A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Tricor Warnings, Precautions, Pregnancy, Nursing, Abuse - Fenofibrate
Tricor Warnings, Precautions, Pregnancy, Nursing, Abuse - Fenofibrate
WARNINGS
Liver Function
Fenofibrate at doses equivalent to 107 mg to 160 mg TRICOR
per day has been associated with increases in 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 107 mg to
160 mg TRICOR per day and was 0% in those receiving dosages equivalent to 54
mg or less TRICOR per day, or placebo. Hepatocellular, chronic active and cholestatic
hepatitis associated with fenofibrate therapy 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 function, including serum
ALT (SGPT) should be performed for the duration of therapy with TRICOR, and
therapy discontinued if enzyme levels persist above three times the normal limit.
Cholelithiasis
Fenofibrate, like clofibrate and gemfibrozil, may increase
cholesterol excretion into the bile, leading to cholelithiasis. If cholelithiasis
is suspected, gallbladder studies are indicated. TRICOR therapy should be discontinued
if gallstones are found.
Concomitant Oral Anticoagulants
Caution should be exercised when anticoagulants are given in
conjunction with TRICOR because of the potentiation of coumarin-type anticoagulants
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.
Concomitant HMG-CoA Reductase Inhibitors
The combined use of TRICOR 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 TRICOR and pravastatin resulted in no clinically
important difference in the pharmacokinetics of fenofibric acid, pravastatin
or its active metabolite 3a-hydroxy iso-pravastatin when compared to either
drug given alone.
The combined use of fibric acid derivatives and HMG-CoA reductase
inhibitors has been associated, in the absence of a marked pharmacokinetic interaction,
in numerous case reports, with rhabdomyolysis, markedly elevated creatine kinase
(CK) levels and myoglobinuria, leading in a high proportion of cases to acute
renal failure.
The use of fibrates alone, including TRICOR, may occasionally
be associated with myositis, myopathy, or rhabdomyolysis. Patients receiving
TRICOR and complaining of muscle pain, tenderness, or weakness should have prompt
medical evaluation for myopathy, including serum creatine kinase level determination.
If myopathy/myositis is suspected or diagnosed, TRICOR therapy should be stopped.
Mortality
The effect of TRICOR on coronary heart disease morbidity and
mortality and non-cardiovascular mortality has not been established.
Other Considerations
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. There
was however, a difference in the rate of cholelithiasis and cholecystitis requiring
surgery between the two groups (3.0% vs. 1.8%).
Because of chemical, pharmacological, and clinical similarities
between TRICOR (fenofibrate tablets), Atromid-S (clofibrate),and Lopid (gemfibrozil),the
adverse findings in 4 large randomized, placebo-controlled clinical studies
with these other fibrate drugs may also apply to TRICOR.
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=<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=4081) 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=.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 World Health Organization study
(RR=1.29). Similarly, the numerical excess of gallbladder surgeries in the gemfibrozil
group did not differ statistically from that observed in the WHO study.
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). The rate of gallbladder surgery was not statistically significant
between study groups, but did trend higher in the gemfibrozil group, (1.9% vs.
0.3%, p=0.07). There was a statistically significant difference in the number
of appendectomies in the gemfibrozil group (6/311 vs. 0/317, p=0.029).
PRECAUTIONS
Initial therapy
Laboratory studies should be done to ascertain that the lipid
levels are consistently abnormal before instituting TRICOR therapy. Every attempt
should be made to control serum lipids with appropriate diet, exercise, weight
loss in obese patients, and control of any medical problems such as diabetes
mellitus and hypothyroidism that are contributing to the lipid abnormalities.
Medications known to exacerbate hypertriglyceridemia (beta-blockers, thiazides,
estrogens) should be discontinued or changed if possible prior to consideration
of triglyceride-lowering drug therapy.
Continued therapy
Periodic determination of serum lipids should be obtained during
initial therapy in order to establish the lowest effective dose of TRICOR. Therapy
should be withdrawn in patients who do not have an adequate response after two
months of treatment with the maximum recommended dose of 160 mg per day.
Pancreatitis
Pancreatitis has been reported in patients taking fenofibrate,
gemfibrozil, and clofibrate. 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.
Hypersensitivity Reactions
Acute hypersensitivity reactions including severe skin rashes
requiring patient hospitalization and treatment with steroids have occurred
very rarely during treatment with fenofibrate, including rare spontaneous reports
of Stevens-Johnson syndrome, and toxic epidermal necrolysis. Urticaria was seen
in 1.1 vs 0%, and rash in 1.4 vs 0.8% of fenofibrate and placebo patients respectively
in controlled trials.
Hematologic Changes
Mild to moderate hemoglobin, hematocrit, and white blood cell
decreases have been observed in patients following initiation of fenofibrate
therapy. However, these levels stabilize during long-term administration. Extremely
rare spontaneous reports of thrombocytopenia and agranulocytosis have been received
during post-marketing surveillance outside of the U.S. Periodic blood counts
are recommended during the first 12 months of TRICOR administration.
Skeletal muscle
The use of fibrates alone, including TRICOR, may occasionally
be associated with myopathy. Treatment with drugs of the fibrate class has been
associated on rare occasions with 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
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.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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/meter2
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/meter2 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/meter2 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/meter2 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.
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/meter2 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.
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.
Nursing mothers
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.
Pediatric Use
Safety and efficacy in pediatric patients have not been established.
Geriatric Use
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. Because elderly patients are more likely to have
decreased renal function, care should be taken in dose selection.
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