Trilipix - instructions for use, dose, side effects, contraindications

Active substanceCholine fenofibrateCholine fenofibrate

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Trilipix®

capsules inwards

Abbot Helskea SAS France

Dosage form: & nbspCapsules with modified release.

Composition:

1 capsule with modified release with a dosage of 45 mg contains

4 mini tablets

Composition per one mini-tablet:

Active substance: choline fenofibrate - 14.9 mg (in terms of fenofibroic acid 11.25 mg).

Excipients: hypromellose - 6.2 mg, povidone - 0.7 mg, giprolose - 0.7 mg, silicon dioxide colloid - 0.1 mg, sodium stearyl fumarate - 0.2 mg, purified water - q.s.

Film Sheath: methacrylic acid and ethacrylate copolymer [1: 1] - 2.2 mg, talc - 1.1 mg, trethyl citrate (E1505) - 0.3 mg.

The composition of the capsule shell for a dosage of 45 mg:

Housing: iron oxide oxide yellow - 0.5581%, titanium dioxide - 0.7872%, gelatin - up to 100%.

Cap: ferric oxide black oxide - 0.0551%, iron dye red oxide - 1,1079%, iron oxide dye yellow 0.0315%, titanium dioxide 0.7821%, gelatin up to 100%.

The composition of the ink on the capsule shell for a dosage of 45 mg: shellac - 24-27%, dehydrated alcohol - 23-26%, isopropanol 0.5-3%, butanol - 0.5-3%; propylene glycol 3-7%, purified water 15-18%, ammonia water 1-2%, potassium hydroxide 0.5-1%, iron dye black oxide (E172) 24-28%.

1 a modified release capsule with a dosage of 135 mg contains 12 mini tablets

Composition per one mini-tablet:

Active substance: choline fenofibrate - 14.9 mg (in terms of fenofibroic acid 11.25 mg).

Excipients: hypromellose - 6.2 mg, povidone - 0.7 mg, giprolose - 0.7 mg, silicon dioxide colloid - 0.1 mg, sodium stearyl fumarate - 0.2 mg, purified water - q.s.

Film Sheath: methacrylic acid and ethacrylate copolymer [1: 1] 2.2 mg, talc 1.1 mg, triethyl citrate (E1505) 0.3 mg.

Composition of gelatin capsule for dosage of 135 mg:

Housing: iron oxide oxide yellow - 0.5581%, titanium dioxide 0.7872%, gelatin - up to 100%.

Cap: the color of the brilliant blue is 0.2112%, titanium dioxide is 1.3465%, gelatin is up to 100%.

The composition of the ink on the capsule shell for a dosage of 135 mg: shellac - 24-27%, dehydrated alcohol - 23-26%, isopropanol 0.5-3%, butanol - 0.5-3; propylene glycol 3-7%, purified water 15-18%, ammonia water 1-2%, potassium hydroxide 0.5-1%, iron dye black oxide (E172) 24-28%.

Description:

Capsules with modified release at a dosage of 45 mg: Hard gelatin capsules №3 with a yellow opaque case and a reddish-brown opaque lid. On the body black ink is printed "45".

Contents of capsules: four mini-pills of round biconvex cylindrical shape, covered with a white film shell.

Cross-sectional view: Rough homogeneous white surface.

Capsules with modified release with a dosage of 135 mg: Hard gelatin capsules №0 with a yellow opaque case and a blue opaque lid.

On the body black ink printed "135".

Contents of the capsules: twelve mini-tablets of a round biconvex cylindrical shape, covered with a white film shell.

Cross-sectional view: rough homogeneous white surface.

Pharmacotherapeutic group:A hypolipidemic agent is a fibrate.

ATX: & nbsp

C.10.A.B.11 Choline fenofibrate

Pharmacodynamics:

The active substance of the preparation Trilipix® is fenofibroic acid. Activating RAPP-alpha (alpha receptors activated by the peroxisome proliferator), fenofibroic acid enhances lipolysis and the removal of high-triglyceride atherogenic lipoproteins from the blood plasma by activating the lipoprotein lipase and reducing the synthesis of the apo-protein CIII (inhibitor of lipoprotein lipase activity). Activation of PPA-alpha also leads to increased synthesis of high-density lipoproteins (HDL) and apo-proteins AI and AII.

The above-described effects of fenofibric acid on lipoproteins lead to a reduction in the content of atherogenic lipoproteins of low (LDL) and very low density (VLDL), including apoprotein B,and an increase in the content of a fraction of high-density lipoproteins, including apoproteins AI and AII.

In addition, due to correction of the synthesis and catabolism of VLDLP, fenofibrate increases the clearance of LDL and reduces the content of dense and small particle size of LDL, the increase of which is observed in patients with atherogenic lipid phenotype, a frequent violation in patients with risk of coronary heart disease. The use of fenofibrate reduces the concentration of total cholesterol and triglycerides with increasing HDL concentration.

There are no advantages of Trllicix ® in reducing cardiovascular morbidity and mortality in comparison with monotherapy of HMG-CoA reductase inhibitors.

Fenofibrate at a dose equivalent to 135 mg of Trilipix® did not show a reduction in the incidence of coronary heart disease (CHD) and mortality in a large randomized controlled trial involving patients with type 2 diabetes mellitus.

Pharmacokinetics:

The main plasma metabolite is fenofibroic acid.

Concentrations of fenofibric acid in blood plasma after the administration of the drug

Trilipix® 135 mg in modified release capsules are equivalent

when taking a capsule 200 mg of finely dispersed fenofibrate at the time of admission

food.

Suction

Phenofibroic acid is well absorbed from the gastrointestinal tract. The absolute bioavailability of fenofibric acid is approximately 81%. The maximum concentration of fenofibric acid in the blood plasma is determined during 4-5 hours after a single intake of fenofibroic acid on an empty stomach. The content of fenofibric acid in the blood plasma, according to the indices Cmah and AUC (area under the pharmacokinetic curve "concentration-time"), does not significantly differ from the content of fenofibroic acid after a single administration of 135 mg of Trilipix® preparation on an empty stomach and after meals.

Distribution

With prolonged use of the drug, the concentration of fenofibric acid in the blood plasma reaches a constant value within 8 days. The constant concentrations of fenofibroic acid are approximately equal to a double single dose. Binding to serum proteins is approximately 99%.

Metabolism

Fenofibroic acid is initially conjugated with glucuronic acid, and then excreted by the kidneys. A small amount of fenofibric acid is decarboxylated to benzgidrolnogo metabolite, which in turn is conjugated to glucuronic acid and excreted by the kidneys. Metabolism data in vivo after the administration of fenofibrate, it is indicated that fenofibroic acid does not undergo oxidation to a large extent (for example, the cytochrome P450 isoenzyme system) /

Excretion

After absorption, Trilipix® is excreted by the kidneys in the form of fenofibric acid and fenofibric acid glucuronide. The half-life of fenofibroic acid (T_1/2) - about 20 hours, which allows the appointment of Trilipix® once a day.

Indications:

Trilipix® is indicated in combination with a diet:

Combination therapy with HMG-CoA reductase inhibitors (statins) of mixed dyslipidemia (type IIa, IIb by Fredrickson), in order to reduce triglycerides (TG) and increase HDL-C levels in patients with coronary artery disease (ischemic heart disease) or a high risk of developing coronary heart disease other clinical forms of atherosclerotic disease: atherosclerosis of peripheral arteries,abdominal aortic aneurysm and symptomatic carotid atherosclerosis; diabetes; multiple risk factors that correspond to a 10-year risk of developing coronary events> 20%);

- to reduce the concentration of TG in patients with severe hyperglyceridemia (dyslipidemia IV, V type by Fredrickson);

- with the aim of reducing the elevated concentrations of LDL, total cholesterol, triglycerides and ApoB (apolipoprotein B) and increasing the HDL concentration in patients with primary hyperlipidemia or mixed dyslipidemia (type IIa, IIb, III, IV according to Fredrickson).

Contraindications:

- hypersensitivity to the active component (fenofibroic acid, choline fenofibrate), fenofibrate, or any of the components of the drug;

- severe renal failure (creatinine clearance less than 30 ml / min);

- hepatic insufficiency (including biliary cirrhosis and persistent liver dysfunction of unclear etiology);

- diseases of the gallbladder;

- acute or chronic pancreatitis, with the exception of acute pancreatitis due to severe hypertriglyceridemia;

- the presence in the anamnesis of photosensitization or phototoxicity in the treatment of fibrates or ketoprofen;

- age under 18 years (effectiveness and safety not established);

- pregnancy;

- lactation period.

When taking Trilipix® with statins at the same time, read the "Contraindications" section of the instructions for the medical use of the appropriate statin.

Carefully:Pi hypothyroidism; patients who abuse alcohol; elderly patients; patients with a history of hereditary muscle diseases; with the simultaneous administration of oral anticoagulants, inhibitors of HMG-CoA reductase (see section "Interaction with other drugs").

Pregnancy and lactation:

There are no data on the use of Trilipix® in pregnant women. The potential risk to humans is unknown. Trilipix® should not be taken during pregnancy, except when the benefit to the mother exceeds the potential risk to the fetus.

It is not known whether fenofibroic acid is excreted in breast milk. The isolation of fenofibroic acid with milk has not been studied in animals. The decision to continue breastfeeding or continue treatment with Trilipix® should be taken only after comparing the benefits of breastfeeding with the potential risk for an infant and the benefits of therapy with the drug for the mother.

Dosing and Administration:Prior to the appointment of Trilipix® to the patient as a monotherapy or with simultaneous administration with statins, a corresponding hypolipidemic diet should be prescribed, which should be followed during treatment. The Trilipix® capsule with modified release should be swallowed whole, without chewing, washed down with water, regardless of food intake.

The maximum daily dose is 135 mg.

Adults

- Combination therapy with HMG-CoA reductase inhibitors (statins) in the treatment of mixed dyslipidemia.

It is possible to take Trilipix® at a dose of 135 mg with the HMG-CoA reductase inhibitor (statin) in patients with mixed dyslipidemia. For convenience, the daily dose of Trilipix® can be taken at the same time as statin, according to the recommended dosage for each drug. Combination therapy for the maximum dose of statin with Trilipix® is not clinically studied, and should therefore be avoided unless the benefits of therapy exceed the possible risk.

- Severe hypertriglyceridemia.

The initial dose of Trilipix® is 45 mg or 135 mg once daily.The dosage should be individually tailored to the patient's response and should be corrected, if necessary, after repeated determinations of lipids in the interval 4-8 weeks. The maximum dose is 135 mg once a day.

- Primary hyperlipidemia or mixed dyslipidemia The dose of Trilipix® is 135 mg once daily.

Elderly patients

The choice of dose for elderly patients should be carried out taking into account the function of the kidneys.

Patients with renal insufficiency

Treatment with Trilipix® should be started at a dose of 45 mg once a day in patients with mild and moderate renal insufficiency (creatinine clearance 30 to 80 ml / min). The dose of the drug can be increased only after evaluating the effect of the drug on renal function and lipid concentration. Trilipix® should be avoided in patients with severe renal failure (see "Contraindications").

Side effects:Phenofibroic acid is an active metabolite of fenofibrate. When fenofibrate was used in placebo-controlled clinical trials, the following adverse effects were identified:

System of organs	Often> 1/100 (> 1% and <10%)	Infrequently> 1 / 1,000 (> 0.1% and <1%)	Rarely> 1/10000 (> 0.01% and <0.1%)	Rarely <1/10000, including single cases (<0.01%)
Hemopoietic and lymphatic systems			Reduction of hemoglobin Reduction in the number of leukocytes
The immune system			Allergic reactions
Nervous system		Headache
The Vesselse violation		Thromboembolism (pulmonary embolism,
System of organs	Often> 1/100 (> 1% and <10%)	Infrequently> 1 / 1,000 (> 0.1% and <1%)	Rarely> 1/10000 (> 0.01% and <0.1%)	Very rarely <1/10000, including single cases (<0.01%)
		deep vein thrombosis)
Digestive system	Gastro- intestinal symptoms (abdominal pain, nausea, vomiting, diarrhea, flatulence)	Pancreatitis
Hepatobiliary system	Increased activity of "liver" transaminases	Chololithiasis	Hepatitis
Skin and subcutaneous tissue		Skin allergy (including rash, itching, urticaria)	Alopecia, reactions photosensitivity
Skeletal musculature, connective and bony tissue		Muscular disorders (including myalgia, myositis, muscle spasms and weakness)
Reproductive system and mammary glands		Sexual dysfunction
Laboratory research		Increase in the concentration of creatinine in the blood	Increase in the concentration of urea in the blood

When using Trilipix ® in monotherapy or in combination with statins duringrandomized controlled clinical trials, the following adverse events in >3% of patients who participated in the study:

Disorders from the gastrointestinal tract: constipation, diarrhea, indigestion, nausea.

General disorders and disorders at the site of administration: increased fatigue, pain.

Infectious and parasitic diseases: nasophagitis, sinusitis, upper respiratory tract infections.

Laboratory and instrumental data: Increased activity ALT (alanine aminotransferase).

Disturbances from musculoskeletal and connective tissue: arthalgia, pain in

back, muscle spasms, myalgia, pain in the limbs.

Impaired nervous system: dizziness, headache.

In addition to the phenomena identified during clinical trials, the following side effects were identified in the post-marketing process (the available data are insufficient to determine their frequency):

Disturbances from the respiratory system, chest and mediastinal organs: interstitial pulmonary process.

Disturbances from the musculoskeletal and connective tissue: acute necrosis of skeletal muscles.

Overdose:Cases of overdose are not described. The specific antidote is unknown. Overdose shows general supportive therapy, including monitoring vital signs and monitoring the clinical condition of the patient. The removal of unabsorbed drug should be achieved by inducing vomiting or washing the stomach, maintaining airway patency. Hemodialysis is ineffective, because fenofibroic acid is largely bound to blood plasma proteins.

Interaction:

Oral anticoagulants

Caution should be exercised while using fenofibroic acid with oral anticoagulants coumarin. Phenofibroic acid enhances the effect of indirect coagulants and may increase the risk of bleeding, which leads to an increase in prothrombin time / INR (International Normalized Ratio). It is recommended to carry out regular monitoring of prothrombin time / INR and selection of oral anticoagulant dose until stabilization

prothrombin time / INR in order to prevent hemorrhagic complications. Cyclosporin

Since the use of cyclosporine can lead to nephrotoxicity with a decrease in creatinine clearance and an increase in serum creatinine, and since renal excretion is the main route for the removal of the fibrate group drug, including fenobroic acid, there is a risk that the interaction of these drugs will lead to a decrease in renal function. It is necessary to carefully weigh the benefits and risks of using fenofibroic acid in combination with immunosuppressants and other potentially nephrotoxic drugs and use the lowest effective dose.

HMG-CoA reductase inhibitors (statins)

With the simultaneous administration of fenofibrate or fenofibric acid with hydroxymethylglutaryl coenzyme A-reductase inhibitors, the risk of developing severe toxic effects on muscles may increase. Such combination therapy should be administered with caution, and patients should be carefully screened for signs of toxic muscle damage (see section "Special instructions"). Clinically significant pharmacokinetic interactions of the drug with lipid-lowering drugs, such as HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, pravastatin, rosuvastatin and simvastatin) and ezetimibe not identified, however, pharmacodynamic interaction can not be ruled out. Correction of a dose of fenofibroic acid or concomitantly taken medications is not required.

Hypoglycemic drugs for oral administration

There was no clinically significant pharmacokinetic interaction between fenofibrate or fenofibric acid and rosiglitazone, metformin or glimepiride. Correction of the dose of Trilipix® or simultaneous preparations is not required.

There was no clinically significant pharmacokinetic interaction between fenofibrate or fenofibroic acid and omeprazole.

In the study in vitro Using human liver microsomes, it has been shown that fenofibroic acid is not an inhibitor of isoenzymes CYP3A4, CYP2D6, CYP2E1, or CYP1A2 cytochrome (CYP)P450. In therapeutic concentrations, fenofibroic acid is a weak inhibitor of isoenzymes CYP2C8, CYP2C19 and CYP2A6, as well as a moderate isoenzyme inhibitor CYP2C9.

Special instructions:

Skeletal muscles

Monotherapy with fibrates and statins increases the risk of myositis and myopathy associated with rhabdomyolysis.Data from experimental studies suggest that the risk of rhabdomyolysis increases with simultaneous administration of fibrates and statins. The risk of serious toxic effects on muscles is likely to increase in elderly patients and in patients with diabetes mellitus, renal failure, or hypothyroidism.

Myopathy can be suspected in patients with diffuse myalgias, muscle soreness or muscle weakness and / or an increased activity of CKK (creatine phosphokinase). Patients should immediately report the occurrence of unexplained pain in the muscles, tenderness, or muscle weakness, especially if these symptoms are accompanied by a malaise or fever. In patients presenting similar complaints, it is necessary to determine the activity of CK. In the case of a significant increase in the activity of CKK (more than 5 times the upper limit of the norm) or diagnosis of myositis or myopathy, Trilipix® and statin should be withdrawn.

Renal function

When Trilipix® was used as monotherapy or in combination with statins, a reversible increase in serum creatinine concentration was noted in patients.The increase in creatinine concentration was generally stable for a time without signs of a further increase in serum creatinine concentration with prolonged therapy, with a tendency to return to baseline values after treatment withdrawal. The clinical significance of these observations is not established. In patients with kidney failure, when taking Trilipix®, it is recommended that kidney function is monitored. Control of renal function should be performed in patients at risk of developing renal failure, namely, elderly patients and patients with diabetes mellitus. Treatment should be reversed if the concentration of creatinine> 50% of the upper limit of the norm is increased. It is recommended to determine the concentration of creatinine during the first 3 months after the start of treatment, and also periodically after its termination.

Liver function

When Trilipix® is used at a dose of 135 mg once a day as monotherapy or when taken together with low or moderate doses of statins, an increase in the activity of "hepatic" transaminases in the serum [ACT (aspartate aminotransferase) or ALT (alanine aminotransferase)].There is evidence that with fenofibrate therapy for several weeks or years, hepatocellular, chronic active and cholestatic hepatitis develop. There are reports of extremely rare cases of liver cirrhosis accompanied by chronic active hepatitis.

Throughout treatment with Trilipix®, regular monitoring of liver function is required, including activity ALT and ACT in the blood serum. Treatment should be stopped when the level of enzymes is increased more than 3 times from the upper limit of the norm.

Pancreatitis

When treating drugs with a group of fibrates, including Trilipix®, cases of pancreatitis have been reported. The occurrence of pancreatitis may be due to the lack of treatment effect in patients with severe hypertriglyceridemia, direct drug exposure or secondary phenomenon caused by a stone in the bile ducts or the formation of a sediment with obstruction of the common bile duct.

Effect on the ability to drive transp. cf. and fur:There is no evidence of the effect of Trilipix® on the ability to drive and other mechanisms.However, there are reports of dizziness and fatigue during the treatment period (see "Side effect"). This should be taken into account when carrying out the above actions.

Form release / dosage:Capsules with a modified release of 45 mg, 135 mg.

Packaging:

Dosage of 45 mg: 10 capsules in the Alu / Alu blister. For 1, 3 or 6 blisters together with instructions for use in a pack of cardboard.

For 60 or 90 capsules in high density polyethylene bottles. A label with instructions for use is applied to the vial.

Dosage of 135 mg: 10 capsules in the Alu / Alu blister. For 1, 2 or 3 blisters together with instructions for use in a pack of cardboard.

For 60 or 90 capsules in high density polyethylene bottles. A label with instructions for use is applied to the vial.

Storage conditions:In a dry, the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children!

Shelf life:

Capsules packed in a blister - 3 years.

Capsules packed in a vial - 18 months.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LP-001501

Date of registration:13.02.2012

Date of cancellation:2017-04-19

The owner of the registration certificate:Abbot Helskea SASAbbot Helskea SAS France

Manufacturer: & nbsp

FOURNIER LABORATORIES IRELAND, Limited Ireland

Representation: & nbspEBOBOT PRODUKTS LLCEBOBOT PRODUKTS LLCRussia

Information update date: & nbsp19.04.2017

Illustrated instructions

Instructions

Trilipix® (Trilipix®)