Included as part of the PRECAUTIONS section.
Mortality And Coronary Heart Disease Morbidity
The effect of Trilipix on coronary heart disease
morbidity and mortality and non-cardiovascular mortality has not been
established. Because of similarities between Trilipix and fenofibrate,
clofibrate, and gemfibrozil, the findings in the following large randomized,
placebo-controlled clinical studies with these fibrate drugs may also apply to
The Action to Control Cardiovascular Risk in Diabetes
Lipid (ACCORD Lipid) trial was a randomized placebo-controlled study of 5518
patients with type 2 diabetes mellitus on background statin therapy treated
with fenofibrate. The mean duration of follow-up was 4.7 years. Fenofibrate
plus statin combination therapy showed a non-significant 8% relative risk
reduction in the primary outcome of major adverse cardiovascular events (MACE),
a composite of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular
disease death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08) (p=0.32) as compared
to statin monotherapy. In a gender subgroup analysis, the hazard ratio for MACE
in men receiving combination therapy versus statin monotherapy was 0.82 (95% CI
0.69-0.99), and the hazard ratio for MACE in women receiving combination
therapy versus statin monotherapy was 1.38 (95% CI 0.98-1.94) (interaction
p=0.01). The clinical significance of this subgroup finding is unclear.
The Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD) study was a 5-year randomized, placebo-controlled study of
9795 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 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%).
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, postcholecystectomy 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 = 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 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
Fibrates increase the risk of myositis or myopathy and
have been associated with rhabdomyolysis. The risk for serious muscle toxicity
appears to be increased in elderly patients and in patients with diabetes,
renal failure, or hypothyroidism.
Myopathy should be considered in any patient with diffuse
myalgias, muscle tenderness or weakness, and/or marked elevations of CPK levels.
Patients should promptly report unexplained muscle pain, tenderness or
weakness, particularly if accompanied by malaise or fever. CPK levels should be
assessed in patients reporting these symptoms, and Trilipix should be
discontinued if markedly elevated CPK levels occur or myopathy or myositis is
suspected or diagnosed.
Data from observational studies suggest that the risk for
rhabdomyolysis is increased when fibrates are co-administered with a statin.
Cases of myopathy, including rhabdomyolysis, have been
reported with fenofibrates co-administered with colchicine, and caution should
be exercised when prescribing fenofibrate with colchicine [see DRUG
Trilipix at a dose of 135 mg once daily has been
associated with increases in serum transaminases [AST (SGOT) or ALT (SGPT)]. In
a pooled analysis of three 12-week, double-blind, controlled studies of
Trilipix, increases in ALT and AST to > 3 times the upper limit of normal on
two consecutive occasions occurred in 1.9% and 0.2%, respectively, of patients
receiving Trilipix without other lipid-altering drugs. Increases in ALT and/or
AST were not accompanied by increases in bilirubin or clinically significant
increases in alkaline phosphatase.
In a pooled analysis of 10 placebo-controlled trials of
fenofibrate, increases to > 3 times the upper limit of normal in ALT
occurred in 5.3% of patients taking fenofibrate versus 1.1% of patients treated
with placebo. The incidence of increases in transaminases observed with fenofibrate
therapy may be dose related. In an 8-week dose-ranging study of fenofibrate in
hypertriglyceridemia, the incidence of ALT or AST elevations ≥ 3 times
the upper limit of normal was 13% in patients receiving dosages equivalent to
90 mg to 135 mg Trilipix once daily and was 0% in those receiving dosages
equivalent to 45 mg Trilipix once daily or less, or placebo. Hepatocellular,
chronic active, and cholestatic hepatitis observed 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
Baseline and regular monitoring of liver function,
including serum ALT (SGPT) should be performed for the duration of therapy with
Trilipix, and therapy discontinued if enzyme levels persist above 3 times the
upper limit of normal.
Reversible elevations in serum creatinine have been
reported in patients receiving Trilipix as well as patients receiving
fenofibrate. In the pooled analysis of three 12-week, double-blind, controlled
studies of Trilipix, increases in creatinine to > 2 mg/dL occurred in 0.8%
of patients treated with Trilipix without other lipid-altering drugs.
Elevations in serum creatinine were generally stable over time with no evidence
for continued increases in serum creatinine with long-term therapy and tended
to return to baseline following discontinuation of treatment. The clinical
significance of these observations is unknown. Monitoring renal function in
patients with renal impairment taking Trilipix is suggested. Renal monitoring
should be considered for patients at risk for renal insufficiency, such as the
elderly and those with diabetes.
Trilipix, like fenofibrate, clofibrate, and gemfibrozil,
may increase cholesterol excretion into the bile, potentially leading to
cholelithiasis. If cholelithiasis is suspected, gallbladder studies are
indicated. Trilipix therapy should be discontinued if gallstones are found.
Caution should be exercised when Trilipix is given in
conjunction with oral coumarin anticoagulants. Trilipix may potentiate the
anticoagulant effects of these agents resulting in prolongation of the
prothrombin time/International Normalized Ratio (PT/INR). Frequent monitoring
of PT/INR and dose adjustment of the oral anticoagulant are recommended until
the PT/INR has stabilized in order to prevent bleeding complications [see DRUG
Pancreatitis has been reported in patients taking drugs
of the fibrate class, including Trilipix. 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.
Mild to moderate hemoglobin, hematocrit, and white blood
cell decreases have been observed in patients following initiation of Trilipix
and fenofibrate therapy. However, these levels stabilize during long-term
administration. Thrombocytopenia and agranulocytosis have been reported in
individuals treated with fenofibrates. Periodic monitoring of red and white
blood cell counts are recommended during the first 12 months of Trilipix
Anaphylaxis and angioedema have been reported
postmarketing with fenofibrate. In some cases, reactions were life-threatening
and required emergency treatment. If a patient develops signs or symptoms of an
acute hypersensitivity reaction, advise them to seek immediate medical
attention and discontinue fenofibrate.
Severe cutaneous adverse drug reactions (SCAR), including
Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Reaction with
Eosinophilia and Systemic Symptoms (DRESS), have been reported postmarketing,
occurring days to weeks after initiation of fenofibrate. The cases of DRESS
were associated with cutaneous reactions (such as rash or exfoliative
dermatitis) and a combination of eosinophilia, fever, systemic organ
involvement (renal, hepatic, or respiratory). Discontinue fenofibrate and treat
patients appropriately if SCAR is suspected.
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 PE or
thrombophlebitis than the placebo group (5.2% vs. 3.3% at five years; p <
Paradoxical Decreases In HDL Cholesterol Levels
There have been postmarketing and clinical trial reports
of severe decreases in HDL cholesterol levels (as low as 2 mg/dL) occurring in
diabetic and non-diabetic patients initiated on fibrate therapy. The decrease
in HDL-C is mirrored by a decrease in apolipoprotein A1. This decrease has been
reported to occur within 2 weeks to years after initiation of fibrate therapy.
The HDL-C levels remain depressed until fibrate therapy has been withdrawn; the
response to withdrawal of fibrate therapy is rapid and sustained. The clinical
significance of this decrease in HDL-C is unknown. It is recommended that HDL-C
levels be checked within the first few months after initiation of fibrate
therapy. If a severely depressed HDL-C level is detected, fibrate therapy
should be withdrawn, and the HDL-C level monitored until it has returned to baseline,
and fibrate therapy should not be re-initiated.
Impairment Of Fertility
Trilipix (Fenofibric Acid)
No carcinogenicity and
fertility studies have been conducted with choline fenofibrate or fenofibric
acid. However, because fenofibrate is rapidly converted to its active
metabolite, fenofibric acid, either during or immediately following absorption
both in animals and humans, studies conducted with fenofibrate are relevant for
the assessment of the toxicity profile of fenofibric acid. A similar toxicity
spectrum is expected after treatment with either Trilipix or fenofibrate.
Two dietary carcinogenicity
studies have been conducted in rats with fenofibrate. In the first 24month
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 135 mg Trilipix 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/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, 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).
Use In Specific Populations
Limited available data with fenofibrate use in pregnant
women are insufficient to determine a drug associated risk of major birth
defects, miscarriage or adverse maternal or fetal outcomes. In animal
reproduction studies, no evidence of embryo-fetal toxicity was observed with
oral administration of fenofibrate in rats and rabbits during organogenesis at
doses less than or equivalent to the maximum recommended clinical dose of 135
mg daily, based on body surface area (mg/m²). Adverse reproductive outcomes occurred
at higher doses in the presence of maternal toxicity (see Data).
Trilipix should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
The estimated background risk of major birth defects and
miscarriage for the indicated population is unknown. In the U.S. general
population, the estimated background risk of major birth defects and
miscarriage in clinically recognized pregnancies is 2-4% and 15-20%,
In pregnant rats given oral dietary doses of 14, 127, and
361 mg/kg/day from gestation day 6-15 during the period of organogenesis, no
adverse developmental findings were observed at 14 mg/kg/day (less than the
clinical exposure at the maximum recommended human dose [MRHD] of 300 mg
fenofibrate daily, equivalent to 135 mg Trilipix daily, based on body surface
area comparisons). Increased fetal skeletal malformations were observed at
maternally toxic doses (361 mg/kg/day, corresponding to 12 times the clinical
exposure at the MRHD) that significantly suppressed maternal body weight gain.
In pregnant rabbits given oral gavage doses of 15, 150,
and 300 mg/kg/day from gestation day 618 during the period of organogenesis and
allowed to deliver, no adverse developmental findings were observed at 15
mg/kg/day (a dose that approximates the clinical exposure at the MRHD, based on
body surface area comparisons). Aborted litters were observed at maternally
toxic doses (≥ 150 mg/kg/day, corresponding to ≥ 10 times the
clinical exposure at the MRHD) that suppressed maternal body weight gain.
In pregnant rats given oral dietary doses of 15, 75, and
300 mg/kg/day from gestation day 15 through lactation day 21 (weaning), no
adverse developmental effects were observed at 15 mg/kg/day (less than the
clinical exposure at the MRHD, based on body surface area comparisons), despite
maternal toxicity (decreased weight gain). Post-implantation loss was observed
at ≥ 75 mg/kg/day (≥ 2 times the clinical exposure at the MRHD) in
the presence of maternal toxicity (decreased weight gain). Decreased pup
survival was noted at 300 mg/kg/day (10 times the clinical exposure at the
MRHD), which was associated with decreased maternal body weight gain/maternal
There is no available information on the presence of
fenofibrate in human milk, effects of the drug on the breastfed infant, or the
effects on milk production. Fenofibrate is present in the milk of rats, and is
therefore likely to be present in human milk. Because of the potential for
serious adverse reactions in breastfed infants, such as disruption of infant
lipid metabolism, women should not breastfeed during treatment with Trilipix
and for 5 days after the final dose [see CONTRAINDICATIONS].
The safety and effectiveness of Trilipix in pediatric
patients have not been established.
Trilipix is substantially excreted by the kidney as
fenofibric acid and fenofibric acid glucuronide, and the risk of adverse
reactions to this drug may be greater in patients with impaired renal function.
Fenofibric acid exposure is not influenced by age. Since elderly patients have
a higher incidence of renal impairment, dose selection for the elderly should
be made on the basis of renal function [see DOSAGE AND ADMINISTRATION and
CLINICAL PHARMACOLOGY]. Elderly patients with normal renal function
should require no dose modifications. Consider monitoring renal function in
elderly patients taking Trilipix.
The use of Trilipix should be avoided in patients who
have severe renal impairment [see CONTRAINDICATIONS]. Dose reduction is
required in patients with mild to moderate renal impairment [see DOSAGE AND
ADMINISTRATION and CLINICAL PHARMACOLOGY]. Monitoring renal function
in patients with renal impairment is recommended.
The use of Trilipix has not been evaluated in subjects
with hepatic impairment [see CONTRAINDICATIONS and CLINICAL