Triglide (Fenofibrate) - Description and Clinical Pharmacology

DESCRIPTION

      Triglide (fenofibrate) Tablets, is a lipid regulating agent available as tablets for oral administration. Each tablet contains 50 mg or 160 mg of 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 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 is a white solid which is stable under ordinary conditions.

      Inactive Ingredients: Each tablet contains crospovidone, lactose monohydrate, mannitol, maltodextrin, carboxymethylcellulose sodium, egg lecithin, croscarmellose sodium, sodium lauryl sulfate, colloidal silicon dioxide, magnesium stearate, and monobasic sodium phosphate.

CLINICAL PHARMACOLOGY

Mechanism of Action

      The active moiety of Triglide 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 perxisome proliferators 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 artherogenic 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.

Pharmacodynamics

      A variety of clinical studies have demonstrated that elevated levels of TC, 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 TC, LDL-C, and triglycerides (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 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.

Pharmacokinetics

      Triglide 160 mg tablet was shown to have comparable bioavailability to a single dose of 200 mg fenofibrate capsule, micronized. 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. Fenofibrate is insoluble in water and its bioavailability is optimized when taken with meals. However, after fenofibrate is dissolved, 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 an average of 3 hours after administration. The extent of absorption of Triglide (AUC) is comparable between fed and fasted conditions.  Food increases the rate of absorption of Triglide approximately 55%.

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.

E limination: 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 approximately 16 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  and Use in Specific Populations .]

Pediatrics: Pharmacokinetics of Triglide 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 severe renal impairment (creatinine clearance [CrCl ≤ 30 mL/min] < 30 mL/min or estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m²) 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 eGRF 30-59 mL/min/1.73 m²) 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 Triglide 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 .]

Hepatic I mpairment: 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 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

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%
1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule

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
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%
1 TriCor (fenofibrate) oral tablet 2 TriCor (fenofibrate) oral micronized capsule

NONCLINICAL TOXICOLOGY

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 area 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).

CLINICAL STUDIES

Primary Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia

      The effects of fenofibrate at a dose comparable to Triglide 160 mg 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; 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
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%
* 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).

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 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, treatment with fenofibrate at dosages equivalent to 160 mg Triglide 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 low density lipoprotein (LDL) cholesterol (see Table 5).

Table 5. Effects of Fenofibrate in Patients With Severe 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	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*
* =p<0.05 vs. placebo ** Dosage comparable to 160 mg Triglide

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

HOW SUPPLIED/STORAGE AND HANDLING

• NDC 59630-480-30: bottles of 30 tablets. 50 mg, off-white round tablets, debossed "FH 50".
  
• NDC 59630-485-30: bottles of 30 tablets. 160 mg, off-white round tablets, debossed "FH 160".

      Store at 20°-25°C (68°-77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light and moisture. Store tablets only in the moisture protective container.