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Antara (Fenofibrate) - Description and Clinical Pharmacology

 
 



DESCRIPTION

Antara (fenofibrate) Capsules, is a lipid regulating agent available as capsules for oral administration. Each capsule contains 43 mg or 130 mg of micronized fenofibrate. The chemical name for fenofibrate is 2-[4-(4-chlorobenzoyl) phenoxy]-2-methyl-propanoic acid, l-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°-82°C. Fenofibrate is a white solid which is stable under ordinary conditions.

Inactive Ingredients: Each gelatin capsule contains sugar spheres, hypromellose, sodium lauryl sulfate, dimethicone, simethicone, and talc. The gelatin capsules also contain black iron oxide, D&C Yellow #10, Indigo carmine FD&C Blue #2, shellac, soya lecithin, sulfur dioxide, titanium dioxide and yellow iron oxide.

CLINICAL PHARMACOLOGY

Mechanism of Action

The active moiety of Antara 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 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 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 total-C, DL-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 All) 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 triglycerides, 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 in treated patients. In addition, treatment with fenofibrate results in increases in high density lipoprotein (HDL) and apoproteins Apo AI and Apo AII.

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.

•       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 radio-labeled 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 Antara occur within 4 to 8 hours after administration. There was less than dose-proportional increase in the systemic exposure of fenofibric acid from 43 mg and 130 mg of Antara under fasting conditions.

Doses of three-capsules of 43 mg Antara given concurrently were dose equivalent to single-capsule doses of 130 mg.

The extent of absorption of fenofibric acid was unaffected when Antara was taken either in fasted state or with a low-fat meal. However, the Cmax of Antara increased in the presence of a low-fat meal. Tmax was unaffected in the presence of a low-fat meal. In the presence of a high-fat meal, there was a 26% increase in AUC and 108% increase in Cmax of fenofibric acid from Antara relative to fasting state.

•       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 (eg, 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 the feces.

Fenofibrate acid from Antara 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 with normal renal function, without increasing accumulation of the drug or metabolites [see Dosage and Administration and Use in Special Populations].

•       Pediatrics: The pharmacokinetics of Antara 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 (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 (CrCl 30-80 mL/min or eGFR 30-59 mL/min/1.73m2) renal impairment 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 Antara 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 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 (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitor 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 fenofibric acid on exposure to other drugs.

Table 2 Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from Antara or Fenofibrate Administration
Co - Administered  Drug
Dosage  Regimen  of  Co - Administered  Drug
Dosage  Regimen  of  Fenofibrate
Changes  in  Fenofibric  Acid  Exposure



AUC
Cmax
No  doing  adjustments  required  for  Antara  with  the  following  co - administered  drugs
Lipid - lowing  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 as a single dose
↓2%
↓10%
Anti - diabetic  agents
Glimepiride
1 mg once daily  as a single dose
Fenofibrate 145 mg once daily  for 10 days
↑1%
↓1%
Metformin
850 mg three times daily for 10 days
Fenofibrate 54 mg three times daily for 10 days
↓9%
↓6%
Rosiglitazone
8 mg once daily  for 5 days
Fenofibrate 145 mg once daily  for 14 days
↑10%
↑3%

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

Table 3 Effects of Antara or Fenofibrate Co-Administration on Systemic Exposure of Other Drugs
Dosage  Regimen  of  Fenofibrate
Dosage  Regimen  of  Co - Administered  Drug
Changes  in  Co - Administered  Drug  Exposure


Analyte
AUC
Cm a x
No  doing  adjustments  required  for  these  co - administered  drugs  with  Antara
Lipid - lowing  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  once daily for 10 days
Pravastatin, 40 mg once daily for 10 days
Pravastatin
↑28%
↑36%


3α-Hydroxyl-iso-pravastatin
↑39%
↑55%
Fenofibrate 160 mg  as a single dose
Fluvastatin, 40 mg as a single dose
(+)-3R, 5S-Fluvastatin
↑15%
↑16%
Anti - diabetic  agents
Fenofibrate 145 mg  once daily for 10 days
Glimepiride, 1 mg once daily as a single dose
Glimepiride
↑35%
↑18%
Fenofibrate 54 mg  three times daily for 10 days
Metformin, 850 mg three times daily for 10 days
Metformin
↑3%
↑6%
Fenofibrate 145 mg  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

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 the MRHD), the incidence of liver carcinomas 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 at 6 times the MRHD in males. In a second 24-month rat carcinogenicity 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/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m2 surface area). Fenofibrate increased pancreatic acinar adenomas in both sexes. Clofibrate increased hepatocellular carcinoma and pancreatic acinar adenomas 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 (~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 equivalent to 130 mg Antara 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; and 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

Duration of study treatment was 3 to 6 months.

*p=<0.05 vs. placebo

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 - 160  mg / dL  and 
TG  150  mg / dL  ( Type  IIa )




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 - 160  mg / dL  and 
TG  ≥  150  mg / dL  ( Type  IIb )




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%

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 TG levels of 500 to 1500 mg/dL, and the other TG levels of 350 to 499 mg/dL. In patients with hypertriglyceridemia and normal cholesterolemia with or without hyperchylomicronemia, treatment with fenofibrate at dosages equivalent to 130 mg Antara 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 LDL-C (See Table 5).

Table 5 Effects of Fenofibrate in Patients with 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 1
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
1.2
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

1 p < 0.05 vs. placebo

The effect of Antara on serum triglycerides was studied in a double-blind, randomized, 3 arm parallel-group trial of 146. The study population was comprised of 61 % male and 39% female patients. Approximately 70% of patients had hypertension and 32% had diabetes. Patients were treated for eight weeks with either Antara 130 mg taken once daily with meals, Antara 130 mg taken once daily between meals, or placebo. Antara 130 mg, whether taken with meals or between meals, had comparable effects on TG and all lipid parameters (See Table 6).

Table 6 Antara Treatment in Patients with Hypertriglyceridemia

Placebo
( = 50 )
Antara
with  meals  ( n = 54 )
Antara
between  meals  ( n = 42 )

Baseline
mg/dL
(mean)
% Change
at endpoint
(mean)
Baseline
mg/dL
(mean)
% Change at
endpoint
(mean)
Baseline
mg/dL
(mean)
% Change at
endpoint
(mean)
Triglycerides
479
+0.7
475
-36.7 1
487
-36.6
Total Cholesterol
237
-0.8
248
-5.1
241
-3.4
HDL Cholesterol
35
+0.8
36
+13.7
36
+14.3
Non-HDL Cholesterol
202
-1.1
212
-8.2 2
205
-6.6
LDL Cholesterol
115
+3.2
120
+15.4
122
+14.5
VLDL Cholesterol
87
-1.6
92
-34.4
83
-30.4

1 p ≤0.05 vs placebo
2 p ≤0.05 vs placebo (log transformed data)

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

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