Prescription Drug Information: Fenofibrate (Page 3 of 5)

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 145 mg daily, based on body surface area (mg/m 2). Adverse reproductive outcomes occurred at higher doses in the presence of maternal toxicity (see Data). Fenofibrate 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 daily, equivalent to 145 mg fenofibrate daily, based on body surface area comparisons). Increased fetal skeletal malformations were observed at maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical exposure at the MRHD) that significantly suppressed maternal body weight gain.

In pregnant rabbits given oral gavage doses of 15, 150, and 300 mg/kg/day from gestation day 6 to 18 during the period of organogenesis and allowed to deliver, no adverse developmental findings were observed at 15 mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on body surface area comparisons). Aborted litters were observed at maternally toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the clinical exposure at the MRHD) that suppressed maternal body weight gain.

In pregnant rats given oral dietary doses of 15, 75, and 300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no adverse developmental effects were observed at 15 mg/kg/day (less than the clinical exposure at the MRHD, based on body surface area comparisons), despite maternal toxicity (decreased weight gain). Post-implantation loss was observed at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in the presence of maternal toxicity (decreased weight gain). Decreased pup survival was noted at 300 mg/kg/day (10 times the clinical exposure at the MRHD), which was associated with decreased maternal body weight gain/maternal neglect.

8.2 Lactation

Risk Summary

There is no available information on the presence of fenofibrate in human milk, effects of the drug on the breastfed infant, or the effects on milk production. Fenofibrate is present in the milk of rats, and is therefore likely to be present in human milk. Because of the potential for serious adverse reactions in breastfed infants, such as disruption of infant lipid metabolism, women should not breastfeed during treatment with fenofibrate and for 5 days after the final dose [see Contraindications (4)].

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

The use of fenofibrate should be avoided in patients who have 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 fenofibric acid is highly bound to plasma proteins, hemodialysis should not be considered.

11 DESCRIPTION

Fenofibrate, USP is a lipid regulating agent available as tablets for oral administration. Each tablet contains 48 mg or 145 mg of fenofibrate, USP. The chemical name for fenofibrate, USP is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, 1-methylethyl ester with the following structural formula:

Structural Formula
(click image for full-size original)

The molecular formula is C 20 H 21 O 4 Cl and the molecular weight is 360.83; fenofibrate, USP is very soluble in methylene chloride, slightly soluble in alcohol and practically insoluble in water.

The melting point is 79-82° C. Fenofibrate, USP is a white or almost white crystalline powder.

Inactive Ingredients

Each film-coated tablet contains colloidal silicon dioxide, crospovidone, hypromellose (3 cps), microcrystalline cellulose, polyvinyl alcohol, pregelatinized starch, sucrose, sodium lauryl sulfate, sodium stearyl fumarate, soybean lecithin, talc, titanium dioxide, and xanthan gum.

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-modifying effects of fenofibric acid seen in clinical practice have been explained in vivo in transgenic mice and in vitro in human hepatocyte cultures by the activation of peroxisome proliferator activated receptor α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity).

The resulting decrease in TG produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of apolipoproteins 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, LDL-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 TG, 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 apoAI and apoAII.

12.3 Pharmacokinetics

Plasma concentrations of fenofibric acid after administration of three 48 mg or one 145 mg tablets are equivalent under fed conditions to one 200 mg micronized fenofibrate capsule.

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 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.

Exposure to fenofibric acid in plasma, as measured by C max and AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.

Distribution

Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady state are approximately double of 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; 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 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 dosing.

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 elderly 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

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 (estimated glomerular filtration rate [eGFR] < 30 mL/min/1.73 m 2) 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 (eGFR 30 to 59 mL/min/1.73 m 2) 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 with hepatic impairment.

Drug-drug Interactions

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

Table 2 describes the effects of co-administered drugs on fenofibric acid systemic exposure. Table 3 describes the effects of co-administered fenofibrate or fenofibric acid on other drugs.

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

Co- Administered Drug

Dosage Regimen of Co-Administered Drug

Dosage Regimen of Fenofibrate

Changes in Fenofibric Acid Exposure

AUC

C max

Lipid-lowering agents

Atorvastatin

20 mg once daily for 10 days

Fenofibrate 160 mg 1 once daily for 10 days

↓2%

↓4%

Pravastatin

40 mg as a single dose

Fenofibrate 3 x 67 mg 2 as a single dose

↓1%

↓2%

Fluvastatin

40 mg as a single dose

Fenofibrate 160 mg 1 as a single dose

↓2%

↓10%

Anti-diabetic agents

Glimepiride

1 mg as a single dose

Fenofibrate 145 mg 1 once daily for 10 days

↑1%

↓1%

Metformin

850 mg three times daily for 10 days

Fenofibrate 54 mg 1 three times daily for 10 days

↓9%

↓6%

Rosiglitazone

8 mg once daily for 5 days

Fenofibrate 145 mg 1 once daily for 14 days

↑10%

↑3%

1 Fenofibrate oral tablet

2 Fenofibrate oral micronized capsule

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

Dosage Regimen of Fenofibrate

Dosage Regimen of Co-Administered Drug

Change in Co-Administered Drug Exposure

Analyte

AUC

C max

Lipid-lowering agents

Fenofibrate 160 mg 1 once daily for 10 days

Atorvastatin, 20 mg once daily for 10 days

Atorvastatin

↓17%

0%

Fenofibrate 3 x 67 mg 2 as a single dose

Pravastatin, 40 mg as a single dose

Pravastatin

↑13%

↑13%

3α -Hydroxyl-iso‑ pravastatin

↑26%

↑29%

Fenofibrate 160 mg 1 as a single dose

Fluvastatin, 40 mg as a single dose

(+)-3R, 5S‑ Fluvastatin

↑15%

↑16%

Anti-diabetic agents

Fenofibrate 145 mg 1 once daily for 10 days

Glimepiride, 1 mg as a single dose

Glimepiride

↑35%

↑18%

Fenofibrate 54 mg 1 three times daily for 10 days

Metformin, 850 mg three times daily for 10 days

Metformin

↑3%

↑6%

Fenofibrate 145 mg 1 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

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