Tricor^® (Tablets) Instructions for Use

ATC Code

C10AB05 (Fenofibrate)

Active Substance

Fenofibrate (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agents; fibrates

Pharmacological Action

Mechanism of action and pharmacodynamic effects

By activating PPAR-alpha (peroxisome proliferator-activated receptor alpha), Fenofibrate enhances lipolysis and the elimination of atherogenic lipoproteins with high TG concentration from plasma by activating lipoprotein lipase and reducing the synthesis of apolipoproteins C-III. Activation of PPAR-alpha also leads to increased synthesis of apolipoproteins A-I and A-II.

Fenofibrate is a fibric acid derivative, the ability of which to alter lipid levels in the human body is mediated by the activation of PPAR-alpha.

The effects of fenofibrate on lipoproteins described above lead to a decrease in the concentration of the LDL and VLDL fractions, which include apolipoprotein B (Apo-B), and an increase in the concentration of the HDL fraction, which includes apolipoprotein A-I (apoA-I) and apolipoprotein A-II (apoA-II).

Furthermore, by correcting disturbances in the synthesis and catabolism of VLDL, Fenofibrate increases LDL clearance and reduces the concentration of dense, small LDL particles, an increase of which is observed in patients with an atherogenic lipid phenotype, a common disorder in patients at risk for CHD.

In clinical studies, it was noted that the use of fenofibrate reduces total cholesterol concentration by 20-25% and TGs by 40-55% and increases HDL-cholesterol concentration by 10-30%. In patients with hypercholesterolemia, in whom LDL-cholesterol concentration decreases by 20-35%, the use of fenofibrate led to a reduction in the ratios: total cholesterol/HDL-cholesterol, LDL-cholesterol/HDL-cholesterol and Apo-B/ApoA-I, or to a decrease in the level of non-HDL-cholesterol, which are markers of atherogenic risk.

Given the effect of fenofibrate on LDL-cholesterol and TG concentrations, the drug is effective in patients with hypercholesterolemia, both with and without hypertriglyceridemia, including secondary hyperlipoproteinemia, for example, in type 2 diabetes mellitus.

During treatment with fenofibrate, extravascular cholesterol deposits (tendinous and tuberous xanthomas) may significantly decrease or even disappear completely.

In patients with elevated fibrinogen concentration receiving fenofibrate treatment, a significant decrease in this parameter was noted, as well as in patients with elevated lipoprotein concentration. Other markers of inflammation, such as C-reactive protein, also decrease during treatment with fenofibrate.

For patients with dyslipidemia and hyperuricemia, an additional benefit is the uricosuric effect of fenofibrate, leading to a reduction in uric acid concentration by approximately 25%.

In a clinical study and in experimental animal studies, it was shown that Fenofibrate reduces platelet aggregation induced by adenosine diphosphate, arachidonic acid, and epinephrine.

The effect of fenofibrate on the progression of microvascular complications in patients with type 2 diabetes mellitus was demonstrated in international randomized placebo-controlled studies.

Clinical efficacy and safety

In the ACCORD study (the “ACCORD-eye” sub-study) in a subgroup of 1593 patients with type 2 diabetes mellitus, progression of diabetic retinopathy by 3 or more points on the international scale (The Early Treatment Diabetic Retinopathy Study Severity Scale – ETDRS) was detected in 6.5% of patients receiving combined hypolipidemic therapy, including simvastatin and Fenofibrate, compared to 10.2% of patients receiving simvastatin and placebo (OR 0.60; 95% CI, 0.42-0.87; P=0.006).

Fenofibrate therapy also led to a reduced need for laser treatment of diabetic retinopathy (3.6% compared to 5.2%, P=0.0003) in the FIELD study.

Effect on cardiovascular morbidity and mortality

A clinical randomized placebo-controlled ACCORD study was conducted with 5518 patients with type 2 diabetes mellitus receiving Fenofibrate in addition to simvastatin therapy. The group receiving the combination of fenofibrate with simvastatin demonstrated a statistically non-significant 8% reduction in the relative risk of major cardiovascular events, including non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular events, compared to simvastatin monotherapy (hazard ratio 0.92, 95% CI 0.79-1.08, P=0.32; absolute risk reduction: 0.74%). Analysis of a subgroup of patients with dyslipidemia (TG ≥ 2.3 mmol/L and HDL cholesterol level ≤0.88 mmol/L) demonstrated a statistically significant 31% reduction in the relative risk of major cardiovascular events in the group receiving the combination of fenofibrate with simvastatin compared to the simvastatin monotherapy group (hazard ratio 0.69, 95% CI 0.49- 0.97, P=0.03; absolute risk reduction: 4.95%). Another subgroup analysis revealed a statistically significant difference between genders (P=0.01), indicating a possible benefit of combination therapy in men (P=0.037), but a potentially higher risk in women (P=0.069) compared to simvastatin monotherapy.

A 5-year randomized placebo-controlled FIELD study was conducted with 9795 patients with type 2 diabetes mellitus receiving Fenofibrate. Fenofibrate demonstrated a statistically non-significant 11% reduction in the primary outcome of cardiovascular disease (hazard ratio 0.89, 95% CI 0.75-1.05, P=0.16) and a statistically significant 11% reduction in the secondary outcome of total cardiovascular disease (hazard ratio 0.89 (0.80-0.99), P=0.04). There was a non-significant 11% increase in all-cause mortality (hazard ratio 1.11, 95% CI 0.95-1.29, P=0.18) and a non-significant 19% increase in CHD mortality (hazard ratio 1.19, 95% CI 0.90-1.57, P=0.22) with fenofibrate use compared to placebo.

Thromboembolic complications

During the FIELD study, a comparatively higher incidence of pulmonary embolism and deep vein thrombosis was observed in the group of patients receiving Fenofibrate than in the group of patients receiving placebo. Of the 9795 patients included in the FIELD study, 4900 patients were randomized to the placebo group and 4985 patients to the fenofibrate group. In the placebo group, 48 cases (1.0%) of deep vein thrombosis were reported, and in the group receiving Fenofibrate, 67 such cases (1.4%) were reported; P=0.074. In the placebo group, 32 cases (0.7%) of pulmonary embolism were reported; in the group receiving Fenofibrate – 53 cases (1.0%); P=0.022.

Preclinical safety data

In a 3-month preclinical oral study in rats with fenofibric acid, the active metabolite of fenofibrate, toxic effects on skeletal muscles (especially those rich in slow-twitch type I oxidative muscle fibers), degeneration of cardiac tissue, anemia, and weight loss were observed. No toxic effects on skeletal muscles were observed at doses up to 30 mg/kg (approximately 17 times the systemic exposure at the maximum recommended human dose). At a dose approximately 3 times the maximum recommended human dose, no signs of cardiotoxicity were observed. In dogs receiving the drug for 3 months, reversible cases of gastrointestinal ulcers and erosions were observed. In this study, no gastrointestinal damage was noted at a dose approximately 5 times the maximum recommended human dose.

Mutagenicity studies of fenofibrate yielded negative results.

In rats and mice at high doses, liver tumors were observed, which were associated with peroxisome proliferation. These manifestations are specific to small rodents and were not observed in other animal species. These results have no consequences for therapeutic use in humans.

In studies on mice, rats, and rabbits, no cases of teratogenic effects were identified. Embryotoxic effects were observed at doses corresponding to the level of toxic exposure for the mother. At high doses, prolongation of pregnancy and difficulties during childbirth were observed.

In a study of the toxicity of repeated administration of fenofibric acid in young dogs, reversible hypospermia, testicular vacuolization, and ovarian immaturity were observed. However, in animal fertility studies conducted with fenofibrate, no effect on fertility was found.

Pharmacokinetics

Tricor^® 145 mg film-coated tablets contain 145 mg of micronized fenofibrate in the form of nanoparticles.

The original Fenofibrate is not detected in plasma. The main plasma metabolite is fenofibric acid.

Absorption

C_max in blood plasma is reached 2-4 hours after oral administration. With long-term use, the drug concentration in plasma remains stable regardless of the patient’s individual characteristics. Unlike previous dosage forms of fenofibrate, C_max in blood plasma and the overall effect of fenofibrate in nanoparticle form do not depend on the time of food intake. Therefore, Tricor^® 145 mg can be taken at any time, regardless of meals.

Distribution

Fenofibric acid is strongly bound to plasma albumin (>99%).

Metabolism

After oral administration, Fenofibrate is rapidly hydrolyzed by esterases. Only the main active metabolite of fenofibrate, fenofibric acid, is detected in plasma. Fenofibrate is not a substrate for the CYP3A4 isoenzyme and does not participate in microsomal metabolism.

Excretion

T_1/2 of fenofibric acid is about 20 hours.

It is excreted mainly by the kidneys in the form of fenofibric acid and a glucuronide conjugate. Within 6 days, Fenofibrate is almost completely eliminated. The total clearance of fenofibric acid, determined in elderly patients, does not change. The drug does not accumulate after a single dose or with long-term use.

It is not eliminated by hemodialysis.

Pharmacokinetics in special clinical cases

Patients with renal impairment. In patients with severe renal impairment, the clearance rate of fenofibric acid is significantly reduced, which may lead to accumulation of the compound with repeated use.

In patients with moderate renal impairment (CrCl 30-60 ml/min), the clearance and V_d after oral administration of fenofibric acid are increased compared to healthy volunteers (2.1 L/h and 95 L compared to 1.1 L/h and 30 L, respectively). In patients with moderate renal impairment, dose adjustment is required. If a lower dosage is not available, then Fenofibrate is not recommended for use.

In patients with severe renal impairment (CrCl < 30 ml/min), the use of fenofibrate is contraindicated (see “Contraindications”).

Patients with hepatic impairment. Pharmacokinetic studies in patients with hepatic impairment have not been conducted.

Elderly patients. The risk of adverse reactions to the drug Tricor^® may be higher in patients with renal impairment, since fenofibric acid is largely excreted by the kidneys. Exposure to fenofibric acid does not depend on age . Since the prevalence of renal impairment is higher among elderly patients, dosing of Tricor^® should be based on renal function (see sections “Dosage Regimen” and “Contraindications”). No dose adjustment is required for elderly patients with normal renal function. Monitoring of renal function in this category of patients is necessary when using Tricor^®.

Indications

Adults aged 18 years and older

• Hypercholesterolemia and hypertriglyceridemia, isolated or mixed (dyslipidemia type IIa, IIb, III, IV, V according to the Fredrickson classification) in patients for whom diet or other non-pharmacological therapeutic measures (e.g., weight loss or increased physical activity) have been ineffective, especially in the presence of dyslipidemia-related risk factors such as arterial hypertension and smoking;
• Secondary hyperlipoproteinemia in cases where hyperlipoproteinemia persists despite effective treatment of the underlying disease (e.g., dyslipidemia in diabetes mellitus).

ICD codes

Dosage Regimen

Tablets

It is necessary to continue following the hypocholesterolemic diet that the patient adhered to before starting treatment with Tricor^®.

The drug is taken orally, at any time of day, regardless of meals. The tablets should be swallowed whole, without chewing, with water.

Adults

The recommended dose for adults is 145 mg (1 tablet) once daily.

Patients taking one capsule of micronized fenofibrate 200 mg or one tablet of micronized fenofibrate 160 mg/day can switch to taking one tablet of Tricor^® 145 mg without additional dose adjustment.

Special patient groups

Elderly patients without renal impairment

It is recommended to take the standard adult dose (1 tablet/day). The effectiveness of therapy should be assessed by the concentration of lipids (total cholesterol, LDL, TGs) in the blood serum. If there is no therapeutic effect after several months of therapy (usually after 3 months), the advisability of prescribing concomitant or alternative therapy should be considered.

Patients with hepatic impairment

Due to insufficient accumulated data on the use of Tricor^® in patients with hepatic impairment, it is not possible to provide recommendations for the use of the drug in this category of patients.

Patients with renal impairment

Fenofibrate should not be used in severe renal failure (eGFR < 30 ml/min/1.73 m²).

If eGFR is between 30 and 59 ml/min/1.73 m², the dose should not exceed 100 mg of standard fenofibrate or 67 mg of micronized fenofibrate once daily.

If during the observation period the eGFR persistently decreases to <30 ml/min/1.73 m², fenofibrate treatment should be discontinued.

Children

Efficacy and safety have not been established, data are lacking. Therefore, the use of Tricor^® is contraindicated in children under 18 years of age (see section “Contraindications”).

Adverse Reactions

During placebo-controlled clinical studies, the following adverse reactions were observed, with frequency classified as follows: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000) and very rare (<1/10000), frequency unknown (cannot be estimated from the available data).

From the hematopoietic system rare – decrease in hemoglobin and leukocytes.

From the immune system: rare – hypersensitivity reactions (including anaphylactic reactions).

From the nervous system: uncommon – headache.

From the cardiovascular system uncommon – thromboembolism (pulmonary embolism and deep vein thrombosis of the lower extremities)**.

From the digestive system common – signs and symptoms of gastrointestinal disorders (abdominal pain, nausea, vomiting, diarrhea, flatulence); uncommon – pancreatitis*.

From the liver and biliary tract: common – increased concentration of serum transaminases; uncommon – cholelithiasis; rare – hepatitis.

From the skin and subcutaneous tissues uncommon – hypersensitivity skin reactions (e.g., skin rash, pruritus, urticaria); rare – alopecia, photosensitivity reactions.

From the musculoskeletal system and connective tissue: uncommon – muscle lesions (e.g., diffuse myalgia, myositis, muscle spasm, and muscle weakness).

Disorders of the reproductive system and mammary glands : uncommon – erectile dysfunction.

Effect on laboratory and instrumental test results very common – increased blood homocysteine level***; uncommon – increased serum creatinine concentration; rare – increased serum urea nitrogen concentration.

* In the randomized, placebo-controlled FIELD clinical study conducted in 9795 patients with type 2 diabetes mellitus receiving Fenofibrate, a statistically significant increase in the frequency of pancreatitis cases (0.8%, 40 out of 4895 patients) was detected compared to 0.5% in the placebo group (23 out of 4900 patients); P=0.031.

** A statistically significant increase in the frequency of pulmonary embolism development was reported (0.7% (32 out of 4900 patients) in the placebo group compared to 1.1% (53 out of 4895 patients) in the group of patients taking Fenofibrate; P=0.022) and a statistically non-significant increase in the frequency of deep vein thrombosis development (with placebo use: 1.0% (48 out of 4900 patients); with fenofibrate use: 1.4% (67 out of 4895 patients); P=0.074).

*** The average increase in blood homocysteine level in patients receiving Fenofibrate was 6.5 µmol/L and had a reversible effect upon discontinuation of fenofibrate treatment. The increased risk of deep vein thrombosis may be associated with an increase in homocysteine level. However, the clinical significance of the above phenomenon has not been established.

During post-marketing use, spontaneous reports of a number of side effects have been received. Based on the available data, it is impossible to establish the exact frequency of these effects, so it is classified as “frequency unknown”.

Nervous system disorders fatigue.

Respiratory, thoracic and mediastinal disorders interstitial lung disease.

Hepatobiliary disorders jaundice, complications of cholelithiasis (e.g., cholecystitis, cholangitis, biliary colic).

Skin and subcutaneous tissue disorders severe skin reactions (e.g., erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Musculoskeletal and connective tissue disorders rhabdomyolysis.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product to ensure continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are recommended to report any suspected adverse reactions of the medicinal product through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to fenofibrate, soybeans, peanuts, or to any of the excipients of the drug;
• Severe hepatic impairment – Child-Pugh class C (including biliary cirrhosis and persistent hepatic impairment of unknown etiology);
• Severe and moderate renal impairment (creatinine clearance <60 ml/min for this drug dosage);
• History of photosensitivity or phototoxicity during treatment with fibrates or ketoprofen;
• History of gallbladder disease;
• Chronic or acute pancreatitis, except for cases of acute pancreatitis due to severe hypertriglyceridemia;

• Breastfeeding period.

With caution

• In patients with factors predisposing to the development of myopathy and/or rhabdomyolysis, including age over 70 years, history of hereditary muscle diseases, hypothyroidism, and alcohol abuse (see section “Special Precautions”);
• Use during pregnancy;
• Concomitant use of oral anticoagulants, HMG-CoA reductase inhibitors (see section “Drug Interactions”).

Use in Pregnancy and Lactation

Pregnancy

There are insufficient data on the use of fenofibrate in pregnant women.

In studies conducted in mice, rats, and rabbits, no teratogenic effect of fenofibrate was observed.

Embryotoxicity was noted when doses toxic to the maternal organism were administered during preclinical trials. Prolongation of pregnancy and complications during childbirth were observed when the drug was taken in high doses.

The potential risk to humans is unknown. Therefore, the drug should be used during pregnancy only after a thorough assessment of the expected benefit to the possible risk.

Breastfeeding period

There is insufficient information on the excretion of fenofibrate and/or its metabolites into breast milk. The risk to breastfed infants cannot be ruled out.

The drug should not be used during breastfeeding. If it is necessary to use the drug during breastfeeding, breastfeeding should be discontinued.

Fertility

In preclinical studies of reproductive toxicity, no effects on animal fertility were identified with the use of fenofibrate. However, reversible hypospermia and testicular vacuolization, as well as ovarian immaturity, were observed in a toxicity study in young dogs with repeated administration of fenofibric acid. There are no clinical data on the effect of the drug on fertility in men or women.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment – Child-Pugh class C (including biliary cirrhosis and persistent hepatic impairment of unknown etiology).

Use in Renal Impairment

Contraindicated in severe and moderate renal impairment (creatinine clearance <60 ml/min for this drug dosage).

In patients with moderate renal impairment, dose adjustment is required.

Pediatric Use

Contraindicated under 18 years of age (efficacy and safety have not been established).

Geriatric Use

For elderly patients without renal impairment it is recommended to prescribe the standard adult dose (1 tablet of Tricor^® 145 mg once/day).

Monitoring of renal function in this category of patients is necessary when using the drug Tricor^®®.

Special Precautions

Before starting treatment with Tricor^® 145 mg, appropriate treatment should be carried out to eliminate the cause of secondary hypercholesterolemia, for example, in diseases such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver diseases, consequences of drug therapy, alcoholism.

In patients with hyperlipidemia taking estrogens or hormonal contraceptives containing estrogens, it is necessary to determine whether hyperlipidemia is primary or secondary. In such cases, the increase in lipid levels may be caused by the intake of estrogens.

Liver function

When taking fenofibrate and other lipid-lowering drugs, increased activity of liver transaminases has been described in some patients. In most cases, this increase was temporary, minor, and asymptomatic. It is recommended to monitor transaminase activity (ALT, AST) every 3 months during the first 12 months and periodically during further treatment. Patients who have increased liver transaminase activity during treatment require attention, and if ALT and AST activity increases more than 3 times the upper limit of normal, the drug should be discontinued. If symptoms of hepatitis (jaundice, pruritus) appear, laboratory tests should be performed and, if the diagnosis of hepatitis is confirmed, the drug Tricor^® should be discontinued.

Pancreatitis

Cases of pancreatitis development during treatment with fenofibrate have been described. Possible causes of pancreatitis in these cases were: insufficient effectiveness of the drug in patients with severe hypertriglyceridemia, direct effect of the drug, as well as secondary phenomena associated with the presence of stones or sludge formation in the bile ducts, accompanied by obstruction of the common bile duct.

Muscles

When taking the drug Tricor^® and other lipid-lowering drugs, cases of toxic effects on muscle tissue, with or without renal impairment, including very rare cases of rhabdomyolysis, have been described. The frequency of such disorders increases in cases of hypoalbuminemia and a history of renal impairment.

A toxic effect on muscle tissue may be suspected based on patient complaints of weakness, diffuse myalgia, myositis, muscle spasms and cramps, and/or a marked increase in CPK activity (more than 5 times the ULN). In these cases, treatment with Tricor^® 145 mg should be discontinued.

The risk of developing rhabdomyolysis may be increased in patients with a predisposition to myopathy and/or rhabdomyolysis, including age over 70 years, history of hereditary muscle diseases, hypothyroidism, alcohol abuse. Such patients should be prescribed the drug only if the expected benefit outweighs the possible risk of developing rhabdomyolysis.

When taking the drug Tricor^® 145 mg simultaneously with HMG-CoA reductase inhibitors or other fibrates, the risk of serious toxic effects on muscle fibers increases, especially if the patient had a muscle disease before starting treatment. In this regard, the combined prescription of the drug Tricor^® 145 mg and a statin is permissible only in the presence of severe mixed dyslipidemia and high cardiovascular risk, in the absence of a history of muscle disease and under close monitoring aimed at identifying signs of toxic effects on muscle tissue.

Renal function

Fenofibrate is contraindicated in severe renal failure (see section “Contraindications”).

Fenofibrate should be used with caution in patients with mild and moderate renal failure. Patients with eGFR from 30 to 59 ml/min/1.73 m² require dose adjustment (see section “Dosage and Administration”).

Reversible increases in serum creatinine levels have been reported in patients receiving Fenofibrate as monotherapy or in combination with statins. The increase in creatinine concentration was generally stable over time without signs of further increase in serum creatinine concentration during long-term therapy, with a tendency to return to baseline after discontinuation of treatment.

In clinical studies, 10% of patients had an increase in creatinine levels of more than 30 pmol/l compared to baseline when taking fenofibrate and simvastatin simultaneously, compared with 4.4% of patients receiving statin as monotherapy. In 0.3% of patients receiving combination therapy, a clinically significant increase in creatinine levels to values >200 pmol/l was observed.

Treatment should be discontinued if the creatinine concentration increases >50% above the ULN. It is recommended to determine the creatinine concentration during the first 3 months after starting treatment, as well as periodically after its completion.

Hematological disorders

After starting therapy with fenofibrate, patients experienced a mild or moderate decrease in hemoglobin levels, a decrease in hematocrit, and a decrease in the number of leukocytes. However, with long-term use of the drug, the values of these indicators stabilize. Thrombocytopenia and agranulocytosis have been reported in individual patients receiving Fenofibrate. During the first twelve months from the start of therapy with Tricor^®, periodic monitoring of red and white blood cell levels is recommended.

Hypersensitivity reactions

Immediate-type hypersensitivity. During post-registration use of fenofibrate, cases of anaphylaxis and angioedema have been recorded. In some cases, such reactions were life-threatening and required emergency therapy. If signs or symptoms of immediate-type hypersensitivity are observed, it is necessary to immediately consult a doctor and discontinue the use of fenofibrate.

Delayed-type hypersensitivity. During post-registration use of fenofibrate, cases of serious adverse drug reactions from the skin have been recorded, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome). Such reactions developed over a period of time ranging from several days to several weeks from the start of fenofibrate therapy. Cases of DRESS syndrome were accompanied by skin reactions, such as rash or exfoliative dermatitis, and a combination of eosinophilia and fever with involvement of the renal, hepatic, or respiratory systems. If serious adverse drug reactions from the skin are suspected, the use of fenofibrate should be discontinued and specific treatment should be carried out.

Paradoxical decrease in HDL cholesterol

In clinical studies and post-marketing use, cases of a marked decrease in HDL cholesterol (less than 2 mg/dl) after starting fibrate therapy have been described in patients with and without diabetes. The decrease in HDL cholesterol was accompanied by a decrease in apolipoprotein A-I. Such a decrease usually developed within a period of 2 weeks to several years after starting fibrate use. HDL cholesterol levels remained low as long as fibrate therapy continued. After discontinuation of fibrate therapy, a rapid and sustained response was noted.

The clinical significance of such a decrease in HDL cholesterol has not been established. It is recommended to monitor HDL cholesterol levels during the first few months after starting fibrate therapy. If a marked decrease in HDL cholesterol occurs, the drug should be discontinued and HDL monitoring should be continued until it returns to baseline values. Fibrates should not be re-prescribed to such patients.

Excipients

The drug Tricor^® contains sucrose. Patients with rare hereditary fructose intolerance, glucose-galactose malabsorption, or sucrase-isomaltase deficiency should not take this drug.

The drug Tricor^® contains lactose. Patients with rare hereditary galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this drug.

The drug Tricor^® contains soy lecithin. Patients with a history of allergy to peanuts, peanut oil, soy lecithin, or related products should not take this drug (due to the risk of developing a hypersensitivity reaction; see section “Contraindications”).

Effect on ability to drive vehicles and machinery

The drug Tricor^® 145 mg does not affect or minimally affects the ability to drive vehicles and operate machinery (risk of dizziness).

Overdose

There are only isolated reports of overdose. In most cases, no symptoms of overdose were reported.

No specific antidote is known. If an overdose is suspected, symptomatic and, if necessary, supportive therapy should be prescribed. Hemodialysis is not effective.

Drug Interactions

Oral anticoagulants

Fenofibrate enhances the effect of oral anticoagulants and may increase the risk of bleeding, which is associated with displacement of the anticoagulant from plasma protein binding sites. At the start of fenofibrate treatment, it is recommended to reduce the dose of anticoagulants (warfarin) by approximately one third with subsequent gradual dose titration. Dose titration is recommended under the control of INR levels.

Cyclosporine

Several severe cases of reversible renal function impairment during simultaneous treatment with fenofibrate and cyclosporine have been described. Therefore, it is necessary to monitor the renal function status in such patients and discontinue Fenofibrate in case of serious changes in laboratory parameters.

HMG-CoA reductase inhibitors (statins) and other fibrates

When taking fenofibrate simultaneously with HMG-CoA reductase inhibitors or other fibrates, the risk of serious toxic effects on muscle fibers increases. Such combination therapy should be carried out with caution and patients should be carefully monitored for signs of toxic effects on muscle tissue (see section “Special Precautions”).

Pravastatin

Simultaneous use of fenofibrate (at a dose equivalent to 145 mg of fenofibrate) and pravastatin (40 mg once/day) for 10 days in 23 healthy volunteers was accompanied by an increase in the mean C_max of pravastatin by 36% (range of changes: from a decrease of 69% to an increase of 321%) and an increase in the mean AUC of pravastatin by 28% (range of changes: from a decrease of 54% to an increase of 128%). When pravastatin was used simultaneously with fenofibrate, an increase in the mean C_max of the main metabolite of pravastatin (3-alpha-hydroxy-iso-pravastatin) by 55% (range of changes: from a decrease of 32% to an increase of 314%) and an increase in the mean AUC of the main metabolite of pravastatin by 39% (range of changes: from a decrease of 24% to an increase of 261%) were also observed.

Simvastatin

In a clinical study, Fenofibrate was used at a dose equivalent to 145 mg of fenofibrate once/day for 10 days. On day 10, simvastatin 40 mg was added to fenofibrate. The mean AUC of simvastatin acid, the main active metabolite, decreased by 42% (range of changes: from a decrease of 77% to an increase of 50%) while taking fenofibrate. Fenofibrate did not affect (0%) the mean C_max of simvastatin acid (range of changes: from a decrease of 67% to an increase of 92%). The C_min of fenofibric acid increased by 14% (range of changes: from a decrease of 7% to an increase of 48%) after the use of simvastatin, indicating no effect of simvastatin 40 mg on the plasma concentration of fenofibric acid.

Atorvastatin

Simultaneous use of fenofibrate (at a dose equivalent to 145 mg of fenofibrate) and atorvastatin (20 mg) once/day for 10 days in 22 healthy male volunteers was accompanied by a 14% decrease in the mean AUC of atorvastatin (range of changes: from a decrease of 67% to an increase of 44%). The mean C_max of atorvastatin did not change (0%) (range of changes: from a decrease of 60% to an increase of 136%). With simultaneous multiple administration of fenofibrate and atorvastatin, no significant pharmacokinetic changes in the mean AUC (decrease of 2.3%; range of changes: from a decrease of 39% to an increase of 40%) or mean C_max (decrease of 3.8%; range of changes: from a decrease of 29% to an increase of 42%) of fenofibric acid were identified.

Rosuvastatin

Simultaneous use of fenofibrate (67 mg three times/day) and rosuvastatin (10 mg once/day) for 7 days did not lead to clinically significant changes in the plasma concentration of both active substances.

Ezetimibe

In a pharmacokinetic study, when used concomitantly with fenofibrate, the concentration of total ezetimibe increased approximately 1.5-fold. This increase is considered clinically insignificant. The efficacy and safety of fenofibrate when used concomitantly with ezetimibe were studied in a clinical trial. The simultaneous use of ezetimibe with other fibrates (clofibrate, bezafibrate, gemfibrozil) has not been studied (see the instructions for use of the drug ezetimibe).

Bile acid sequestrants

The absorption of fibrates is reduced by cholestyramine.

Estrogens

Estrogens may lead to an increase in lipid levels.

Thiazolidinedione derivatives (glitazones)

When fenofibrate and glitazones were used concomitantly, several cases of reversible paradoxical decrease in HDL cholesterol concentration were reported. Therefore, during concomitant therapy, monitoring of HDL cholesterol concentration is recommended, and in case of a marked decrease in HDL cholesterol concentration, the drugs should be discontinued.

Cytochrome P450 isoenzymes

Studies of human liver microsomes in vitro have shown that Fenofibrate and fenofibric acid are not inhibitors of the following cytochrome P450 isoenzymes (CYP3A4, CYP2D6, CYP2E1 or CYP1A2). At therapeutic concentrations, these compounds are weak inhibitors of CYP2C19 and CYP2A6 isoenzymes and weak or moderate inhibitors of CYP2C9.

Patients using Fenofibrate concomitantly with drugs metabolized by CYP2C19, CYP2A6, and especially CYP2C9 isoenzymes with a narrow therapeutic index should be under close observation and, if necessary, dose adjustment of these drugs is recommended.

Storage Conditions

The drug should be stored out of the reach of children, at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life – 3 years.

Do not use after the expiration date indicated on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.