP)

Product Characteristics Color ORANGE Score no score Shape CAPSULE Size 21mm Flavor Imprint Code ap;FEN200 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:27241-120-04 100 in 1 BOTTLE; Type 0: Not a Combination Product 09/10/2018

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA210705 09/10/2018

Labeler - Ajanta Pharma Limited (918594859)

Establishment
Name	Address	ID/FEI	Business Operations
Ajanta Pharma Limited		918594859	MANUFACTURE(27241-118, 27241-119, 27241-120)

Revised: 4/2019 Document Id: 57b52c72-f357-4fee-a042-e60cfe417448 34391-3 Set id: da2f0ba4-7c16-4fb0-bc1c-45540e8fefbf Version: 4 Effective Time: 20190410 Ajanta Pharma Limited

Packaging Information ⮝

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from Impax Generics as follows:
(134 mg / 20 UD) NDC 68084-835-32 packaged from NDC 0115-0522
(200 mg / 30 UD) NDC 68084-329-21 packaged from NDC 0115-0533

Distributed by:
American Health Packaging
Columbus, OH 43217

8232921/0619

Package/label Display Panel Carton 134 Mg ⮝

NDC 68084- 835-32

Fenofibrate
Capsules (Micronized)

134 mg*

20 Capsules (5 x 4) Rx Only

*Each Capsule Contains:
Micronized fenofibrate .................................134 mg

Usual Dosage: See package insert for full
prescribing information.

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

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is
torn or broken.

The drug product contained in this package is from
NDC # 0115-0522, Impax Generics.

Distributed by:
American Health Packaging
Columbus, Ohio 43217

083532
0283532/0619OS

Package/label Display Panel Blister 134 Mg ⮝

Fenofibrate
Capsule
(Micronized)

134 mg

Package/label Display Panel Carton 200 Mg ⮝

NDC 68084- 329-21

Fenofibrate
Capsules (Micronized)

200 mg*

30 Capsules (3 x 10) Rx Only

*Each Capsule Contains:
Micronized fenofibrate ........................................................... 200 mg

Usual Dosage: See package insert for full prescribing
information.

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

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

The drug product contained in this package is from
NDC # 0115-0533, Impax Generics.

Packaged and Distributed by:
American Health Packaging
Columbus, Ohio 43217

032921
0232921/0619

Package/label Display Panel Blister 200 Mg ⮝

Fenofibrate
Capsule (Micronized)

200 mg

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68084-835(NDC:0115-0522) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 134 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) SODIUM LAURYL SULFATE (UNII: 368GB5141J) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) SHELLAC (UNII: 46N107B71O) FERROSOFERRIC OXIDE (UNII: XM0M87F357) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) FD&C RED NO. 40 (UNII: WZB9127XOA) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) ALUMINUM OXIDE (UNII: LMI26O6933) FD&C BLUE NO. 1 (UNII: H3R47K3TBD)

Product Characteristics Color white Score no score Shape CAPSULE Size 19mm Flavor Imprint Code G;0522 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68084-835-32 20 in 1 BOX, UNIT-DOSE 09/23/2014 1 NDC:68084-835-33 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075868 09/23/2014

FENOFIBRATE fenofibrate capsule

Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:68084-329(NDC:0115-0533) Route of Administration ORAL

Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength FENOFIBRATE (UNII: U202363UOS) (FENOFIBRIC ACID - UNII:BGF9MN2HU1) FENOFIBRATE 200 mg

Inactive Ingredients Ingredient Name Strength CROSCARMELLOSE SODIUM (UNII: M28OL1HH48) HYPROMELLOSE 2910 (6 MPA.S) (UNII: 0WZ8WG20P6) MAGNESIUM STEARATE (UNII: 70097M6I30) MICROCRYSTALLINE CELLULOSE (UNII: OP1R32D61U) SODIUM LAURYL SULFATE (UNII: 368GB5141J) GELATIN, UNSPECIFIED (UNII: 2G86QN327L) TITANIUM DIOXIDE (UNII: 15FIX9V2JP) D&C RED NO. 28 (UNII: 767IP0Y5NH) D&C YELLOW NO. 10 (UNII: 35SW5USQ3G) FD&C RED NO. 40 (UNII: WZB9127XOA) SHELLAC (UNII: 46N107B71O) FERROSOFERRIC OXIDE (UNII: XM0M87F357) PROPYLENE GLYCOL (UNII: 6DC9Q167V3) FD&C BLUE NO. 2 (UNII: L06K8R7DQK) ALUMINUM OXIDE (UNII: LMI26O6933) FD&C BLUE NO. 1 (UNII: H3R47K3TBD)

Product Characteristics Color orange Score no score Shape CAPSULE Size 19mm Flavor Imprint Code G;0533 Contains

Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:68084-329-21 30 in 1 BOX, UNIT-DOSE 01/21/2009 1 NDC:68084-329-11 1 in 1 BLISTER PACK; Type 0: Not a Combination Product

Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA075868 01/21/2009

Labeler - American Health Packaging (929561009)

Establishment
Name	Address	ID/FEI	Business Operations
American Health Packaging		929561009	repack(68084-835, 68084-329)

Revised: 6/2019 Document Id: 8c152ba6-a24c-2ed1-e053-2995a90afd9b 34391-3 Set id: c850d4e4-2dce-4a03-964f-b9397ec20514 Version: 7 Effective Time: 20190624 American Health Packaging

Fenofibrate Capsules, Micronized ⮝

Rx only

No Title 1572448705 ⮝

Rx only

Description ⮝

Fenofibrate capsules (micronized), is a lipid regulating agent available as capsules for oral administration. Each capsule contains 67 mg, 134 mg or 200 mg of micronized fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:

The 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 solid which is stable under ordinary conditions.

Inactive Ingredients: The inactive ingredients in fenofibrate capsules include croscarmellose sodium, hypromellose type 2910/6 cP, magnesium stearate, microcrystalline cellulose, and sodium lauryl sulfate. The capsule shells contain gelatin and titanium dioxide. The 67 mg capsule shells also contain D&C Yellow No. 10 and FD&C Yellow No. 6. The 200 mg capsule shells also contain D&C Red No. 28, D&C Yellow No. 10, and FD&C Red No. 40.

Additionally, the capsule imprint ink contains shellac glaze, ferrosoferric oxide, propylene glycol, FD&C Blue No. 2, FD&C Red No. 40, D&C Yellow No. 10 Aluminum Lake, and FD&C Blue No. 1.

Clinical Pharmacology ⮝

A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (HDL-C) and its transport complex, apolipoprotein A (apo AI and apo AII) are associated with the development of atherosclerosis. Epidemiologic investigations have established that cardiovascular morbidity and mortality vary directly with 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 apoproteins apo AI and apo AII).

The effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor (PPAR ). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting fall in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR also induces an increase in the synthesis of apoproteins A-I, A-II and HDL-cholesterol.

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

Pharmacokinetics/Metabolism

Clinical experience has been obtained with two different formulations of fenofibrate: a "micronized" and "non- micronized" formulation, which have been demonstrated to be bioequivalent. Comparisons of blood levels following oral administration of both formulations in healthy volunteers demonstrate that a single capsule containing 67 mg of the "micronized" formulation is bioequivalent to 100 mg of the "non-micronized" formulation. Three capsules containing 67 mg fenofibrate are bioequivalent to a single 200 mg fenofibrate capsule.

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-labelled fenofibrate appeared in urine, primarily as fenofibric acid and its glucuronate conjugate, and 25% was excreted in the feces. Peak plasma levels of fenofibric acid occur within 6 to 8 hours after administration.

The absorption of fenofibrate is increased when administered with food. With micronized fenofibrate, the absorption is increased by approximately 35% under fed as compared to fasting conditions.

Distribution

In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days of dosing with single oral doses equivalent to 67 mg of fenofibrate capsules and did not demonstrate accumulation across time following multiple-dose administration. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.

Metabolism

Following oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid; no unchanged fenofibrate is detected in plasma.

Fenofibric acid is primarily conjugated with glucuronic acid and then excreted in urine. A small amount of fenofibric acid is reduced at the carbonyl moiety to a benzhydrol metabolite which is, in turn, conjugated with glucuronic acid and excreted in urine.

In vivo metabolism data indicate that neither fenofibrate nor fenofibric acid undergo oxidative metabolism (e.g., cytochrome P450) to a significant extent.

Excretion

After absorption, fenofibrate is mainly excreted in the urine in the form of metabolites, primarily fenofibric acid and fenofibric acid glucuronide. After administration of radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.

Fenofibric acid is eliminated with a half-life of 20 hours, allowing once daily administration in a clinical setting.

Special Populations

Geriatrics

In elderly volunteers 77 to 87 years of age, the oral clearance of fenofibric acid following a single oral dose of fenofibrate was 1.2 L/h, which compares to 1.1 L/h in young adults. This indicates that a similar dosage regimen can be used in the elderly, without increasing accumulation of the drug or metabolites.

Pediatrics

Fenofibrate capsules have not been investigated in adequate and well-controlled trials in pediatric patients.

Gender

No pharmacokinetic difference between males and females has been observed for fenofibrate.

Race

The influence of race on the pharmacokinetics of fenofibrate has not been studied, however fenofibrate is not metabolized by enzymes known for exhibiting inter-ethnic variability. Therefore, inter-ethnic pharmacokinetic differences are very unlikely.

Renal insufficiency

In a study in patients with severe renal impairment (creatinine clearance < 50 mL/min), the rate of clearance of fenofibric acid was greatly reduced, and the compound accumulated during chronic dosage. However, in patients having moderate renal impairment (creatinine clearance of 50 mL/min to 90 mL/min), the oral clearance and the oral volume of distribution of fenofibric acid are increased compared to healthy adults (2.1 L/h and 95 L versus 1.1 L/h and 30 L, respectively). Therefore, the dosage of fenofibrate capsules should be minimized in patients who have severe renal impairment, while no modification of dosage is required in patients having moderate renal impairment.

Hepatic insufficiency

No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.

Drug-drug interactions

In vitro studies using human liver microsomes indicate that fenofibrate and fenofibric acid are not inhibitors of cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.

Potentiation of coumarin-type anti-coagulants has been observed with prolongation of the prothrombin time/INR.

Bile acid sequestrants have been shown to bind other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption (see WARNINGS and PRECAUTIONS).

Clinical Trials

Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)

The effects of fenofibrate at a dose equivalent to 200 mg fenofibrate capsules 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 capsules therapy lowered LDL-C, Total-C and the LDL-C/HDL-C ratio. Fenofibrate capsules therapy also lowered triglycerides and raised HDL-C (see Table 1).

Table 1: Mean Percent Change in Lipid Parameters at End of Treatment+

Treatment Group	Total-C	LDL-C	HDL-C	TG
Pooled Cohort
Mean baseline lipid values (n=646)	306.9 mg/dL	213.8 mg/dL	52.3 mg/dL	191.0 mg/dL
All FEN (n=361)	-18.7%*	-20.6%*	+11.0%*	-28.9%*
Placebo (n=285)	-0.4%	-2.2%	+0.7%	+7.7%
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL (Type IIa)
Mean baseline lipid values (n=334)	307.7 mg/dL	227.7 mg/dL	58.1 mg/dL	101.7 mg/dL
All FEN (n=193)	-22.4%*	-31.4%*	+9.8%*	-23.5%*
Placebo (n=141)	0.2%	-2.2%	+2.6%	+11.7%
Baseline LDL-C > 160 mg/dL and TG < 150 mg/dL (Type IIb)
Mean baseline lipid values (n=242)	312.8 mg/dL	219.8 mg/dL	46.7 mg/dL	231.9 mg/dL
All FEN (n=126)	-16.8%*	-20.1%*	+14.6%*	-35.9%*
Placebo (n=116)	-3.0%	-6.6%	+2.3%	+0.9%
+ 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 capsules treatment significantly reduced apo B from baseline to endpoint as compared with placebo (-25.1% vs. 2.4%, p < 0.0001, n=213 and 143 respectively).

Hypertriglyceridemia (Fredrickson Type IV and V)

The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials1 of 147 hypertriglyceridemia patients (Fredrickson Types IV and V). Patients were treated for eight weeks under protocols that differed only in that one entered patients with baseline triglyceride (TG) levels of 500 to 1,500 mg/dL, and the other TG levels of 350 to 500 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia (Type IV/V hyperlipidemia), treatment with fenofibrate at dosages equivalent to 200 mg fenofibrate capsules per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2).

Table 2: Effects of Fenofibrate Capsules in Patients with Fredricks on Type IV/V Hyperlipidemia

Study 1	Placebo				Fenofibrate Capsules
Baseline TG levels 350 to 499 mg/dL	N	Baseline (Mean)	Endpoint (Mean)	% Change (Mean)	N	Baseline (Mean)	Endpoint (Mean)	% Change (Mean)
Triglycerides	28	449	450	-0.5	27	432	223	-46.2*
VLDL Triglycerides	19	367	350	2.7	19	350	178	-44.1*
Total Cholesterol	28	255	261	2.8	27	252	227	-9.1*
HDL Cholesterol	28	35	36	4	27	34	40	19.6*
LDL Cholesterol	28	120	129	12	27	128	137	14.5
VLDL Cholesterol	27	99	99	5.8	27	92	46	-44.7*
Study 2	Placebo				Fenofibrate Capsules
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*
* = p < 0.05 vs. Placebo

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