Tricor® [Fenofibrate]

Pharmacological properties

Pharmacodynamics

Dyslipidemia. Fenofibrate is a derivative of fibroic acid, the lipid-modifying effects of which in humans are mediated by the activation of a receptor activated by the alpha-type peroxisome proliferator (PPARα).

Due to the activation of PPARα, fenofibrate enhances lipolysis and excretion of atherogenic particles rich in TG 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 effects of fenofibrate on lipoproteins lead to a decrease in the fractions of VLDL and LDL that contain apoprotein B, and an increase in the fraction of HDL containing apoproteins AI and AII.

In addition, by modulating the synthesis and catabolism of VLDL fractions, fenofibrate enhances the clearance of LDL and reduces the number of small dense LDL, the level of which is increased in people with atherogenic lipoprotein phenotype, which is often found in patients at risk of developing coronary artery disease.

In clinical studies, with the use of fenofibrate, the level of total cholesterol decreased by 20–25%, TG by 40–55%, and the level of HDL cholesterol increased by 10–30%.

In patients with hypercholesterolemia, whose LDL cholesterol levels are reduced by 20–35%, the overall effect on the level of cholesterol leads to a decrease in the ratio of total cholesterol / HDL cholesterol, LDL cholesterol / HDL cholesterol or apoprotein B / apoprotein AI, which are markers of atherogenic risk.

There is evidence that fibrate treatment can reduce the incidence of coronary heart disease, but fibrates have not shown a decrease in overall mortality in primary or secondary prevention of cardiovascular disease.

ACCORD lipid is a randomized, placebo-controlled study in 5518 patients with type II diabetes who were treated with fenofibrate in addition to simvastatin. Fenofibrate therapy with simvastatin compared with simvastatin monotherapy did not show significant differences in terms of the effect on the combined primary endpoint - nonfatal myocardial infarction, nonfatal stroke and cardiovascular death (risk ratio (RR) 0.92; 95% confidence interval (CI) ) 0.79–1.08; p = 0.32; absolute risk reduction - 0.74%). In a pre-selected subgroup of patients with dyslipidemia who had the lowest level of HDL cholesterol cholesterol (≤34 mg / dL or 0.88 mmol / L) and the highest level of TG tertyl (≥204 mg / dL or 2.3 mmol / L) , combination therapy with fenofibrate with simvastatin compared with simvastatin monotherapy showed a 31% relative decrease in the risk of combined primary endpoint (RR 0.69; 95% CI 0.49–0.97; p = 0.03; reduction in absolute risk - 4, 95%). Analysis of another pre-selected subgroup revealed a statistically significant relationship between treatment and gender (p = 0.01), indicating a possible benefit from combination therapy in men (p = 0.037), but a potentially higher risk of a primary endpoint in women receiving combination therapy compared to 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 an advantage for women with dyslipidemia who received fenofibrate with simvastatin, and a possible negative effect in this subgroup cannot be ruled out.

Extravascular deposits of cholesterol (tendon and tuberous xanthomas) can significantly decrease or completely disappear during treatment with fenofibrate.

Patients with elevated fibrinogen levels who were treated with fenofibrate showed a significant decrease in this indicator, as well as in patients with elevated levels of lipoprotein (a). Fenofibrate reduces the levels of other markers of inflammation, such as C-reactive protein.

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

The antiplatelet effect of fenofibrate on platelets was revealed in animal studies and in a clinical study that demonstrated a decrease in platelet aggregation caused by ADP, arachidonic acid and adrenaline.

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

FIELD is a multinational randomized trial involving 9795 patients with type II diabetes mellitus. Selected patients were randomized to 200 mg / day fenofibrate treatment groups (n = 4895) or placebo (n = 4900). In an ophthalmological sub-study involving 1012 patients, standardized retinal photographs were taken, which were evaluated using the ETDRS (Early Treatment Diabetic Retinopathy Study) criteria to determine the cumulative frequency of development of diabetic retinopathy and its individual manifestations. Analyzes were performed in all patients who began to receive treatment. In the ophthalmic sub-study, the primary endpoint, 2-step progression of the retinopathy stage, did not significantly differ in the 2 groups as a whole (46 [9.6%] patients in the fenofibrate group and 57 [12.3%] in the placebo group, p = 0 , 19) or in a subgroup of patients without preexisting retinopathy (43 [11.4%] and 43 [11.7%] patients, p = 0.87). Conversely, in the group of patients with pre-existing retinopathy, 2-step progression was observed in a significantly smaller number of patients receiving fenofibrate than in the placebo group (3 [3.1%] and 14 [14.6%] patients, p = 0.004).

Laser treatment information for diabetic retinopathy, which is a predefined tertiary endpoint in the main study, was collected at each patient visit to the clinic. The need for the first laser treatment of all retinopathies was significantly less with fenofibrate compared with placebo (164 [3.4%] patients in the fenofibrate group and 238 [4.9%] in the placebo group; RR 0.69; 95% CI 0.56–0.84; p = 0.0002; absolute risk reduction - 1.5% [0.7–2.3]). The need for such therapy did not depend on the concentration of lipids in the blood plasma.

In a subgroup of 2856 participants in the ACCORD (ACCORD Eye) study, the effect of 3 treatment strategies on the progression of diabetic retinopathy was evaluated: intensive or standard glycemic therapy (target HbA1c level of 6.0% or from 7.0 to 7.9%, respectively), dyslipidemia (combined therapy fenofibrate 160 mg / day + simvastatin or placebo + simvastatin) or control systolic blood pressure (target of 120 or 140 mm Hg). The progression of diabetic retinopathy was determined after 4 years by increasing the ETDRS score by 3 or more points (based on the evaluation of stereoscopic photographs of 7 fundus fields) or developing diabetic retinopathy, which needed laser photocoagulation or vitrectomy.

The rate of progression of diabetic retinopathy was 6.5% in the intensive care group of dyslipidemia using 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 rate of progression of diabetic retinopathy.

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

Pharmacokinetics

Suction. C_max the drug in the blood plasma is achieved 2-4 hours after oral administration. Plasma concentration remains stable with prolonged use in all patients.

Unlike previous fenofibrate preparations, when using the drug Tricor 145 mg in the form of its nanoparticles, C_max in plasma and total exposure are independent of food intake, therefore, Tricor 145 mg can be taken without regard to food.

In a study of the effect of food on drug absorption after the use of new 145 mg fenofibrate tablets in healthy men and women on an empty stomach and with high-fat foods, it was shown that eating does not affect exposure (AUC and C_max) fenofibroic acid.

Distribution. Fenofibroic acid is largely associated with plasma albumin (more than 99%).

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

The drug is excreted mainly in the urine. It is almost completely removed in 6 days. Fenofibrate is excreted mainly in the form of fenofibroic acid and its glucuronide conjugate. In elderly patients, the apparent total clearance of fenofibroic acid from blood plasma does not change.

Kinetics studies after a single dose and long-term treatment have shown that the drug does not accumulate in the body. Fenofibroic acid is not excreted by hemodialysis.

T_½ fenofibroic acid is approximately 20 hours

Indications

Tricor 145 mg is indicated as an addition to diet and other non-drug methods of treatment (for example, exercise, weight loss) in such conditions:

- severe hypertriglyceridemia, including with a low level of HDL cholesterol;

- mixed hyperlipidemia in cases where the use of statins is contraindicated or their intolerance exists;

- mixed hyperlipidemia in patients with high cardiovascular risk in addition to statin therapy, when the level of TG and HDL cholesterol is not adequately controlled.

Diabetic retinopathy: Tricor 145 mg is indicated to reduce the progression of diabetic retinopathy in patients with type II diabetes mellitus and existing diabetic retinopathy.

Application

Film-coated tablets can be taken at any time of the day, regardless of food intake. tablets should be swallowed whole with a glass of water.

Diet therapy, begun before the appointment of the drug, must be continued.

During treatment of hyperlipidemia, the effectiveness of therapy should be monitored by determining the level of lipids in the blood serum. If after a few months (for example 3 months) an adequate response to treatment is not achieved, additional or other therapeutic measures should be considered.

For adults. The recommended dose is 1 tablet containing 145 mg of fenofibrate, 1 time per day. Patients who take 1 capsule containing 200 mg of fenofibrate, or 1 tablet containing 160 mg of fenofibrate, can replace them with 1 tablet of Tricor 145 mg without additional dose selection.

If the patient needs to use fenofibrate for 2 indications (hyperlipidemia and diabetic retinopathy), only 1 tablet of Tricor 145 mg / day should be prescribed.

Elderly patients. Elderly patients who do not have renal failure, the usual dose for adults is recommended.

Impaired renal function. Patients with impaired renal function need to reduce the dose. Fenofibrate is not recommended for use in patients with severe chronic kidney disease.

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

Children.The safety and effectiveness of fenofibrate in children and adolescents under the age of 18 years have not been established, relevant data are missing. Therefore, fenofibrate is not recommended for use in children and adolescents under the age of 18 years.

Contraindications

Hepatic failure (including biliary cirrhosis and vague persistent impaired liver function); established diseases of the gallbladder; severe chronic kidney disease; chronic or acute pancreatitis, except in cases of acute pancreatitis caused by severe hypertriglyceridemia; established photoallergy or phototoxic reactions during treatment with fibrates or ketoprofen; hypersensitivity to the active substance or to any auxiliary substance; Also, the drug should not be used in patients with an allergy to peanuts, peanut butter, soya lecithin or similar products because of the risk of hypersensitivity reactions.

Side effects

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

The following adverse events were observed in placebo-controlled clinical trials (n = 2344) with the indicated frequency:

* In the FIELD study, a randomized, placebo-controlled study in which 9795 type II diabetes patients participated, patients taking fenofibrate showed a statistically significant increase in the incidence of pancreatitis compared with patients in the placebo group (0.8 and 0.5 %, respectively; p = 0.031). In the same study, there was a statistically significant increase in the incidence of lung embolism (0.7% in the placebo group and 1.1% in the fenofibrate group; p = 0.022) and a statistically insignificant increase in deep vein thrombosis (1.0% in the group placebo [48/4900 patients] and 1.4% in the fenofibrate group [67/4895 patients]; p = 0.074).

In addition to the phenomena noted in clinical trials, in the post-marketing period of the use of the drug Tricor 145, spontaneous reports were received about the side effects listed below; it is impossible to establish their exact frequency from the available data, therefore they are assigned to phenomena with an unknown frequency:

Disorders of the respiratory system, chest and mediastinum: interstitial lung disease.

Disorders from skeletal muscles, connective tissue and bones: rhabdomyolysis.

Disorders from the hepatobiliary system: jaundice, complications of gallstone disease (e.g. cholecystitis, cholangitis, biliary colic).

On the part of the skin and subcutaneous tissue: severe skin reactions (e.g. erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis).

Others: fatigue, dizziness.

special instructions

Secondary hyperlipidemia. Before starting fenofibrate therapy, it is necessary to carry out the necessary treatment of the relevant conditions that cause secondary hypercholesterolemia, such as uncontrolled type II diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease or alcoholism. secondary hypercholesterolemia associated with pharmacological treatment may be observed in patients taking