Source: FDA, National Drug Code (US) Revision Year: 2020
The active moiety of FIBRICOR 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, fenofibric acid 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 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.
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 apo AI and apo AII.
The absolute bioavailability of FIBRICOR has not been determined as the compound is virtually insoluble in aqueous media suitable for injection. Following oral administration of FIBRICOR in healthy volunteers, median peak plasma levels of fenofibric acid occur by approximately 2.5 hours after administration. Exposure after administration of 3 × 35 mg FIBRICOR tablets is comparable to 1 × 105 mg FIBRICOR tablets.
A food-effect study involving administration of FIBRICOR to healthy volunteers under fasting conditions and with a high-fat meal indicated that the Cmax was decreased by approximately 35% while the AUC remained unchanged. This decrease in exposure is not considered clinically significant, and therefore FIBRICOR can be taken without regards to meals.
The extent and rate of absorption of fenofibric acid after administration of 105 mg FIBRICOR tablets are equivalent to those after administration of 145 mg fenofibrate tablets (TriCor) under fasted conditions.
Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 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.
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 fenofibric acid does not undergo oxidative metabolism (e.g. cytochrome P450) to a significant extent. The enzymes CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4 do not play a role in the metabolism of fenofibric acid.
After absorption, fenofibric acid is eliminated with a half-life of approximately 20 hours, allowing once-daily dosing.
In five 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 an equivalent dose of FIBRICOR can be used in elderly subjects with normal renal function, without increasing accumulation of the drug or metabolites [see Use in Specific Populations (8.5) and Dosage and Administration (2.5)].
The pharmacokinetics of FIBRICOR has not been studied in pediatric populations.
No pharmacokinetic difference between males and females has been observed for fenofibrate.
The influence of race on the pharmacokinetics of fenofibric acid has not been studied, however, fenofibric acid is not metabolized by enzymes known for exhibiting inter-ethnic variability.
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/1.73m²) 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. Patients with mild-to-moderate (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 FIBRICOR should be avoided in patients who have severe renal impairment and dose reduction is required in patients with mild-to-moderate renal impairment.
No pharmacokinetic studies of fenofibric acid have been conducted in patients with hepatic impairment.
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 fenofibric acid on exposure to other drugs.
Table 2. Effects of Co-Administered Drugs on Fenofibric Acid Systemic Exposure from FIBRICOR or Fenofibrate Administration:
| Co-Administered Drug | Dosage Regimen of Co-Administered Drug | Dosage Regimen of Fenofibrate | Changes in Fenofibric Acid Exposure | |
|---|---|---|---|---|
| AUC | Cmax | |||
| No dosing adjustment required for FIBRICOR with the following co-administered drugs | ||||
| Lipid-lowering agents | ||||
| Atorvastatin | 20 mg once daily for 10 days | Fenofibrate 160 mg* once daily for 10 days | ↓2% | ↓4% |
| Pravastatin | 40 mg as a single dose | Fenofibrate 3 × 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 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% |
* TriCor (fenofibrate) oral tablet
† TriCor (fenofibrate) oral micronized capsule
Table 3. Effects of FIBRICOR or 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 | Cmax | ||
| No dosing adjustment required for these co-administered drugs with FIBRICOR | ||||
| Lipid-lowering agents | ||||
| Fenofibrate 160 mg* once daily for 10 days | Atorvastatin, 20 mg once daily for 10 days | Atorvastatin | ↓17% | 0% |
| Fenofibrate 3 × 67 mg† 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 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% |
| Anti-viral agents | ||||
| FIBRICOR 105 mg once daily for 10 days | Efavirenz, 600 mg as a single dose | Efavirenz | ↓8% | ↑1% |
* TriCor (fenofibrate) oral tablet
† TriCor (fenofibrate) oral micronized capsule
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) of 300 mg fenofibrate daily, equivalent to 105 mg of FIBRICOR daily, based on body surface area comparisons. 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, based on body surface area comparisons), clofibrate (400 mg/kg/day; 2 times the human dose), and gemfibrozil (250 mg/kg/day; 2 times the human dose, based on mg/m 2 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, based on body surface area comparisons) 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.
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.
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 body surface area comparisons).
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 protocol 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 105 mg of FIBRICOR decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of some with elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 4).
Table 4. 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?footnote? |
| 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
The effects of fenofibrate at doses equivalent to 105 mg of FIBRICOR 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 5).
Table 5. Mean Percent Change in Lipid Parameters at End of Fenofibrate 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 (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-C >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% |
* Duration of study treatment was 3 to 6 months.
† p = <0.05 vs. Placebo
In a subset of the subjects, measurement of Apo B was 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).
The effect of FIBRICOR on cardiovascular morbidity and mortality has not been determined.
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