FENOFIBRIC ACID capsule, delayed release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
FENOFIBRIC ACID (UNII: BGF9MN2HU1) (FENOFIBRIC ACID - UNII:BGF9MN2HU1)
Available from:
Aurobindo Pharma Limited
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce triglycerides (TG) in patients with severe hypertriglyceridemia. Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually obviate the need for pharmacological intervention. Markedly elevated levels of serum triglycerides (e.g., > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibric acid delayed-release capsules therapy on reducing this risk has not been adequately studied. Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce elevated low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG), and apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in patients with primary hypercholesterolemia or mixed dyslipidemia. Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsules did no
Product summary:
Fenofibric Acid Delayed-Release Capsules 45 mg are orange opaque cap/yellow opaque body size "3" hard gelatin capsules imprinted with "CFB" on cap and "45" on body with black ink and filled with white to off-white round cylindrical mini tablets. Bottles of 90                           NDC 59651-216-90 Fenofibric Acid Delayed-Release Capsules 135 mg are blue opaque cap/yellow opaque body size "0" hard gelatin capsules imprinted with "CFB" on cap and "135" on body with black ink and filled with white to off-white round cylindrical mini tablets. Bottles of 90                          NDC 59651-217-90 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.
Authorization status:
Abbreviated New Drug Application
Authorization number:
59651-216-90, 59651-217-90

FENOFIBRIC ACID - fenofibric acid capsule, delayed release

Aurobindo Pharma Limited

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use FENOFIBRIC ACID DELAYED-RELEASE

CAPSULES safely and effectively. See full prescribing information for FENOFIBRIC ACID DELAYED-RELEASE

CAPSULES.

FENOFIBRIC ACID delayed-release capsules, for oral use

Initial U.S. Approval: 2008

RECENT MAJOR CHANGES

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

INDICATIONS AND USAGE

Fenofibric acid delayed-release capsules are a peroxisome proliferator-activated receptor (PPAR) alpha agonist indicated

as adjunctive therapy to diet to:

Reduce TG in patients with severe hypertriglyceridemia (1.1).

Reduce elevated LDL-C, Total-C, TG and Apo B, and to increase HDL-C in patients with primary hypercholesterolemia

or mixed dyslipidemia (1.2).

Limitations of Use: Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsules did not reduce

coronary heart disease morbidity and mortality in patients with type 2 diabetes mellitus (5.1).

DOSAGE AND ADMINISTRATION

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

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

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

Maximum dose: 135 mg once daily (2.1).

May be taken without regard to food (2.1).

DOSAGE FORMS AND STRENGTHS

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

CONTRAINDICATIONS

Severe renal dysfunction, including patients receiving dialysis (4, 12.3).

Active liver disease (4, 5.3).

Gallbladder disease (4, 5.5).

Nursing mothers (4, 8.2).

Known hypersensitivity to fenofibric acid or fenofibrate (4, 5.9).

WARNINGS AND PRECAUTIONS

Myopathy and rhabdomyolysis have been reported in patients taking fenofibrate. Risks are increased in elderly patients

and patients with diabetes, renal failure, hypothyroidism, or statin co-administration (5.2).

Fenofibric acid delayed-release capsules can increase serum transaminases. Liver tests should be monitored

periodically (5.3).

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

periodically in patients with renal insufficiency (8.6).

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

suspected, gallbladder studies are indicated (5.5).

Use caution in concomitant treatment with oral coumarin anticoagulants. Adjust the dosage of coumarin anticoagulant to

maintain the prothrombin time/INR at the desired level to prevent bleeding complications (5.6).

Acute hypersensitivity reactions, including anaphylaxis and angioedema, and delayed hypersensitivity reactions,

including severe cutaneous adverse drug reactions have been reported postmarketing. Some cases were life-

threatening and required emergency treatment. Discontinue fenofibrate and treat patients appropriately if reactions

occur (5.9).

ADVERSE REACTIONS

The most common adverse events reported during clinical trials with fenofibrate (≥ 2% and at least 1% greater than

placebo) were abnormal liver tests, increased AST, increased ALT, increased CPK, and rhinitis (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact Aurobindo Pharma USA, Inc. at 1-866-850-2876 or

FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

Coumarin Anticoagulants: (7.1).

Bile Acid Binding Resins: (7.2).

Immunosuppressants: (7.3).

USE IN SPECIFIC POPULATIONS

Geriatric Use: Dose selection should be made based on renal function (8.5).

Renal Impairment: Avoid use in severe renal impairment patients. Dose adjustment is required in mild to moderate

renal impairment patients (8.6).

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 8/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

1.1 Treatment of Severe Hypertriglyceridemia

1.2 Treatment of Primary Hypercholesterolemia or Mixed Dyslipidemia

1.3 Limitations of Use

1.4 General Considerations for Treatment

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

2.2 Severe Hypertriglyceridemia

2.3 Primary Hypercholesterolemia or Mixed Dyslipidemia

2.4 Impaired Renal Function

2.5 Geriatric Patients

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Mortality and Coronary Heart Disease Morbidity

5.2 Skeletal Muscle

5.3 Liver Function

5.4 Serum Creatinine

5.5 Cholelithiasis

5.6 Coumarin Anticoagulants

5.7 Pancreatitis

5.8 Hematological Changes

5.9 Hypersensitivity Reactions

5.10 Venothromboembolic Disease

5.11 Paradoxical Decreases in HDL Cholesterol Levels

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Coumarin Anticoagulants

7.2 Bile Acid Binding Resins

7.3 Immunosuppressants

7.4 Colchicine

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

8.7 Hepatic Impairment

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Severe Hypertriglyceridemia

14.2 Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed

Dyslipidemia

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

1.1 Treatment of Severe Hypertriglyceridemia

Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce

triglycerides (TG) in patients with severe hypertriglyceridemia. Improving glycemic control in diabetic

patients showing fasting chylomicronemia will usually obviate the need for pharmacological

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

risk of developing pancreatitis. The effect of fenofibric acid delayed-release capsules therapy on

reducing this risk has not been adequately studied.

1.2 Treatment of Primary Hypercholesterolemia or Mixed Dyslipidemia

Fenofibric acid delayed-release capsules are indicated as adjunctive therapy to diet to reduce elevated

low-density lipoprotein cholesterol (LDL-C), total cholesterol (Total-C), triglycerides (TG), and

apolipoprotein B (Apo B), and to increase high-density lipoprotein cholesterol (HDL-C) in patients

with primary hypercholesterolemia or mixed dyslipidemia.

1.3 Limitations of Use

Fenofibrate at a dose equivalent to 135 mg of fenofibric acid delayed-release capsules did not reduce

coronary heart disease morbidity and mortality in 2 large, randomized controlled trials of patients with

type 2 diabetes mellitus [see Warnings and Precautions (5.1)].

1.4 General Considerations for Treatment

Laboratory studies should be performed to establish that lipid levels are abnormal before instituting

fenofibric acid delayed-release capsules therapy.

Every reasonable attempt should be made to control serum lipids with non-drug methods including

appropriate diet, exercise, weight loss in obese patients, and control of any medical problems such as

Sections or subsections omitted from the full prescribing information are not listed.

diabetes mellitus and hypothyroidism that may be contributing to the lipid abnormalities. Medications

known to exacerbate hypertriglyceridemia (beta-blockers, thiazides, estrogens) should be discontinued

or changed if possible, and excessive alcohol intake should be addressed before triglyceride-lowering

drug therapy is considered. If the decision is made to use lipid-altering drugs, the patient should be

instructed that this does not reduce the importance of adhering to diet.

Drug therapy is not indicated for patients who have elevations of chylomicrons and plasma

triglycerides, but who have normal levels of VLDL.

2 DOSAGE AND ADMINISTRATION

2.1 General Considerations

Patients should be placed on an appropriate lipid-lowering diet before receiving fenofibric acid

delayed-release capsules and should continue this diet during treatment. Fenofibric acid delayed-

release capsules can be taken without regard to meals. Patients should be advised to swallow

fenofibric acid delayed-release capsules whole. Do not open, crush, dissolve, or chew capsules.

Serum lipids should be monitored periodically.

2.2 Severe Hypertriglyceridemia

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

should be individualized according to patient response, and should be adjusted if necessary following

repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 135 mg once daily.

2.3 Primary Hypercholesterolemia or Mixed Dyslipidemia

The dose of fenofibric acid delayed-release capsules is 135 mg once daily.

2.4 Impaired Renal Function

Treatment with fenofibric acid delayed-release capsules should be initiated at a dose of 45 mg once

daily in patients with mild to moderate renal impairment and should only be increased after evaluation of

the effects on renal function and lipid levels at this dose. The use of fenofibric acid delayed-release

capsules should be avoided in patients with severely impaired renal function [see Use in Specific

Populations (8.6) and Clinical Pharmacology (12.3)].

2.5 Geriatric Patients

Dose selection for the elderly should be made on the basis of renal function [see Use in Specific

Populations (8.5)].

3 DOSAGE FORMS AND STRENGTHS

45 mg capsules with a orange opaque cap/yellow opaque body size "3" hard gelatin capsules

imprinted with "CFB" on cap and "45" on body with black ink and filled with white to off-white

round cylindrical mini tablets.

135 mg capsules with a blue opaque cap/yellow opaque body size "0" hard gelatin capsules

imprinted with "CFB" on cap and "135" on body with black ink and filled with white to off-white

round cylindrical mini tablets.

4 CONTRAINDICATIONS

Fenofibric acid delayed-release 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)].

nursing mothers [see Use in Specific Populations (8.2)].

patients with 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 effect of fenofibric acid delayed-release capsules on coronary heart disease morbidity and

mortality and non-cardiovascular mortality has not been established. Because of similarities between

fenofibric acid delayed-release capsules and fenofibrate, clofibrate, and gemfibrozil, the findings in the

following large randomized, placebo-controlled clinical studies with these fibrate drugs may also apply

to fenofibric acid delayed-release capsules.

The Action to Control Cardiovascular Risk in Diabetes Lipid (ACCORD Lipid) trial was a randomized

placebo-controlled study of 5518 patients with type 2 diabetes mellitus on background statin therapy

treated with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate plus statin

combination therapy showed a non-significant 8% relative risk reduction in the primary outcome of

major adverse cardiovascular events (MACE), a composite of non-fatal myocardial infarction, non-fatal

stroke, and cardiovascular disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p=0.32) as

compared to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE in men

receiving combination therapy versus statin monotherapy was 0.82 (95% CI 0.69-0.99), and the hazard

ratio for MACE in women receiving combination therapy versus statin monotherapy was 1.38 (95% CI

0.98-1.94) (interaction p=0.01). The clinical significance of this subgroup finding is unclear.

The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) study was a 5-year randomized,

placebo-controlled study of 9795 patients with type 2 diabetes mellitus treated with fenofibrate.

Fenofibrate demonstrated a non-significant 11% relative reduction in the primary outcome of coronary

heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p = 0.16) and a significant 11%

reduction in the secondary outcome of total cardiovascular disease events (HR 0.89 [0.80-0.99], p =

0.04). There was a non-significant 11% (HR 1.11 [0.95, 1.29], p = 0.18) and 19% (HR 1.19 [0.90, 1.57],

p = 0.22) increase in total and coronary heart disease mortality, respectively, with fenofibrate as

compared to placebo.

In the Coronary Drug Project, a large study of post-myocardial infarction patients treated for 5 years

with clofibrate, there was no difference in mortality seen between the clofibrate group and the placebo

group. There was, however, a difference in the rate of cholelithiasis and cholecystitis requiring

surgery between the two groups (3.0% vs. 1.8%).

In a study conducted by the World Health Organization (WHO), 5000 subjects without known coronary

artery disease were treated with placebo or clofibrate for 5 years and followed for an additional one

year. There was a statistically significant, higher age-adjusted all-cause mortality in the clofibrate

group compared with the placebo group (5.70% vs. 3.96%, p = < 0.01). Excess mortality was due to a

33% increase in non-cardiovascular causes, including malignancy, post- cholecystectomy

complications, and pancreatitis. This appeared to confirm the higher risk of gallbladder disease seen in

clofibrate-treated patients studied in the Coronary Drug Project.

The Helsinki Heart Study was a large (N = 4081) study of middle-aged men without a history of

coronary artery disease. Subjects received either placebo or gemfibrozil for 5 years, with a 3.5 year

open extension afterward. Total mortality was numerically higher in the gemfibrozil randomization

group but did not achieve statistical significance (p = 0.19, 95% confidence interval for relative risk

G:P = 0.91-1.64). Although cancer deaths trended higher in the gemfibrozil group (p = 0.11), cancers

(excluding basal cell carcinoma) were diagnosed with equal frequency in both study groups. Due to the

limited size of the study, the relative risk of death from any cause was not shown to be different than that

seen in the 9 year follow-up data from WHO study (RR = 1.29). A secondary prevention component of

the Helsinki Heart Study enrolled middle-aged men excluded from the primary prevention study because

of known or suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5 years.

Although cardiac deaths trended higher in the gemfibrozil group, this was not statistically significant

(hazard ratio 2.2, 95% confidence interval: 0.94-5.05).

5.2 Skeletal Muscle

Fibrates increase the risk of myositis or myopathy and have been associated with rhabdomyolysis. The

risk for serious muscle toxicity appears to be increased in elderly patients and in patients with diabetes,

renal failure, or hypothyroidism.

Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or weakness,

and/or marked elevations of CPK levels. Patients should promptly report unexplained muscle pain,

tenderness or weakness, particularly if accompanied by malaise or fever. CPK levels should be

assessed in patients reporting these symptoms, and fenofibric acid delayed-release capsules should be

discontinued if markedly elevated CPK levels occur or myopathy or myositis is suspected or

diagnosed.

Data from observational studies suggest that the risk for rhabdomyolysis is increased when fibrates are

co-administered with a statin.

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered

with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine [see

Drug Interactions (7.4)].

5.3 Liver Function

Fenofibric acid delayed-release capsules at a dose of 135 mg once daily has been associated with

increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In a pooled analysis of three 12-

week, double-blind, controlled studies of fenofibric acid delayed-release capsules, increases in ALT

and AST to > 3 times the upper limit of normal on two consecutive occasions occurred in 1.9% and

0.2%, respectively, of patients receiving fenofibric acid delayed-release capsules without other lipid-

altering drugs. Increases in ALT and/or AST were not accompanied by increases in bilirubin or

clinically significant increases in alkaline phosphatase.

In a pooled analysis of 10 placebo-controlled trials of fenofibrate, increases to > 3 times the upper limit

of normal in ALT occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated with

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

related. In an 8-week dose-ranging study of fenofibrate in hypertriglyceridemia, the incidence of ALT

or AST elevations ≥ 3 times the upper limit of normal was 13% in patients receiving dosages equivalent

to 90 mg to 135 mg fenofibric acid delayed-release capsules once daily and was 0% in those receiving

dosages equivalent to 45 mg fenofibric acid delayed-release capsules once daily or less, or placebo.

Hepatocellular, chronic active, and cholestatic hepatitis observed with fenofibrate therapy have been

reported after exposures of weeks to several years. In extremely rare cases, cirrhosis has been

reported in association with chronic active hepatitis.

Baseline and regular monitoring of liver function, including serum ALT (SGPT) should be performed

for the duration of therapy with fenofibric acid delayed-release capsules, and therapy discontinued if

enzyme levels persist above 3 times the upper limit of normal.

5.4 Serum Creatinine

Reversible elevations in serum creatinine have been reported in patients receiving fenofibric acid

delayed-release capsules as well as patients receiving fenofibrate. In the pooled analysis of three 12-

week, double-blind, controlled studies of fenofibric acid delayed-release capsules, increases in

creatinine to > 2 mg/dL occurred in 0.8% of patients treated with fenofibric acid delayed-release

capsules without other lipid-altering drugs. Elevations in serum creatinine were generally stable over

time with no evidence for continued increases in serum creatinine with long-term therapy and tended to

return to baseline following discontinuation of treatment. The clinical significance of these

observations is unknown. Monitoring renal function in patients with renal impairment taking fenofibric

acid delayed-release capsules are suggested. Renal monitoring should be considered for patients at risk

for renal insufficiency, such as the elderly and those with diabetes.

5.5 Cholelithiasis

Fenofibric acid delayed-release capsules, like fenofibrate, clofibrate, and gemfibrozil, may increase

cholesterol excretion into the bile, potentially leading to cholelithiasis. If cholelithiasis is suspected,

gallbladder studies are indicated. Fenofibric acid delayed-release capsules therapy should be

discontinued if gallstones are found.

5.6 Coumarin Anticoagulants

Caution should be exercised when fenofibric acid delayed-release capsules are given in conjunction

with oral coumarin anticoagulants. Fenofibric acid delayed-release capsules may potentiate the

anticoagulant effects of these agents resulting in prolongation of the prothrombin time/International

Normalized Ratio (PT/INR). Frequent monitoring of PT/INR and dose adjustment of the oral

anticoagulant are recommended until the PT/INR has stabilized in order to prevent bleeding

complications [see Drug Interactions (7.1)].

5.7 Pancreatitis

Pancreatitis has been reported in patients taking drugs of the fibrate class, including fenofibric acid

delayed-release capsules. This occurrence may represent a failure of efficacy in patients with severe

hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated through biliary tract

stone or sludge formation with obstruction of the common bile duct.

5.8 Hematological Changes

Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have been observed in

patients following initiation of fenofibric acid delayed-release capsules and fenofibrate therapy.

However, these levels stabilize during long-term administration. Thrombocytopenia and

agranulocytosis have been reported in individuals treated with fenofibrates. Periodic monitoring of red

and white blood cell counts are recommended during the first 12 months of fenofibric acid delayed-

release capsules administration.

5.9 Hypersensitivity Reactions

Acute Hypersensitivity

Anaphylaxis and angioedema have been reported postmarketing with fenofibrate. In some cases,

reactions were life-threatening and required emergency treatment. If a patient develops signs or

symptoms of an acute hypersensitivity reaction, advise them to seek immediate medical attention and

discontinue fenofibrate.

Delayed Hypersensitivity

Severe cutaneous adverse drug reactions (SCAR), including Stevens-Johnson syndrome, toxic

epidermal necrolysis, and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), have

been reported postmarketing, occurring days to weeks after initiation of fenofibrate. The cases of

DRESS were associated with cutaneous reactions (such as rash or exfoliative dermatitis) and a

combination of eosinophilia, fever, systemic organ involvement (renal, hepatic, or respiratory).

Discontinue fenofibrate and treat patients appropriately if SCAR is suspected.

5.10 Venothromboembolic Disease

In the FIELD trial, pulmonary embolus (PE) and deep vein thrombosis (DVT) were observed at higher

rates in the fenofibrate- than the placebo-treated group. Of 9,795 patients enrolled in FIELD, there were

4,900 in the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48 events (1%) in

the placebo group and 67 (1%) in the fenofibrate group (p = 0.074); and for PE, there were 32 (0.7%)

events in the placebo group and 53 (1%) in the fenofibrate group (p = 0.022).

In the Coronary Drug Project, a higher proportion of the clofibrate group experienced definite or

suspected fatal or nonfatal PE or thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years;

p < 0.01).

5.11 Paradoxical Decreases in HDL Cholesterol Levels

There have been postmarketing and clinical trial reports of severe decreases in HDL cholesterol levels

(as low as 2 mg/dL) occurring in diabetic and non-diabetic patients initiated on fibrate therapy. The

decrease in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been reported to

occur within 2 weeks to years after initiation of fibrate therapy. The HDL-C levels remain depressed

until fibrate therapy has been withdrawn; the response to withdrawal of fibrate therapy is rapid and

sustained. The clinical significance of this decrease in HDL-C is unknown. It is recommended that

HDL-C levels be checked within the first few months after initiation of fibrate therapy. If a severely

depressed HDL-C level is detected, fibrate therapy should be withdrawn, and the HDL-C level

monitored until it has returned to baseline, and fibrate therapy should not be re-initiated.

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 the rates observed in practice.

Fenofibric acid is the active metabolite of fenofibrate. Adverse events reported by 2% or more of

patients treated with fenofibrate and greater than placebo during double-blind, placebo-controlled trials

are listed in Table 1. 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 tests were the most frequent events,

causing discontinuation of fenofibrate treatment in 1.6% of patients in double-blind trials.

Table 1. Adverse Events 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 Event

(N = 439)

(N = 365)

BODY AS A WHOLE

Abdominal Pain

4.6%

4.4%

Back Pain

3.4%

2.5%

Headache

3.2%

2.7%

DIGESTIVE

Nausea

2.3%

1.9%

Constipation

2.1%

1.4%

INVESTIGATIONS

Abnormal Liver Tests

7.5%

1.4%

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 135 mg fenofibric acid delayed-release capsules

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.

Clinical trials with fenofibric acid delayed-release capsules did not include a placebo-control arm.

However, the adverse event profile of fenofibric acid delayed-release capsules was generally

consistent with that of fenofibrate. The following adverse events not listed above were reported in ≥

3% of patients taking fenofibric acid delayed-release capsules alone:

Gastrointestinal Disorders: Diarrhea, dyspepsia

General Disorders and Administration Site Conditions: Pain

Infections and Infestations: Nasopharyngitis, sinusitis, upper respiratory tract infection

Musculoskeletal and Connective Tissue Disorders: Arthralgia, myalgia, pain in extremity

Nervous System Disorders: Dizziness

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval 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: rhabdomyolysis,

pancreatitis, renal failure, muscle spasms, acute renal failure, hepatitis, cirrhosis, anemia, asthenia,

severely depressed HDL-cholesterol levels, and interstitial lung disease. Photosensitivity reactions to

fenofibrate 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 effect has been observed with prolongation of the PT/INR.

Caution should be exercised when oral coumarin anticoagulants are given in conjunction with fenofibric

acid delayed-release capsules. The dosage of the anticoagulant should be reduced to maintain the

PT/INR at the desired level to prevent bleeding complications. Frequent PT/INR determinations are

advisable until it has been definitely determined that the PT/INR has stabilized [see Warnings and

Precautions (5.6)].

7.2 Bile Acid Binding Resins

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

acid delayed-release capsules at least 1 hour before or 4 to 6 hours after a bile acid resin to avoid

impeding its absorption.

7.3 Immunosuppressants

Immunosuppressants such as cyclosporine and tacrolimus can produce nephrotoxicity with decreases in

creatinine clearance and rises in serum creatinine, and because renal excretion is the primary elimination

route of drugs of the fibrate class including fenofibric acid delayed-release capsules, there is a risk

that an interaction will lead to deterioration of renal function. The benefits and risks of using fenofibric

acid delayed-release capsules with immunosuppressants and other potentially nephrotoxic agents should

be carefully considered, and the lowest effective dose employed.

7.4 Colchicine

Cases of myopathy, including rhabdomyolysis, have been reported with fenofibrates co-administered

with colchicine, and caution should be exercised when prescribing fenofibrate with colchicine.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary

Limited available data with fenofibrate use in pregnant women are insufficient to determine a drug

associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. In animal

reproduction studies, no evidence of embryo-fetal toxicity was observed with oral administration of

fenofibrate in rats and rabbits during organogenesis at doses less than or equivalent to the maximum

recommended clinical dose of 135 mg daily, based on body surface area (mg/m ). Adverse reproductive

outcomes occurred at higher doses in the presence of maternal toxicity (see Data). Fenofibric acid

delayed-release capsules should be used during pregnancy only if the potential benefit justifies the

potential risk to the fetus.

The estimated background risk of major birth defects and miscarriage for the indicated population is

unknown. In the U.S. general population, the estimated background risk of major birth defects and

miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data

Animal Data

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, no adverse developmental findings were observed at 14 mg/kg/day (less

than the clinical exposure at the maximum recommended human dose [MRHD] of 300 mg fenofibrate

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