Exlip^® (Capsules) Instructions for Use

Marketing Authorization Holder

Nobel Ilac Sanayii Ve Ticaret, A.S. (Turkey)

ATC Code

C10AB05 (Fenofibrate)

Active Substance

Fenofibrate (Rec.INN registered by WHO)

Dosage Form

Exlip®

Extended-release capsules 250 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Extended-release capsules hard gelatin, size No. 1, with an orange transparent body and a light orange opaque cap; the capsule contents are spherical microgranules of almost white or cream color.

Excipients: sugar microgranules (sucrose 92%, corn starch 8%) – 62.5 mg, butylmethacrylate, dimethylaminoethyl methacrylate, and methylmethacrylate copolymer [1:2:1] (Eudragit E100) – 15.6 mg, methacrylic acid and methyl methacrylate copolymer [1:1] (Eudragit L100) – 3.3 mg, talc – 2.825 mg.

Composition of the hard gelatin capsule gelatin, titanium dioxide, dye sunset yellow.

15 pcs. – blisters (2) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – fibrate

Pharmacological Action

Hypolipidemic agent from the group of fibric acid derivatives.

By activating PPAR-alpha (peroxisome proliferator-activated receptor alpha), Fenofibrate enhances lipolysis and the removal from blood plasma of atherogenic lipoproteins with a high concentration of triglycerides by activating lipoprotein lipase and reducing the synthesis of apoprotein CIII. Activation of PPAR-alpha also leads to increased synthesis of apoproteins AI and AII.

Fenofibrate is a derivative of fibric acid, the ability of which to change lipid concentrations 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 LDL and VLDL, which include apoprotein B, and an increase in the concentration of HDL, which include apoproteins AI and AII.

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

Fenofibrate reduces platelet aggregation, lowers elevated plasma fibrinogen levels, can slightly lower blood glucose levels in patients with diabetes mellitus; reduces blood uric acid levels.

Pharmacokinetics

After oral administration, Fenofibrate is rapidly hydrolyzed by esterases. Only the main active metabolite of fenofibrate, fenofibric acid, is detected in blood plasma. Fenofibrate is not a substrate for the CYP3A4 isoenzyme and does not participate in microsomal metabolism. The original Fenofibrate is not detected in blood plasma. C_max in blood plasma is reached 2-4 hours after oral administration. With long-term use, the concentration in blood plasma remains stable regardless of the patient’s individual characteristics. Binding to plasma proteins (albumin) is high – more than 99%. It is excreted mainly by the kidneys in the form of fenofibric acid and a glucuronide conjugate. Within 6 days, Fenofibrate is excreted almost completely.

Indications

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-drug therapeutic measures (for example, weight loss or increased physical activity) are ineffective, especially in the presence of dyslipidemia-related risk factors such as arterial hypertension and smoking.

For the treatment of secondary hyperlipoproteinemia, the drug is used in cases where hyperlipoproteinemia persists despite effective treatment of the underlying disease (for example, dyslipidemia in diabetes mellitus).

ICD codes

Dosage Regimen

Before starting and during treatment, the patient must follow a hypocholesterolemic diet.

Take orally once a day.

The dose depends on the dosage form used.

Treatment is long-term. The effectiveness of therapy should be assessed by the concentration of lipids (total cholesterol, LDL, triglycerides) in the blood serum. In the absence of a therapeutic effect after several months of therapy (usually after 3 months), the advisability of prescribing concomitant or alternative therapy should be considered.

Adverse Reactions

From the blood and lymphatic system rarely – decrease in hemoglobin and leukocytes.

From the immune system rarely – hypersensitivity reactions.

From the nervous system uncommon – headache.

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

From the digestive system often – abdominal pain, nausea, vomiting, diarrhea, flatulence, increased activity of liver transaminases; uncommon – pancreatitis, cholelithiasis; rarely – hepatitis.

From the skin and subcutaneous tissues rarely – alopecia, photosensitivity reactions.

Allergic reactions uncommon – skin rash, skin itching, urticaria.

From the musculoskeletal system uncommon – muscle lesions, including diffuse myalgia, myositis, muscle spasm and muscle weakness.

From the reproductive system uncommon – erectile dysfunction.

From laboratory parameters very often – increased concentration of homocysteine in the blood; uncommon – increased concentration of creatinine in the blood serum; rarely – increased concentration of blood urea nitrogen in the blood serum.

Contraindications

Hypersensitivity to fenofibrate; severe liver dysfunction – class C according to the Child-Pugh scale (including biliary cirrhosis and persistent liver dysfunction of unknown etiology); history of gallbladder disease; severe and moderate renal impairment (CrCl<60 ml/min); chronic or acute pancreatitis, except for cases of acute pancreatitis due to severe hypertriglyceridemia; history of photosensitivity or phototoxicity during treatment with fibrates or ketoprofen; breastfeeding period; age under 18 years.

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; use during pregnancy; with simultaneous use of oral anticoagulants, HMG-CoA reductase inhibitors

Use in Pregnancy and Lactation

The potential risk for humans is unknown, therefore use during pregnancy is possible only after a thorough assessment of the ratio of the expected benefit of therapy for the mother and the probable risk to the fetus.

Fenofibrate is contraindicated for use during breastfeeding.

Use in Hepatic Impairment

Contraindicated in severe liver dysfunction – class C according to the Child-Pugh scale (including biliary cirrhosis and persistent liver dysfunction of unknown etiology).

Use in Renal Impairment

Contraindicated in severe and moderate renal impairment (CrCl<60 ml/min).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in patients over 70 years of age.

Special Precautions

Before starting the use of fenofibrate, treatment of diseases that can cause secondary hypercholesterolemia should be carried out, including: 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, an increase in lipid concentration may be caused by the intake of estrogens.

It is recommended to monitor ALT, AST activity every 3 months during the first 12 months and periodically during further treatment. Patients whose liver transaminase activity has increased during treatment require attention, and if ALT and AST activity increases more than 3 times the upper limit of normal, fenofibrate should be discontinued. If symptoms of hepatitis (jaundice, skin itching) appear, laboratory tests should be performed and, if the diagnosis of hepatitis is confirmed, Fenofibrate should be discontinued.

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

If the creatinine concentration increases by more than 50% above the upper limit of normal, treatment should be suspended. It is recommended to determine the creatinine concentration in the first 3 months and periodically during further treatment.

During the first twelve months from the start of fenofibrate therapy, periodic monitoring of the content of erythrocytes and leukocytes is recommended.

In case signs or symptoms of immediate hypersensitivity are observed, it is necessary to immediately consult a doctor and discontinue the use of fenofibrate.

Drug Interactions

Fenofibrate enhances the effect of oral anticoagulants and may increase the risk of bleeding, which is associated with the displacement of the anticoagulant from plasma protein binding sites.

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

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.

Several cases of reversible paradoxical decrease in HDL cholesterol concentration have been reported with the simultaneous use of fenofibrate and glitazones. Therefore, during simultaneous therapy, it is recommended to monitor the concentration of HDL cholesterol, and in case of a pronounced decrease in HDL cholesterol concentration, the drugs should be discontinued.

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, adjustment of the doses of these drugs is recommended.

Storage Conditions

Store at 2°C (36°F) to 30°C (86°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.