Tricor 145 mg film-coated tablets 145 mg No. 20

Instructions for use Tricor 145 mg film-coated tablets 145 mg No. 20

Composition

active ingredient: fenofibrate;

1 tablet contains 145 mg of fenofibrate;

excipients: hypromellose, sodium docusate, sucrose, sodium lauryl sulfate, lactose monohydrate, silicified microcrystalline cellulose, crospovidone, magnesium stearate, Opadry® OY-B-28920 (polyvinyl alcohol, titanium dioxide (E 171), talc, soy lecithin, xanthan gum).

Dosage form

Film-coated tablets.

Main physicochemical properties: white, oval, film-coated tablets marked "145" on one side and the Fournier company logo on the other.

Pharmacotherapeutic group

Hypolipidemic agents. Drugs that lower serum cholesterol and triglyceride levels. Fibrates. ATC code C10A B05.

Pharmacological properties

Pharmacodynamics

Dyslipidemia

Fenofibrate is a fibric acid derivative whose lipid-modifying effects in humans are mediated by activation of the peroxisome proliferator-activated receptor alpha (PPARα).

Through activation of PPARα, fenofibrate enhances lipolysis and the clearance of atherogenic triglyceride-rich particles from plasma by activating lipoprotein lipase and reducing the formation of apoprotein CIII. Activation of PPARα also causes an increase in the synthesis of apoproteins AI and AII.

The above-mentioned effects of fenofibrate on lipoproteins lead to a decrease in the fraction of very low and low density lipoproteins (VLDL and LDL) containing apoprotein B and an increase in the fraction of high density lipoproteins (HDL) containing apoproteins AI and AII.

In addition, by modulating the synthesis and catabolism of VLDL fractions, fenofibrate enhances LDL clearance and reduces the amount of small dense LDL, the levels of which are elevated in individuals with an atherogenic lipoprotein phenotype, which is often found in patients at risk of developing coronary heart disease.

In clinical studies, when using fenofibrate, total cholesterol levels decreased by 20–25%, triglycerides by 40–55%, and HDL cholesterol levels increased by 10–30%.

In hypercholesterolemic patients whose LDL cholesterol levels are reduced by 20–35%, the overall effect on cholesterol levels results in a reduction in the ratios of total cholesterol/HDL cholesterol, LDL cholesterol/HDL cholesterol, or apoprotein B/apoprotein AI, which are markers of atherogenic risk.

There is evidence that treatment with fibrates can reduce the incidence of events in ischemic heart disease, but fibrates have not been shown to reduce overall mortality in the primary or secondary prevention of cardiovascular disease.

The ACCORD lipid trial was a randomized, placebo-controlled trial of 5518 patients with type 2 diabetes treated with fenofibrate in addition to simvastatin. Fenofibrate plus simvastatin therapy compared with simvastatin alone did not show significant differences in the effects on the combined primary endpoint of nonfatal myocardial infarction, nonfatal stroke, and cardiovascular death (hazard ratio [HR] 0.92, 95% CI 0.79-1.08, p = 0.32; absolute risk reduction: 0.74%). In a pre-selected subgroup of dyslipidemic patients with the lowest tertile of HDL-C (≤ 34 mg/dL or 0.88 mmol/L) and the highest tertile of TG (≥ 204 mg/dL or 2.3 mmol/L) at baseline, fenofibrate plus simvastatin combination therapy compared with simvastatin monotherapy demonstrated a 31% relative risk reduction in the combined primary endpoint (hazard ratio [HR] 0.69, 95% CI 0.49-0.97, p = 0.03; absolute risk reduction: 4.95%). Analysis of another pre-selected subgroup revealed a statistically significant relationship between treatment and gender (p = 0.01), indicating a possible benefit of combination therapy in men (p = 0.037), but a potentially higher risk of the primary endpoint in women receiving combination therapy compared with simvastatin monotherapy (p = 0.069). This phenomenon was not observed in the aforementioned subgroup of patients with dyslipidemia, but there was also no clear evidence of a benefit for women with dyslipidemia receiving fenofibrate together with simvastatin, and a possible harmful effect in this subgroup cannot be excluded.

Extravascular cholesterol deposits (tendinous and tuberous xanthomas) may be significantly reduced or completely eliminated during treatment with fenofibrate.

Patients with elevated fibrinogen levels treated with fenofibrate showed significant reductions in this parameter, as did patients with elevated lipoprotein(a) levels. Fenofibrate also reduces levels of other inflammatory markers, such as C-reactive protein.

The uricosuric effect of fenofibrate, which leads to a decrease in uric acid levels by approximately 25%, should be considered an additional beneficial effect of the drug in patients with dyslipidemia and hyperuricemia.

The antiplatelet effect of fenofibrate on platelets has been demonstrated in animal studies and in a clinical trial, which demonstrated a reduction in platelet aggregation induced by ADP, arachidonic acid and adrenaline.

Several mechanisms have been proposed to explain the effects of fenofibrate in patients with proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) in vitro and in rodent models. Fenofibrate has been shown to reduce retinal expression of vascular endothelial growth factor (VEGF), a major angiogenic factor in PDR, and to reduce vascular permeability and apoptosis of the retinal pigment epithelium, which contribute to the development of DME.

The FIELD study was a multinational randomized trial involving 9795 patients with type 2 diabetes. The selected patients were randomized to receive fenofibrate 200 mg daily (n = 4895) or placebo (n = 4900). In an ophthalmological substudy involving 1012 patients, standardized retinal photographs were taken and scored according to the Early Treatment Diabetic Retinopathy Study (ETDRS) criteria to determine the cumulative incidence of diabetic retinopathy and its individual manifestations. Analyses were performed in all patients who started treatment. In the ophthalmology substudy, the primary endpoint, 2-step progression of retinopathy, was not significantly different between the two groups overall (46 [9.6%] patients in the fenofibrate group vs. 57 [12.3%] in the placebo group, p = 0.19) or in the subgroup of patients without pre-existing retinopathy (43 [11.4%] vs. 43 [11.7%], p = 0.87). In contrast, in the group of patients with pre-existing retinopathy, significantly fewer patients with fenofibrate than with placebo experienced 2-step progression (3 [3.1%] vs. 14 [14.6%] patients, p = 0.004).

Information on laser treatment of diabetic retinopathy, a pre-specified tertiary endpoint in the pivotal study, was collected at each patient visit to the clinic. The need for first laser treatment of all retinopathies was significantly lower with fenofibrate compared with placebo (164 [3.4%] patients in the fenofibrate group vs. 238 [4.9%] in the placebo group; hazard ratio [HR] 0.69, 95% CI 0.56-0.84, p = 0.0002; absolute risk reduction 1.5% [0.7-2.3]). The need for such treatment was independent of plasma lipid concentrations.

In a subset of 2856 participants from the ACCORD trial (ACCORD Eye), the effects of three treatment strategies on progression of diabetic retinopathy were evaluated: intensive or standard glycemic control (target HbA1c <6.0% or 7.0 to 7.9%, respectively), dyslipidemia (combination therapy of fenofibrate 160 mg/day plus simvastatin or placebo plus simvastatin), or systolic blood pressure control (target <120 or <140 mmHg). Progression of diabetic retinopathy was defined after 4 years as an increase of 3 or more points in the ETDRS score (based on seven-field stereoscopic fundus photography) or the development of diabetic retinopathy requiring laser photocoagulation or vitrectomy.

The incidence of progression of diabetic retinopathy was 6.5% in the intensive dyslipidemia treatment group with fenofibrate compared with 10.2% in the placebo group (adjusted odds ratio 0.60; 95% CI 0.42-0.87, p = 0.006). It was concluded that intensive combination therapy of dyslipidemia reduced the incidence of progression of diabetic retinopathy.

An integrated analysis of individual patient data from the FIELD study and published data from the ACCORD Eye study was performed. The combined primary endpoint of the ACCORD Eye study was applied to the FIELD study, i.e., a 3-point increase in ETDRS severity, photocoagulation, or vitrectomy for the treatment of proliferative diabetic retinopathy. Both studies were homogeneous (fixed-effect model applied) and showed an overall 60% reduction in the progression of diabetic retinopathy (odds ratio: 0.40, 95% CI 0.26-0.61).

Progression of diabetic retinopathy (DR) in patients with DR at baseline: a pooled analysis of the FIELD PSP-DR and ACCORD Eye studies using the primary endpoint of the ACCORD Eye study.

Pharmacokinetics

Absorption.

The maximum plasma concentration (Cmax) of the drug is reached 2–4 hours after oral administration. Plasma concentration remains stable during long-term use in all patients.

Unlike previous fenofibrate preparations, when using Tricor® 145 mg in the form of nanoparticles, its maximum plasma concentration and total exposure are not dependent on food intake, so Tricor® 145 mg can be taken regardless of food intake.

In a study of the effect of food on the absorption of the drug after administration of a new 145 mg tablet formulation of fenofibrate to healthy men and women in the fasted state and with a high-fat meal, it was shown that food intake did not affect the exposure (AUC and Cmax) of fenofibric acid.

Distribution.

Fenofibric acid is extensively bound to plasma albumin (more than 99%).

Metabolism and excretion.

After oral administration, fenofibrate is rapidly hydrolyzed by esterases to the active metabolite, fenofibric acid. Unchanged fenofibrate is not detected in plasma. Fenofibrate is not a substrate for CYP 3A4 and does not participate in hepatic microsomal metabolism.

Kinetic studies after single-dose and long-term treatment have shown that the drug does not accumulate in the body. Fenofibric acid is not removed by hemodialysis.

The half-life of fenofibric acid is approximately 20 hours.

Indication

Tricor® 145 mg is indicated as an adjunct to diet and other non-drug treatments (e.g. exercise, weight loss) for the following conditions:

severe hypertriglyceridemia with or without low HDL cholesterol; mixed hyperlipidemia in cases where statins are contraindicated or statins are intolerant; mixed hyperlipidemia in patients at high cardiovascular risk, as an adjunct to statin therapy, when triglycerides and HDL cholesterol are not adequately controlled.

Diabetic retinopathy: Tricor® 145 mg is indicated for the reduction of progression of diabetic retinopathy in patients with type 2 diabetes mellitus and existing diabetic retinopathy.

Contraindication

Hepatic failure (including biliary cirrhosis and unexplained persistent liver dysfunction).

Gallbladder diseases have been identified.

Severe chronic kidney disease.

Chronic or acute pancreatitis, except in cases of acute pancreatitis caused by severe hypertriglyceridemia.

Photoallergy or phototoxic reactions have been established during treatment with fibrates or ketoprofen.

Hypersensitivity to the active substance or to any of the excipients listed in the "Composition" section.

Also, Tricor® 145 mg should not be used in patients with allergies to peanuts, peanut oil or soy lecithin, or similar products due to the risk of hypersensitivity reactions.

Interaction with other medicinal products and other types of interactions

Oral anticoagulants.

Fenofibrate enhances the effect of oral anticoagulants and may increase the risk of bleeding. It is recommended to reduce the dose of anticoagulants by approximately 1/3 at the beginning of treatment and then gradually adjust it according to the INR (international normalized ratio).

Cyclosporine.

Several serious cases of reversible renal impairment have been reported with concomitant use of fenofibrate and cyclosporine. Therefore, renal function should be closely monitored in patients receiving this combination and fenofibrate discontinued in the event of severe laboratory abnormalities.

HMG-CoA reductase inhibitors and other fibrates.

The risk of serious muscle toxicity is increased when fibrates are used concomitantly with HMG-CoA reductase inhibitors or other fibrates. Such combination therapy should be used with caution and patients should be closely monitored for signs of muscle toxicity (see section 4.4).

Glitazones.

Cases of reversible paradoxical reduction in HDL-cholesterol have been reported with concomitant use of fenofibrate and glitazones. Therefore, it is recommended to monitor HDL-cholesterol levels when using the combination of these drugs and to discontinue their use if HDL-cholesterol levels become too low.

Cytochrome P450 enzymes.

In vitro studies using human liver microsomes have shown that fenofibrate and fenofibric acid are not inhibitors of the cytochrome (CYP) P450 isoforms CYP3A4, CYP2D6, CYP2E1, or CYP1A2. They are weak inhibitors of CYP2C19 and CYP2A6 and weak to moderate inhibitors of CYP2C9 at therapeutic concentrations.

Patients who concomitantly use fenofibrate and drugs metabolized by CYP2C19, CYP2A6 and especially CYP2C9 and have a narrow therapeutic index should be carefully monitored and the dose of these drugs adjusted if necessary.

Application features

Secondary hyperlipidemia.

Before starting therapy with fenofibrate, appropriate treatment of relevant conditions that cause secondary hypercholesterolemia, such as uncontrolled type 2 diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease or alcoholism, should be carried out. Secondary hypercholesterolemia associated with pharmacological treatment may occur in patients taking diuretics, β-blockers, estrogens, progestogens, combined oral contraceptives, immunosuppressants and protease inhibitors. In such cases, it is necessary to establish whether the hyperlipidemia is primary or secondary (possible increase in lipid levels caused by the above therapeutic agents).

Liver function.

As with other lipid-lowering drugs, some patients have reported elevations in transaminase levels. In most cases, these elevations were transient, minor, and asymptomatic. It is recommended that transaminase levels be monitored every 3 months for the first 12 months of therapy and periodically thereafter. Attention should be paid to patients who develop elevations in transaminase levels and treatment should be discontinued if AST and ALT levels exceed 3 times the upper limit of normal. Fenofibrate should be discontinued if symptoms of hepatitis (e.g. jaundice, pruritus) occur and the diagnosis is confirmed by laboratory tests.

Pancreatitis has been reported in patients taking fenofibrate (see sections 4.3 and 4.8). This may be due to inadequate treatment in patients with severe hypertriglyceridemia, a direct effect of the drug, or a secondary effect mediated by gallstones or sludge formation with obstruction of the common bile duct.

Muscles.

Muscle toxicity, including rare cases of rhabdomyolysis with or without renal failure, has been reported with fibrates and other lipid-lowering drugs. The incidence of this disorder increases with hypoalbuminemia and a history of renal failure. Patients with risk factors for myopathy and/or rhabdomyolysis, including age ≥70 years, personal or family history of hereditary muscle disorders, renal impairment, hypothyroidism, and alcohol abuse, may be at increased risk of rhabdomyolysis. The benefits and risks of fenofibrate therapy should be carefully weighed in these patients.

Muscle toxicity should be suspected in patients with diffuse myalgia, myositis, muscle cramps and weakness and/or marked elevations in CPK (>5 times the upper limit of normal). In such cases, fenofibrate treatment should be discontinued.

The risk of muscle toxicity may be increased when the drug is used with another fibrate or an HMG-CoA reductase inhibitor, especially in the presence of pre-existing muscle disease. Therefore, concomitant use of fenofibrate with an HMG-CoA reductase inhibitor or another fibrate should be reserved for patients with severe combined dyslipidemia and high cardiovascular risk without any history of muscle disease and with careful monitoring for possible muscle toxicity.

Kidney function.

If creatinine levels increase by more than 50% of the ULN (upper limit of normal), fenofibrate treatment should be discontinued. It is recommended to monitor creatinine levels during the first 3 months after initiation of treatment and periodically thereafter (for dosage, see section 4.2).

Excipients.

The medicine contains lactose, therefore patients with rare hereditary diseases such as galactose intolerance, lactase deficiency or glucose-galactose malabsorption should not take this medicine.

The medicine contains sucrose, therefore patients with rare hereditary diseases such as fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

Ability to influence reaction speed when driving vehicles or other mechanisms

Tricor® 145 mg has no or negligible influence on the ability to drive or operate machinery.

Use during pregnancy or breastfeeding

Pregnancy. There are no adequate data on the use of fenofibrate in pregnant women. No teratogenic effects were observed in animal studies. Embryotoxic effects were observed when the drug was used in doses toxic to the mother. The potential risk to humans is unknown. Therefore, Tricor® 145 mg should be used during pregnancy only after careful benefit/risk assessment.

Breast-feeding: It is not known whether fenofibrate and/or its metabolites are excreted in human milk. A risk to the nursing infant cannot be excluded, therefore fenofibrate should not be used during breast-feeding.

Fertility: Reversible effects on fertility have been observed in animal studies. There are no clinical data on the effects on fertility with Tricor® 145 mg.

Method of administration and doses

Tricor® 145 mg can be taken at any time of the day, regardless of food intake (see section "Pharmacological properties. Pharmacokinetics"). The tablets should be swallowed whole with a glass of water.

Diet therapy started before prescribing the drug must be continued.

During the treatment of hyperlipidemia, the effectiveness of the treatment should be monitored by determining serum lipid levels. If an adequate response to treatment is not achieved after several months (e.g. 3 months), additional or different therapeutic measures should be considered.

Adults

The recommended dose is 1 tablet containing 145 mg of fenofibrate once daily. Patients taking 1 capsule containing 200 mg of fenofibrate or 1 tablet containing 160 mg of fenofibrate may be switched to 1 tablet of Tricor® 145 mg without additional dose adjustment.

If a patient needs to use fenofibrate for two indications (hyperlipidemia and diabetic retinopathy), only one tablet of Tricor® 145 mg per day should be taken.

Elderly patients

The usual adult dose is recommended for elderly patients without renal impairment.

Kidney dysfunction

Fenofibrate is contraindicated in patients with severe chronic kidney disease (creatinine clearance < 30 ml/min).

Liver dysfunction

Tricor® 145 mg is not recommended for use in patients with impaired liver function due to lack of data.

Children

The safety and efficacy of fenofibrate in children and adolescents (under 18 years of age) have not been established and there are no relevant data. Therefore, fenofibrate is not recommended for use in children and adolescents (under 18 years of age).

Overdose

Only isolated cases of fenofibrate overdose have been reported. In most cases, no symptoms of overdose were noted.

There is no specific antidote. In case of suspected overdose, symptomatic treatment should be given and appropriate supportive measures should be taken as necessary. Fenofibrate is not removed by haemodialysis.

Adverse reactions

The most frequently observed adverse reactions during fenofibrate therapy are digestive disorders, stomach or intestinal disorders.

The following adverse reactions were observed in placebo-controlled clinical trials (n=2344) with the following frequencies:

Increased transaminase levels (see section "Special warnings and precautions for use")

Gallstone disease (see section "Special instructions")

* In the FIELD study, a randomized, placebo-controlled trial in 9,795 patients with type 2 diabetes, there was a statistically significant increase in the incidence of pancreatitis in patients taking fenofibrate compared to patients in the placebo group (0.8% and 0.5%, respectively, p = 0.031).

** There was a statistically significant increase in the incidence of pulmonary embolism (0.7% in the placebo group and 1.1% in the fenofibrate group; p = 0.022) and a statistically non-significant increase in the incidence of deep vein thrombosis (1.0% in the placebo group [48/4900 patients] and 1.4% in the fenofibrate group [67/4895 patients]; p = 0.074).

*** The mean increase in blood homocysteine levels in patients taking fenofibrate was 6.5 μmol/L and was reversible after discontinuation of fenofibrate therapy. An increased risk of venous thrombotic events may be associated with elevated homocysteine levels. The clinical significance of this is unknown.

In addition to the phenomena observed in clinical studies, during the post-marketing period of the drug Tricor® 145 mg, spontaneous reports of the side effects listed below were received; their exact frequency cannot be determined from the available data, therefore it is classified as "unknown".

Respiratory, thoracic and mediastinal disorders: interstitial lung disease.

Musculoskeletal, connective tissue and bone disorders: rhabdomyolysis.

Hepatobiliary system disorders: jaundice, complications of gallstone disease (e.g. cholecystitis, cholangitis, biliary colic).

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

Nervous system disorders: fatigue.

Expiration date

3 years.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C, out of the reach of children.

Packaging

10 tablets in a blister, 2 blisters in a cardboard box.

Vacation category

According to the recipe.

Producer

Recipharm Fontaine, France.

Location of the manufacturer and its business address

Anngrove, Carrigtwohill, Co. Cork, Ireland/Anngrove, Carrigtwohill, Co. Cork, Ireland.

Rue des Pres Potets, 21121 Fontaine les Dijon, France.