5.1 Mortality and Coronary Heart Disease Morbidity
Additions
and/or revisions underlined:
Fenofibrate
did not reduce cardiovascular disease morbidity or mortality two large, randomized
controlled trials of patients with type 2 diabetes mellitus [see Clinical Studies (14.4)].
Because
of chemical, pharmacological, and clinical similarities between fenofibrates,
including TRICOR; pemafibrate; clofibrate; and gemfibrozil; the
findings in 5 large randomized, placebo- controlled clinical trials with these
other fibrate drugs may also apply to TRICOR.
Pemafibrate
did not reduce cardiovascular disease morbidity or mortality in a large,
randomized, placebo-controlled trial of patients with type 2 diabetes mellitus
on background statin therapy [see
Clinical Studies (14.4)].
In
the Coronary Drug Project, a large trial conducted from 1965 to 1985 in men
post myocardial infarction, there was no difference in mortality or nonfatal
myocardial infarction between the clofibrate group and the placebo group after
5 years of treatment (NCT00000482).
In
a trial conducted by the World Health Organization (WHO) from 1965 to 1976,
men without known coronary artery disease were treated with placebo or
clofibrate for 5 years and followed for an additional 1 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
or equal to 0.01). Excess mortality was due to a 33% increase in
non-cardiovascular causes, including malignancy, post-cholecystectomy complications,
and pancreatitis.
The
Helsinki Heart Study, conducted from 1982 to 1987, was a large (n=4,081)
trial 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 but not statistically
higher in the gemfibrozil randomization group versus placebo [95%
confidence interval (CI) of the hazard ratio (HR) 0.91 to 1.64].
…
5.2 Hepatotoxicity
Additions
and/or revisions underlined:
Serious
drug-induced liver injury (DILI), including liver transplantation and death,
has been reported with postmarketing use of fenofibrates, including TRICOR.
DILI has been reported within the first few weeks of treatment or after several
months of therapy and in some cases has reversed with discontinuation of TRICOR
treatment.
…
In
clinical trials, an intermediate daily dosage or the maximum recommended
daily dosage of fenofibrate have been associated with increases in serum
AST or ALT. The incidence of increases in transaminases may be dose related [see Adverse Reactions (6.1)].
…
5.3 Myopathy and Rhabdomyolysis
Additions
and/or revisions underlined:
TRICOR
may cause
myopathy [muscle pain, tenderness, or weakness associated with elevated
creatine kinase (CK)] and rhabdomyolysis.
Risk
Factors for Myopathy
Risk
factors for myopathy include age 65 years or older, uncontrolled
hypothyroidism, renal impairment, and concomitant use with certain other
drugs [see Drug Interactions (7) and
Use in Specific Populations (8.6)].
Steps
to Prevent or Reduce the Risk of Myopathy and Rhabdomyolysis
Data
from observational studies indicate that the risk for rhabdomyolysis is
increased when fibrates, including fenofibrates, are co-administered
with a statin. Avoid concomitant use unless the benefit of further alterations
in TG levels is likely to outweigh the increased risk of this drug combination [see Drug Interactions (7), Clinical
Pharmacology (12.3), and Clinical
Studies (14.4)].
Cases
of myopathy, including rhabdomyolysis, have been reported with TRICOR co-
administered with colchicine. Consider whether the benefit of using
colchicine concomitantly with TRICOR outweighs the increased risk of
myopathy [see Drug Interactions (7)].
Discontinue
TRICOR if markedly elevated CK levels occur or if myopathy is either diagnosed
or suspected. Muscle symptoms and CK elevations may resolve if TRICOR is
discontinued.
Temporarily
discontinue TRICOR in patients experiencing an acute or serious condition at
high risk of developing renal failure secondary to rhabdomyolysis (e.g.,
sepsis; shock; severe hypovolemia; major surgery; trauma; severe metabolic,
endocrine, or electrolyte disorders; or uncontrolled epilepsy).
Inform
patients of the risk of myopathy and rhabdomyolysis when starting or increasing
the TRICOR dosage. Instruct patients to promptly report any unexplained muscle
pain, tenderness, or weakness, particularly if accompanied by malaise or fever.
5.4 Increases in Serum Creatinine
Section
title revised
Additions
and/or revisions underlined:
Increases
in serum creatinine have been reported in patients receiving fenofibrates.
These increases tend to return to baseline following discontinuation of TRICOR.
The clinical significance of this finding is unknown. Monitor renal function in
patients with renal impairment taking TRICOR. Renal monitoring should also be
considered for patients taking TRICOR at risk for renal insufficiency such as
geriatric patients and patients with diabetes. TRICOR is contraindicated in
patients with severe renal impairment, including those with end-stage renal
disease (ESRD) and those receiving dialysis [see Dosage and Administration (2.3), Use in Specific
Populations (8.6), and Clinical Pharmacology (12.3)].
5.5 Cholelithiasis
Additions
and/or revisions underlined:
Fenofibrate
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. TRICOR is contraindicated in
patients with pre-existing gallbladder disease.
5.6 Increased Bleeding Risk with Coumarin Anticoagulants
Section
title revised
…
5.9 Hypersensitivity Reactions
Additions
and/or revisions underlined:
Acute
Hypersensitivity
Anaphylaxis
and angioedema have been reported with postmarketing use of fenofibrates. 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 TRICOR. TRICOR
is contraindicated in patients with a hypersensitivity to fenofibrate,
fenofibric acid, or any of the ingredients in TRICOR.
Delayed
Hypersensitivity
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 with postmarketing use of fenofibrates occurring
days to weeks after treatment initiation. 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 TRICOR and treat patients appropriately
if SCAR is suspected.
5.10
Venothromboembolic Disease
Additions
and/or revisions underlined:
In
the Fenofibrate Intervention and Event Lowering in Diabetes (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 (1.4%) in the fenofibrate group (p = 0.074); and for PE, there
were 32 (0.7%) events in the placebo group and 53 (1.1%) in the
fenofibrate group (p = 0.022).
…
In
the cardiovascular outcome trial with pemafibrate, pulmonary embolism was
reported for 37 (0.7%) subjects in the pemafibrate group and 16 (0.3%) subjects
in the placebo group. Deep vein thrombosis was reported for 36 (0.7%) subjects
in the pemafibrate group and 13 (0.2%) subjects in
the placebo group.
Addition of the
following to the bulleted line listing:
Myopathy and Rhabdomyolysis [see Warnings and
Precautions (5.3)]
Increases in Serum Creatinine [see Warnings and
Precautions (5.4)]
Cholelithiasis [see Warnings
and Precautions (5.5)]
Increased Bleeding
Risk with Coumarin
Anticoagulants [see Warnings and Precautions
(5.6)]
Hematologic Changes [see Warnings and Precautions
(5.8)]
- Paradoxical
Decreases in HDL Cholesterol Levels [see
Warnings and Precautions (5.11)]
6.1 Clinical
Trials Experience
Additions and/or
revisions underlined:
Extensive changes
to Table 1; please refer to label for complete information
…
The safety of TRICOR has been established in adults
with hypertriglyceridemia or primary hyperlipidemia based on adequate and
well-controlled trials of other formulations of fenofibrate, referenced below
as “fenofibrate” [see Clinical Studies (14)]. Dosages of fenofibrate
used in these trials were comparable to TRICOR 145 mg per day [see Clinical Pharmacology (12.3)].
…
Increases
in Liver Enzymes
In a pooled analysis of 10 placebo-controlled
trials, increases to >3 times the upper limit of normal in ALT occurred in 5.3%
of patients taking either an intermediate or the maximum recommended daily
dosage of fenofibrate versus 1.1% of patients treated with placebo
6.2
Postmarketing Experience
Additions
and/or revisions underlined:
Blood: Anemia, white blood cell decreases
Gastrointestinal: Pancreatitis
General: Asthenia
Hepatobiliary: Increased total
bilirubin, hepatitis, cirrhosis
Immune System: Anaphylaxis,
angioedema
Lipid Disorders: Severely
depressed HDL-cholesterol levels
Musculoskeletal: Myalgia, muscle
spasms, rhabdomyolysis, arthralgia
Renal and Urinary: Acute renal
failure
Respiratory: Interstitial
lung disease
Skin and
Subcutaneous Tissue: Photosensitivity reactions days to months after
initiation. This may occur in patients who report a prior photosensitivity
reaction to ketoprofen.
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