LOFIBRA - fenofibrate tablet, film coated
Gate Pharmaceuticals
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LOFIBRA® (fenofibrate tablets), 54 mg and 160 mg
691
692
Rx only
DESCRIPTION
LOFIBRA® (fenofibrate tablets) is a lipid regulating agent available as tablets for oral administration. Each tablet contains 54 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
C20H21O4Cl M.W. 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.
Each 54 mg LOFIBRA® tablet contains the following inactive ingredients: colloidal silicone dioxide, croscarmellose sodium, crospovidone, iron oxide yellow, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium starch glycolate, sodium stearyl fumarate, talc, titanium dioxide, xanthan gum, and D&C yellow #10 lake.
Each 160 mg LOFIBRA® tablet contains the following inactive ingredients: colloidal silicone dioxide, croscarmellose sodium, crospovidone, lactose monohydrate, lecithin, microcrystalline cellulose, polyvinyl alcohol, povidone, sodium lauryl sulfate, sodium starch glycolate, sodium stearyl fumarate, talc, titanium dioxide, and xanthan gum.
CLINICAL PHARMACOLOGY
A variety of clinical studies have demonstrated that elevated levels of total cholesterol (total-C), low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are associated with human atherosclerosis. Similarly, decreased levels of high density lipoprotein cholesterol (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 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 apoproteins apoAI and apoAII.
The 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 fall 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 bouyant 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.
Pharmacokinetics/Metabolism
Plasma concentrations of fenofibric acid after administration of 54 mg and 160 mg tablets are equivalent under fed conditions to 67 mg and 200 mg capsules, respectively.
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 occur within 6 to 8 hours after administration.
The absorption of fenofibrate is increased when administered with food. With fenofibrate tablets, the extent of absorption is increased by approximately 35% under fed as compared to fasting conditions.
Distribution
In healthy volunteers, steady-state plasma levels of fenofibric acid were shown to be achieved within 5 days 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.
Excretion
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 20 hours, allowing once daily administration in a clinical setting.
Special Populations
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.
Pediatrics
Fenofibrate has not been investigated in adequate and well-controlled trials 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. Therefore, inter-ethnic pharmacokinetic differences are very unlikely.
Renal Insufficiency
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) 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 to 80 mL/min) 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 fenofibrate should be avoided in patients who have severe renal impairment and dose reduction is required in patients having mild to moderate renal impairment.
Hepatic Insufficiency
No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.
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 CYP2C19 and CYP2A6, and mild-to-moderate inhibitors of CYP2C9 at therapeutic concentrations.
Potentiation of coumarin-type anticoagulants has been observed with prolongation of the prothrombin time/INR.
Bile acid sequestrants have been shown to bind other drugs given concurrently. Therefore, fenofibrate should be taken at least 1 hour before or 4 to 6 hours after a bile acid binding resin to avoid impeding its absorption (see WARNINGS and PRECAUTIONS).
Concomitant administration of fenofibrate (equivalent to 160 mg) with pravastatin (40 mg) once daily for 10 days has been shown to increase the mean Cmax and AUC values for pravastatin by 36% (range from 69% decrease to 321% increase) and 28% (range from 54% decrease to 128% increase), respectively, and for 3α-hydroxy-iso-pravastatin by 55% (range from 32% decrease to 314% increase) and 39% (range from 24% decrease to 261% increase), respectively in 23 healthy adults.
Concomitant administration of a single dose of fenofibrate (equivalent to 160 mg) and a single dose of fluvastatin (40 mg) resulted in a small increase (approximately 15 to 16%) in exposure to (+)3R,5S-fluvastatin, the active enantiomer of fluvastatin.
A single dose of either pravastatin or fluvastatin had no clinically important effect on the pharmacokinetics of fenofibric acid.
Concomitant administration of fenofibrate (equivalent to 160 mg) with atorvastatin (20 mg) once daily for 10 days resulted in approximately 17% decrease (range from 67% decrease to 44% increase) in atorvastatin AUC values in 22 healthy males. The atorvastatin Cmax values were not significantly affected by fenofibrate. The pharmacokinetics of fenofibric acid were not significantly affected by atorvastatin.
Concomitant administration of fenofibrate (equivalent to 160 mg) once daily for 10 days with glimepiride (1 mg tablet) single dose simultaneously with the last dose of fenofibrate resulted in a 35% increase in mean AUC of glimepiride in healthy subjects. Glimepiride Cmax was not significantly affected by fenofibrate coadministration. There was no statistically significant effect of multiple doses of fenofibrate on glucose nadir or AUC with the baseline glucose concentration as the covariate after glimepiride administration in healthy volunteers. However, glucose concentrations at 24 hours remained statistically significantly lower after pretreatment with fenofibrate than with glimepiride alone. Glimepiride had no significant effect on the pharmacokinetics of fenofibric acid.
Concomitant administration of fenofibrate (54 mg) and metformin (850 mg) three times a day for 10 days resulted in no significant changes in the pharmacokinetics of fenofibric acid and metformin when compared with the two drugs administered alone in healthy subjects.
Concomitant administration of fenofibrate (equivalent to 160 mg) once daily for 14 days with rosiglitazone tablet (rosiglitazone maleate) (8 mg) once daily for 5 days, Day 10 through Day 14, resulted in no significant changes in the pharmacokinetics of fenofibric acid and rosiglitazone when compared with the two drugs administered alone in healthy subjects.
Concomitant administration of fenofibrate (equivalent to 160 mg) with ezetimibe (10 mg) once daily for 10 days to 18 healthy adults resulted in increases in total ezetimibe AUC, Cmax and Cmin of approximately 43%, 33% and 56%, respectively, and increases in ezetimibe glucuronide AUC, Cmax and Cmin of approximately 49%, 34% and 62%, respectively. The pharmacokinetics of fenofibric acid were not significantly affected by ezetimibe and the multiple-dose pharmacokinetics of free (unconjugated) ezetimibe were not significantly affected by fenofibrate.
Clinical Trials
Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb)
The effects of fenofibrate at a dose equivalent to 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; 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 1).
Table 1. 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 (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% |
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).
Hypertriglyceridemia (Fredrickson Type IV and V)
The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trials1 of 147 hypertriglyceridemic patients (Fredrickson Types IV and V). 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 (Type IV/V hyperlipidemia), treatment with fenofibrate at dosages equivalent to 160 mg per day decreased primarily very low density lipoprotein (VLDL) triglycerides and VLDL cholesterol. Treatment of patients with Type IV hyperlipoproteinemia and elevated triglycerides often results in an increase of low density lipoprotein (LDL) cholesterol (see Table 2).
Table 2: Effects of Fenofibrate in Patients With Fredrickson Type IV/V Hyperlipidemia
|
|
|
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* |
The effect of fenofibrate on cardiovascular morbidity and mortality has not been determined.
INDICATIONS AND USAGE
Treatment of Hypercholesterolemia
LOFIBRA® (fenofibrate tablets) is indicated as adjunctive therapy to diet to reduce elevated LDL-C, Total-C, Triglycerides and Apo B, and to increase HDL-C in adult patients with primary hypercholesterolemia or mixed dyslipidemia (Fredrickson Types IIa and IIb). Lipid-altering agents should be used in addition to a diet restricted in saturated fat and cholesterol when response to diet and non-pharmacological interventions alone has been inadequate (see National Cholesterol Education Program [NCEP] Treatment Guidelines, below).
Treatment of Hypertriglyceridemia
LOFIBRA® (fenofibrate tablets) is also indicated as adjunctive therapy to diet for treatment of adult patients with hypertriglyceridemia (Fredrickson Types IV and V hyperlipidemia). Improving glycemic control in diabetic patients showing fasting chylomicronemia will usually reduce fasting triglycerides and eliminate chylomicronemia thereby obviating the need for pharmacologic intervention.
Markedly elevated levels of serum triglycerides (e.g., > 2,000 mg/dL) may increase the risk of developing pancreatitis. The effect of fenofibrate therapy on reducing this risk has not been adequately studied.
Drug therapy is not indicated for patients with Type I hyperlipoproteinemia, who have elevations of chylomicrons and plasma triglycerides, but who have normal levels of very low density lipoprotein (VLDL). Inspection of plasma refrigerated for 14 hours is helpful in distinguishing Types I, IV and V hyperlipoproteinemia2.
The initial treatment for dyslipidemia is dietary therapy specific for the type of lipoprotein abnormality. Excess body weight and excess alcoholic intake may be important factors in hypertriglyceridemia and should be addressed prior to any drug therapy. Physical exercise can be an important ancillary measure. Diseases contributory to hyperlipidemia, such as hypothyroidism or diabetes mellitus should be looked for and adequately treated. Estrogen therapy, thiazide diuretics and beta-blockers, are sometimes associated with massive rises in plasma triglycerides, especially in subjects with familial hypertriglyceridemia. In such cases, discontinuation of the specific etiologic agent may obviate the need for specific drug therapy of hypertriglyceridemia.
The use of drugs should be considered only when reasonable attempts have been made to obtain satisfactory results with non-drug methods. If the decision is made to use drugs, the patient should be instructed that this does not reduce the importance of adhering to diet (see WARNINGS and PRECAUTIONS).
