Fenoglide (Page 4 of 7)

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

8.4 Pediatric Use

Safety and efficacy 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 FENOGLIDE.

8.6 Renal Impairment

The use of FENOGLIDE 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 FENOGLIDE 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 FENOGLIDE. 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

FENOGLIDE (fenofibrate) Tablets is a lipid regulating agent available as tablets for oral administration. Each tablet contains 40 mg or 120 mg fenofibrate. 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 Cl 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: Each tablet contains lactose monohydrate, NF; Polyethylene Glycol 6000, NF; Poloxamer 188, NF; and magnesium stearate, NF.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The active moiety of FENOGLIDE 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 alpha (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 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, LDL-C, and apo B, an LDL membrane complex, are risk factors for human atherosclerosis. Similarly, decreased levels of HDL-C and its transport complex, apolipoprotein A (apo AI and apo AII) are risk factors for 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 TG on the risk of cardiovascular morbidity and mortality has not been determined.

Fenofibric acid, the active metabolite of fenofibrate, produces reductions in TC, LDL-C, apo B, total triglycerides, and triglyceride-rich lipoprotein (VLDL) in treated patients. In addition, treatment with fenofibrate results in increases in 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.

Plasma concentrations of fenofibric acid after single-dose administration of FENOGLIDE tablets, 120 mg are equivalent to those of Fenofibrate 130 mg capsules under high-fat conditions.

A high-fat meal did not affect the fenofibric acid AUC after FENOGLIDE administration but did increase the mean Cmax by 44% compared to fasting conditions.

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 from FENOGLIDE occur, on average, within 2 to 3 hours after administration.
Doses of three FENOGLIDE (fenofibrate) Tablets, 40 mg are considered to be equivalent to single doses of FENOGLIDE (fenofibrate) Tablets, 120 mg.
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 radiolabelled fenofibrate, approximately 60% of the dose appeared in the urine and 25% was excreted in the feces.
Fenofibric acid from FENOGLIDE 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, 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 FENOGLIDE 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 were 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 renal impairment (CrCl 30-80 mL/min or eGFR 30-59 mL/min/1.73m2) 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 FENOGLIDE 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 systemic exposure of other drugs.
Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Fenofibrate Administration
*
TriCor (fenofibrate) oral tablet
TriCor (fenofibrate) oral micronized capsule

Co-AdministeredDrug

Dosage Regimen ofCo-Administered Drug

Dosage Regimen of

Fenofibrate

Changes in FenofibricAcid Exposure

AUC

Cmax

Lipid-lowering agents

Atorvastatin

20 mg once daily for10 days

Fenofibrate 160 mg *once daily for 10 days

↓2%

↓4%

Pravastatin

40 mg as a single dose

Fenofibrate 3 x 67 mg as a single dose

↓1%

↓2%

Fluvastatin

40 mg as a single dose

Fenofibrate 160 mg *as a single dose

↓2%

↓10%

Anti-diabetic agents

Glimepiride

1 mg as a single dose

Fenofibrate 145 mg *once daily for 10 days

↑1%

↓1%

Metformin

850 mg three times dailyfor 10 days

Fenofibrate 54 mg * threetimes daily for 10 days

↓9%

↓6%

Rosiglitazone

8 mg once daily for 5 days

Fenofibrate 145 mg *once daily for 14 days

↑10%

↑3%

Table 3. Effects of Fenofibrate Co-Administration on Systemic Exposure of Other Drugs
*
TriCor (fenofibrate) oral tablet
TriCor (fenofibrate) oral micronized capsule

Dosage Regimen ofFenofibrate

Dosage Regimen ofCo-Administered Drug

Change in Co-Administered DrugExposure

Analyte

AUC

Cmax

Lipid-lowering agents

Fenofibrate 160 mg *once daily for 10 days

Atorvastatin, 20 mgonce daily for 10 days

Atorvastatin

↓17%

0%

Fenofibrate 3 x 67 mg as asingle dose

Pravastatin, 40 mgas a single dose

Pravastatin

↑13%

↑13%

3α-Hydroxyl-iso-pravastatin

↑26%

↑29%

Fenofibrate 160 mg * as a single dose

Fluvastatin, 40 mgas a single dose

(+)-3R,5S-Fluvastatin

↑15%

↑16%

Anti-diabetic agents

Fenofibrate 145 mg * once daily for 10 days

Glimepiride, 1 mgas a single dose

Glimepiride

↑35%

↑18%

Fenofibrate 54 mg * three times daily for 10 days

Metformin, 850 mg threetimes daily for 10 days

Metformin

↑3%

↑6%

Fenofibrate 145 mg * once daily for 14 days

Rosiglitazone, 8 mg oncedaily for 5 days

Rosiglitazone

↑6%

↓1%

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