Document
DailyMed Label: Fenoglide
Title
DailyMed Label: Fenoglide
Date
2010
Document type
DailyMed Prescription
Name
Fenoglide
Generic name
fenofibrate
Manufacturer
Physicians Total Care, Inc.
Product information
NDC: 54868-6118
Product information
NDC: 54868-6118
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:
The empirical formula is C 20 H 21 O 4 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.
image of chemical structure
Indications
Enter section text here
Fenoglide is a peroxisome proliferator receptor alpha (PPARα)
activator indicated:
as an adjunct to diet to reduce elevated LDL-C, Total-C, TG, and Apo B, and
to increase HDL-C in patients with primary hyperlipidemia or mixed dyslipidemia
when response to diet and non-pharmacological interventions alone has been
inadequate. ( 1.1 )
as an adjunct to diet to treat patients with hypertriglyceridemia. Improving
glycemic control in diabetic patients showing fasting chylomicronemia will
usually obviate the need for pharmacologic intervention. ( 1.2 ).
Fenofibrate was not shown to reduce coronary heart disease morbidity and
mortality in a large, randomized controlled trial of patients with type 2
diabetes mellitus. ( 1.3 ).
Fenoglide 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 hyperlipidemia or mixed dyslipidemia. 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.
Fenoglide is also indicated as adjunctive therapy to diet for treatment of adult
patients with hypertriglyceridemia. Improving glycemic control in diabetic
patients showing fasting chylomicronemia will usually reduce fasting
triglycerides and eliminate chylomicronemia thereby obviating the need for
pharmacologic intervention.
Fenofibrate was not shown to reduce coronary heart disease
morbidity and mortality in a large, randomized controlled trial of patients with
type 2 diabetes mellitus. [ see Warnings and
Precautions(5.6)
.]
Markedly elevated levels of serum triglycerides (e.g. >2,000 mg/dL) may
increase the risk of developing pancreatitis. The effect of Fenoglide therapy on
reducing this risk has not been adequately studied.
Drug therapy is not indicated for patients 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 these patients from those with elevated VLDL. 2
Dosage
Enter section text here
Primary hyperlipidemia and mixed dyslipidemia: 120 mg /day ( 2.1 )
Hypertriglyceridemia: 40 to 120 mg/day; the dose should be adjusted
according to patient response ( 2.2 )
Renally impaired patients: 40 mg/day; the dose should be increased according
to the effect on renal function and lipid levels ( 2.4 )
To increase absorption of Fenoglide, take with food.
The initial dose of Fenoglide is 120 mg per day.
The initial dose is 40 to 120 mg per day. Dosage should be individualized
according to patient response, and should be adjusted if necessary following
repeat lipid determinations at 4 to 8 week intervals. The maximum dose is 120 mg
per day.
Treatment with Fenoglide should be initiated at a dose of 40 mg/day in patients
with mild to moderately impaired renal function, and increased only after
evaluation of the effects on renal function and lipid levels at this dose. The
use of Fenoglide should be avoided in patients with severely impaired renal
function.
Dose selection for the elderly should be made on the basis of renal function.
[ See Use in Specific Populations
(8.5) . ]
To increase absorption of Fenoglide, take with food.
Dosage forms
40 mg: White to off-white oval tablets. Debossed "FLO".
120 mg: White to off-white oval tablets. Debossed "FHI".
40 mg: White to off-white oval tablets. Debossed "FLO".
120 mg: White to off-white oval tablets. Debossed "FHI".
Contraindications
Fenoglide is contraindicated in patients with severe renal dysfunction,
including those receiving dialysis [see Clinical Pharmacology (12.3) ]
Fenoglide is contraindicated in patients with active liver disease,
including those with primary biliary cirrhosis and unexplained persistent liver
function abnormalities [see Warnings and
Precautions(5.1) ]
Fenoglide is contraindicated in patients with gallbladder disease [see Warnings and Precautions (5.2) ]
Fenoglide is contraindicated in nursing mothers [see Use in Specific Populations (8.3) ]
Fenoglide is contraindicated in patients who have a known hypersensitivity
to fenofibrate, such as severe skin rashes, including Stevens-Johnson syndrome
and toxic epidermal necrolysis. [see Warnings and Precautions (5.9) ]
Severe renal dysfunction, including patients receiving dialysis ( 4 , 12.3 )
Active liver disease ( 4 , 5.1 )
Gallbladder disease ( 4 , 5.2 )
Nursing mothers ( 4 , 8.3 )
Warnings
Enter section text here
Fenofibrate can increase serum transaminases. Liver tests should be
periodically monitored ( 5.1 ).
Fenofibrate increases cholesterol excretion into the bile, leading to risk
of cholelithiasis. If cholelithiasis is suspected, gallbladder studies are
indicated. ( 5.2 )
Exercise caution in concomitant treatment with coumarin anticoagulants.
Reduce the dosage of coumarin to maintain the prothrombin time/INR at the
desired level to prevent bleeding complications ( 5.3 ).
Myopathy and rhabdomyolysis have been reported in patients taking
fenofibrate. The risk for serious muscle toxicity appears to be increased in
elderly patients and in patients with diabetes, renal failure, or hypothyroidism
( 5.4 )
Fenofibrate reversibly increases serum creatinine levels ( 5.5 )
Fenofibrate at doses equivalent to 87 mg to 130 mg fenofibrate
per day [at the highest dose, comparable to Fenoglide, 120 mg] can increase
serum transaminases [AST (SGOT) or ALT (SGPT)].
In a pooled analysis of 10 placebo-controlled trials, increases to >3
times the upper limit of normal occurred in 5.3% of patients taking fenofibrate
versus 1.1% of patients treated with placebo.
When transaminase determinations were followed either after discontinuation
of treatment or during continued treatment, a return to normal limits was
usually observed. The incidence of increases in transaminases related to
fenofibrate therapy appear to be dose related. In an 8-week dose-ranging study,
the incidence of ALT or AST elevations to at least three times the upper limit
of normal was 13% in patients receiving dosages equivalent to 87 mg to 130 mg
fenofibrate per day and was 0% in those receiving dosages equivalent to 43 mg or
less fenofibrate per day, or placebo. Hepatocellular, chronic active and
cholestatic hepatitis have been reported after exposures of weeks to several
years. In extremely rare cases, cirrhosis has been reported in association with
chronic active hepatitis.
Regular periodic monitoring of liver tests, including serum ALT (SGPT) should
be performed for the duration of therapy with Fenoglide, and therapy
discontinued if enzyme levels persist above three times the normal limit.
Fenofibrate increases cholesterol excretion into the bile, leading to risk of
cholelithiasis. If cholelithiasis is suspected, gallbladder studies are
indicated. Fenoglide therapy should be discontinued if gallstones are found.
Caution should be exercised when anticoagulants are given in conjunction with
Fenoglide because of the potentiation of coumarin-type anti-coagulants in
prolonging the prothrombin time/INR. The dosage of the anticoagulant should be
reduced to maintain the prothrombin time/INR at the desired level to prevent
bleeding complications. Frequent prothrombin time/INR determinations are
advisable until it has been definitely determined that the prothrombin time/INR
has stabilized. [ See Drug Interactions
(7.1) . ]
Treatment with fenofibrate increases risk of myopathy. Treatment
with fenofibrate increases risk of rhabdomyolysis, usually in patients with
impaired renal function. Myopathy should be considered in any patient with
diffuse myalgias, muscle tenderness or weakness, and/or marked elevations of
creatine phosphokinase (CPK) levels.
Patients should be advised to report promptly unexplained muscle pain,
tenderness or weakness, particularly if accompanied by malaise or fever. CPK
levels should be assessed in patients reporting these symptoms, and fenofibrate
therapy should be discontinued if markedly elevated CPK levels occur or myopathy
is diagnosed.
Elevations in serum creatinine have been reported in patients on fenofibrate.
These elevations tend to return to baseline following discontinuation of
fenofibrate. The clinical significance of these observations is unknown.
The Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) study was a 5-year randomized, placebo-controlled study of 9,795
patients with type 2 diabetes mellitus treated with fenofibrate. Fenofibrate
demonstrated a non-significant 11% relative reduction in the primary outcome of
coronary heart disease events (hazard ratio [HR] 0.89, 95% CI 0.75-1.05, p=0.16)
and a significant 11% reduction in the secondary outcome of total cardiovascular
disease events (HR 0.89 [0.80-0.99], p=0.04). There was a non-significant 11%
(HR 1.11 [0.95, 1.29], p=0.18) and 19% (HR 1.19 [0.90, 1.57], p=0.22) increase
in total and coronary heart disease mortality, respectively, with fenofibrate as
compared to placebo.
In the Coronary Drug Project, a large study of post myocardial infarction of
patients treated for 5 years with clofibrate, there was no difference in
mortality seen between the clofibrate group and the placebo group.
In a study conducted by the World Health Organization (WHO), 5000 subjects
without known coronary artery disease were treated with placebo or clofibrate
for 5 years and followed for an additional one year. There was a statistically
significant, higher age-adjusted all-cause mortality in the clofibrate group
compared with the placebo group (5.70% vs. 3.96%, p= less than 0.01). Excess mortality
was due to a 33% increase in non-cardiovascular causes, including malignancy,
post-cholecystectomy complications, and pancreatitis. This appeared to confirm
the higher risk of gallbladder disease seen in clofibrate-treated patients
studied in the Coronary Drug Project.
The Helsinki Heart Study was a large (n=4,081) study of middle-aged men
without a history of coronary artery disease. Subjects received either placebo
or gemfibrozil for 5 years, with a 3.5 year open extension afterward. Total
mortality was numerically higher in the gemfibrozil randomization group but did
not achieve statistical significance (p=0.19, 95% confidence interval for
relative risk G:P=0.91-1.64). Although cancer deaths trended higher in the
gemfibrozil group (p=0.11), cancers (excluding basal cell carcinoma) were
diagnosed with equal frequency in both study groups. Due to the limited size of
the study, the relative risk of death from any cause was not shown to be
different than that seen in the 9 year follow-up data from the WHO study
(RR=1.29).
A secondary prevention component of the Helsinki Heart Study enrolled
middle-aged men excluded from the primary prevention study because of known or
suspected coronary heart disease. Subjects received gemfibrozil or placebo for 5
years. Although cardiac deaths trended higher in the gemfibrozil group, this was
not statistically significant (hazard ratio 2.2, 95% confidence interval:
0.94-5.05).
Pancreatitis has been reported in patients taking fenofibrate. This occurrence
may represent a failure of efficacy in patients with severe
hypertriglyceridemia, a direct drug effect, or a secondary phenomenon mediated
through biliary tract stone or sludge formation with obstruction of the common
bile duct.
In the FIELD trial, pulmonary embolus (PE) and deep vein
thrombosis (DVT) were observed at higher rates in the fenofibrate- than the
placebo-treated group. Of 9,795 patients enrolled in FIELD, there were 4,900 in
the placebo group and 4,895 in the fenofibrate group. For DVT, there were 48
events (1%) in the placebo group and 67 (1%) in the fenofibrate group (p =
0.074); and for PE, there were 32 (0.7%) events in the placebo group and 53 (1%)
in the fenofibrate group (p = 0.022).
In the Coronary Drug Project, a higher proportion of the clofibrate group
experienced definite or suspected fatal or nonfatal pulmonary embolism or
thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p less than 0.01).
Acute hypersensitivity reactions including severe skin rashes requiring patient
hospitalization and treatment with steroids have occurred rarely during
treatment with fenofibrate, including rare spontaneous reports of
Stevens-Johnson syndrome, and toxic epidermal necrolysis.
Mild to moderate hemoglobin, hematocrit, and white blood cell decreases have
been observed in patients following initiation of fenofibrate therapy.
The combined use of fenofibric acid derivatives, particularly
gemfibrozil, and HMG-CoA reductase inhibitors results in an increased risk of
rhabdomyolysis and myoglobinuria leading in a high proportion of cases to acute
renal failure.
The combined use of Fenoglide and HMG-CoA reductase inhibitors should be
avoided unless the benefit of further alterations in lipid levels is likely to
outweigh the increased risk of this drug combination. [see
Drug Interactions (7.3) .]
Adverse reactions
To report SUSPECTED ADVERSE REACTIONS, contact Sciele Drug Safety Department at
1-800-849-9707 ext. 1454 or FDA at 1-800-FDA-1088 or
Drug interactions
Enter section text here
Coumarin Anticoagulants ( 7.1 )
Cyclosporine ( 7.2 )
HMG-CoA Reductase Inhibitors ( 7.3 )
Bile-Acid Resins ( 7.4 )
Caution should be exercised when coumarin anticoagulants are given in
conjunction with Fenoglide. The dosage of the anticoagulants should be reduced
to maintain the prothrombin time/INR at the desired level to prevent bleeding
complications. Frequent prothrombin time/INR determinations are advisable until
it has been definitely determined that the prothrombin time/INR has stabilized.
[ see Concomitant Coumarin Anticoagulants
(5.3) . ]
Because cyclosporine can produce nephrotoxicity with decreases in creatinine
clearance and rises in serum creatinine, and because renal excretion is the
primary elimination route of fibrate drugs including Fenoglide, there is a risk
that an interaction will lead to deterioration of renal function. The benefits
and risks of using Fenoglide with immunosuppressants and other potentially
nephrotoxic agents should be carefully considered, and the lowest effective dose
employed.
The combined use of fenofibric acid derivatives, particularly
gemfibrozil, and HMG-CoA reductase inhibitors results in an increased risk of
rhabdomyolysis and myoglobinuria leading in a high proportion of cases to acute
renal failure. [ See Concomitant HMG-CoA
Reductase Inhibitors (5.11)
]
The combined use of Fenoglide and HMG-CoA reductase inhibitors should be
avoided unless the benefit of further alterations in lipid levels is likely to
outweigh the increased risk of this drug combination.
In a single-dose drug interaction study in 23 healthy adults the concomitant
administration of fenofibrate and pravastatin resulted in no clinically
important difference in the pharmacokinetics of fenofibric acid, pravastatin, or
its active metabolite 3α-hydroxy iso-pravastatin when compared to either drug
given alone.
Since bile acid sequestrants may bind other drugs given concurrently, patients
should take Fenoglide at least 1 hour before or 4-6 hours after a bile acid
binding resin to avoid impeding its absorption.
Use in_specific_populations
Enter section text here
Geriatric Use: Dose selection for the elderly should be made on the basis of
renal function ( 8.5 ).
Renal impairment: Fenofibrate should be avoided in patients with severe
renal impairment and dose reduction is required in patients with mild to
moderate renal impairment ( 8.6 ).
Revised: 01/2009
Fenofibrate is classified as pregnancy category C. Fenofibrate has been shown to
be embryocidal and teratogenic in rats when given in doses 7 to 10 times the
maximum recommended human dose and embryocidal in rabbits when given at 9 times
the maximum recommended human dose (on the basis of mg/meter 2 surface area). There are no adequate and well-controlled
studies in pregnant women. Fenofibrate should be used during pregnancy only if
the potential benefit justifies the potential risk to the fetus. [see Nonclinical Toxicology [13] ).
Fenofibrate should not be used in nursing mothers. Because of the potential for
tumorigenicity seen in animal studies, a decision should be made whether to
discontinue nursing or to discontinue the drug.
Safety and efficacy in pediatric patients have not been established.
Fenofibric acid exposure is not influenced by age. However, elderly patients
have a higher incidence of renal impairment. Dose selection for the elderly
should be made on the basis of renal function.
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. Fenofibrate should be avoided in patients with severe renal
impairment and dose reduction is required in patients with mild to moderate
renal impairment.
How supplied
• NDC 54868-6118-0 :
120 mg White to off-white oval tablets. Debossed "FHI"; bottle of 30 tablets
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F)
[See USP Controlled Room Temperature].
Clinical pharmacology
Enter section text here
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 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 cholesterol (total-C), low density lipoprotein cholesterol
(LDL-C), and apolipoprotein B (apo B), an LDL membrane complex, are risk factors
for human atherosclerosis. Similarly, decreased levels of high density
lipoprotein cholesterol (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 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 apo AI and apo AII.
Plasma concentrations of fenofibric acid after single-dose
administration of Fenoglide (fenofibrate) 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, Fenoglide 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.
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. Fenofibrate acid from Fenoglide is eliminated with a
half-life of 23 hours, allowing once daily administration in a clinical
setting.
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 (2.4) and Use in
Specific Populations (8.5) . ]
Pediatrics: Fenoglide 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] less than or equal to 30 mL/min or estimated glomerular filtration rate [eGFR] less than 30
mL/min/1.73m 2 ) 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/1.73m 2 ) 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 (2.3) . ]
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. [ See
Concomitant Coumarin Anticoagulants
(5.3) . ] Bile-acid resins 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 Drug Interactions
(7.4) . ]
Nonclinical toxicology
Enter section text here
In a 24-month study in rats (10, 45, and 200 mg/kg; 0.3, 1, and 6
times the maximum recommended human dose on the basis of mg/meter 2 of surface area), the incidence of liver carcinoma was
significantly increased at 6 times the maximum recommended human dose in males
and females. A statistically significant increase in pancreatic carcinomas
occurred in males at 1 and 6 times the maximum recommended human dose; there
were also increases in pancreatic adenomas and benign testicular interstitial
cell tumors at 6 times the maximum recommended human dose in males. In a second
24-month study in a different strain of rats (doses of 10 and 60 mg/kg; 0.3 and
2 times the maximum recommended human dose based on mg/meter 2 surface area), there were significant increases in the
incidence of pancreatic acinar adenomas in both sexes and increases in
interstitial cell tumors of the testes at 2 times the maximum recommended human
dose.
A comparative carcinogenicity study was done in rats comparing three drugs:
fenofibrate (10 and 70 mg/kg; 0.3 and 1.6 times the maximum recommended human
dose), clofibrate (400 mg/kg; 1.6 times the human dose), and gemfibrozil (250
mg/kg; 1.7 times the human dose) (multiples based on mg/meter 2 surface area). Pancreatic acinar adenomas were increased in
males and females on fenofibrate; hepatocellular carcinoma and pancreatic acinar
adenomas were increased in males and hepatic neoplastic nodules in females
treated with clofibrate; hepatic neoplastic nodules were increased in males and
females treated with gemfibrozil while testicular interstitial cell tumors were
increased in males on all three drugs.
In a 21-month study in mice at doses of 10, 45, and 200 mg/kg (approximately
0.2, 0.7 and 3 times the maximum recommended human dose on the basis of
mg/meter 2 surface area), there were statistically
significant increases in liver carcinoma at 3 times the maximum recommended
human dose in both males and females. In a second 18-month study at the same
doses, there was a significant increase in liver carcinoma in male mice and
liver adenoma in female mice at 3 times the maximum recommended human dose.
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.
Administration of 9 times the maximum recommended human dose of fenofibrate
to female rats before and throughout gestation caused 100% of dams to delay
delivery and resulted in a 60% increase in post-implantation loss, a decrease in
litter size, a decrease in birth weight, a 40% survival of pups at birth, a 4%
survival of pups as neonates, and a 0% survival of pups to weaning, and an
increase in spina bifida.
Administration of 10 times the maximum recommended human dose to female rats
on days 6-15 of gestation caused an increase in gross, visceral and skeletal
findings in fetuses (domed head/hunched shoulders/rounded body/abnormal chest,
kyphosis, stunted fetuses, elongated sternal ribs, malformed sternebrae, extra
foramen in palatine, misshapen vertebrae, supernumerary ribs).
Administration of 7 times the maximum recommended human dose to female rats
from day 15 of gestation through weaning caused a delay in delivery, a 40%
decrease in live births, a 75% decrease in neonatal survival, and decreases in
pup weight, at birth as well as on days 4 and 21 post-partum.
Administration of 9 and 18 times the maximum recommended human dose to female
rabbits caused abortions in 10% of dams at 9 times and 25% of dams at 18 times
the maximum recommended human dose and death of 7% of fetuses at 18 times the
maximum recommended human dose.
Clinical studies
Enter section text here
The effects of fenofibrate at a dose equivalent to 120 mg Fenoglide 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 2 ).
Table 2. 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 greater than 160 mg/dL and TG less than 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 greater than 160 mg/dL and TG less than or equal to 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= less than 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 less than 0.0001, n=213 and 143 respectively).
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 120 mg Fenoglide (fenofibrate) Tablets 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
3 ).
Table 3. Effects of Fenofibrate in Patients With Hypertriglyceridemia
Study 1
Pla
cebo
Feno
fibrate
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
Pla
cebo
Feno
fibrate
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 less than 0.05 vs. placebo
Package label
FENOGLIDE (fenofibrate) tablet
120 mg
image of 120 mg package label
3 organizations
1 product
Product
FenofibrateOrganization
Shore Therapeutics, IncOrganization
Santarus, Inc.Organization
Physicians Total Care, Inc.