TRICOR (Tablet)

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Patients should be placed on an appropriate lipid-lowering diet before receiving TRICOR, and should continue this diet during treatment with TRICOR. TRICOR tablets can be given without regard to meals. For the treatment of adult patients with primary hypercholesterolemia or mixed hyperlipidemia, the initial dose of TRICOR is 145 mg per day. For adult patients with hypertriglyceridemia, the initial dose is 48 to 145 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 145 mg per day. Treatment with TRICOR should be initiated at a dose of 48 mg/day in patients having mild to moderately impaired renal function, and increased only after evaluation of the effects on renal function and lipid levels at this dose. Lipid levels should be monitored periodically and consideration should be given to reducing the dosage of TRICOR if lipid levels fall significantly below the targeted range.

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��(PPAR��). 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 greateraffinity for cholesterol receptors and are catabolized rapidly. Activation of PPAR��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.<br/>Pharmacokinetics/Metabolism: Plasma concentrations of fenofibric acid after administration of three 48 mg or one 145 mg tablets are equivalent under fed conditions to one 200 mg capsule.<br/>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. Exposure to fenofibric acid in plasma, as measured by Cand AUC, is not significantly different when a single 145 mg dose of fenofibrate is administered under fasting or nonfasting conditions.<br/>Distribution: Upon multiple dosing of fenofibrate, fenofibric acid steady state is achieved within 9 days. Plasma concentrations of fenofibric acid at steady state are approximately double those following a single dose. Serum protein binding was approximately 99% in normal and hyperlipidemic subjects.<br/>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.<br/>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.<br/>Special Populations:<br/>Geriatrics: In elderly volunteers 77 - 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.<br/>Pediatrics: TRICOR has not been investigated in adequate and well-controlled trials in pediatric patients.<br/>Gender: No pharmacokinetic difference between males and females has been observed for fenofibrate.<br/>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.<br/>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 30-80 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 TRICOR should be avoided in patients who have severe renalimpairment and dose reduction is required in patients having mild to moderate renal impairment.<br/>Hepatic Insufficiency: No pharmacokinetic studies have been conducted in patients having hepatic insufficiency.<br/>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 CYP2C8, 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 4-6 hours after a bile acid binding resin to avoid impeding its absorption. (See WARNINGS and PRECAUTIONS). Concomitant administration of fenofibrate (equivalent to TRICOR 145 mg) with pravastatin (40 mg) once daily for 10 days has been shown to increase the mean Cand 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 3��-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 145 mg TRICOR) and a single dose of fluvastatin (40 mg) resulted in a small increase (approximately 15-16%) 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 TRICOR 145 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 valuesin 22 healthy males. The atorvastatin Cvalues were not significantly affected by fenofibrate. The pharmacokinetics of fenofibric acid were not significantly affected by atorvastatin. Concomitant administration of fenofibrate (equivalent to TRICOR 145 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 Cwas not significantly affected by fenofibrate co-administration. 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 TRICOR 145 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 withthe two drugs administered alone in healthy subjects. Concomitant administration of fenofibrate (145 mg TRICOR) with ezetimibe (10 mg) once daily for 10 days to 18 healthy adults resulted in increases in total ezetimibe AUC, Cand Cof approximately 43%, 33% and 56%, respectively, and increases in ezetimibe glucuronide AUC, Cand Cof 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.<br/>Clinical Trials:<br/>Hypercholesterolemia (Heterozygous Familial and Nonfamilial) and Mixed Dyslipidemia (Fredrickson Types IIa and IIb): The effects of fenofibrate at a dose equivalent to 145 mg TRICOR (fenofibrate tablets) 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. TRICOR therapy lowered LDL-C, Total-C, and the LDL-C/HDL-C ratio. TRICOR therapy also lowered triglycerides and raised HDL-C (see Table 1). In a subset of the subjects, measurements of apo B were conducted. TRICOR 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).<br/>Hypertriglyceridemia (Fredrickson Type IV and V): The effects of fenofibrate on serum triglycerides were studied in two randomized, double-blind, placebo-controlled clinical trialsof 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 TRICOR 145 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). The effect of TRICOR on cardiovascular morbidity and mortality has not been determined.

TRICOR is contraindicated in patients who exhibit hypersensitivity to fenofibrate. TRICOR is contraindicated in patients with hepatic or severe renal dysfunction, including primary biliary cirrhosis, and patients with unexplained persistent liver function abnormality. TRICOR is contraindicated in patients with preexisting gallbladder disease (see WARNINGS).

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There is no specific treatment for overdose with TRICOR. General supportive care of the patient is indicated, including monitoring of vital signs and observation of clinical status, should an overdose occur. If indicated, elimination of unabsorbed drug should be achieved by emesis or gastric lavage; usual precautions should be observed to maintain the airway. Because fenofibrate is highly bound to plasma proteins, hemodialysis should not be considered.

TRICOR (Tablet)

Liver Function: Fenofibrate at doses equivalent to 96 mg to 145 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 96 mg to 145 mg TRICOR per day and was 0% in those receiving dosages equivalent to 48 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.<br/>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.<br/>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.<br/>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. Concomitant administration of fenofibrate (equivalent to TRICOR 145 mg) and pravastatin (40 mg) once daily for 10 days increased the mean Cand 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 3��-hydroxy-iso-pravastatin by 55% (range from 32% decrease to 314% increase) and 39% (range from 24% decrease to 261% increase), respectively. (See also CLINICAL PHARMACOLOGY, Drug-drug Interactions). 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.<br/>Mortality: The effect of TRICOR on coronary heart disease morbidity and mortality and non-cardiovascular mortality has not been established.<br/>Other Considerations: 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 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).

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TRICOR