Prescription Drug Information: Fenofibrate (Page 3 of 5)

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 capsules and for 5 days after the final dose [see Contraindications (4)].

8.3 Females and Males of Reproductive Potential

Infertility

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) [see Carcinogenesis, Mutagenesis, Impairment of Fertility (13.1)].

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 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 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:

structure
(click image for full-size original)

The empirical formula is C20 H21 O4 C1 and the molecular weight is 360.83; fenofibrate is insoluble in water. The melting point is 79-82o C. 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 α (PPARα). Through this mechanism, fenofibrate increases lipolysis and elimination of triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing production of apoprotein C-III (an inhibitor of lipoprotein lipase activity). The resulting decrease in triglycerides produces an alteration in the size and composition of LDL from small, dense particles (which are thought to be atherogenic due to their susceptibility to oxidation), to large buoyant particles. These larger particles have a greater affinity for cholesterol receptors and are catabolized rapidly. Activation of PPARα also induces an increase in the synthesis of 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 μg/mL compared to 204 μg/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%

3α-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%

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