Lescol^® (Tablets, Capsules) Instructions for Use

ATC Code

C10AA04 (Fluvastatin)

Active Substance

Fluvastatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

Hypolipidemic agent from the group of statins, an inhibitor of HMG-CoA reductase. Through the principle of competitive antagonism, the statin molecule binds to the part of the coenzyme A receptor where this enzyme attaches. Another part of the statin molecule inhibits the process of converting hydroxymethylglutarate to mevalonate, an intermediate product in the synthesis of the cholesterol molecule.

Inhibition of HMG-CoA reductase activity leads to a series of sequential reactions, resulting in a decrease in intracellular cholesterol content and a compensatory increase in LDL receptor activity and, accordingly, an acceleration of Xc-LDL cholesterol catabolism.

The hypolipidemic effect of statins is associated with a decrease in total cholesterol levels due to Xc-LDL. The reduction in LDL levels is dose-dependent and not linear, but exponential.

Statins do not affect the activity of lipoprotein and hepatic lipases, do not have a significant effect on the synthesis and catabolism of free fatty acids, so their effect on TG levels is secondary and mediated through their main effects of reducing Xc-LDL levels. The moderate decrease in TG levels during treatment with statins is apparently associated with the expression of remnant (apo E) receptors on the surface of hepatocytes, involved in the catabolism of IDL, which contain approximately 30% TG.

In addition to the hypolipidemic effect, statins have a positive effect on endothelial dysfunction (a preclinical sign of early atherosclerosis), on the vascular wall, the condition of atheroma, improve the rheological properties of blood, and have antioxidant and antiproliferative properties.

Pharmacokinetics

C_max, AUC, T_1/2 of fluvastatin depend on the dosage form taken, time of food intake, fat content in food, duration of use, and individual metabolic characteristics.

V_d – 330 L. Plasma protein binding – more than 98%.

It undergoes intensive metabolism during the “first pass” through the liver before entering the systemic circulation. In patients with hepatic insufficiency, there is a possibility of fluvastatin accumulation.

It is excreted as metabolites through the biliary tract (93%), in the urine (6%), unchanged – 2%. The biotransformation pathways of fluvastatin are not associated with the cytochrome P450 isoenzyme system, and metabolism is practically unchanged under the influence of drugs affecting this enzyme system. The main components circulating in the blood are Fluvastatin and a pharmacologically inactive metabolite – N-deisopropyl-propionic acid. Hydroxylated metabolites have pharmacological activity but do not enter the systemic circulation.

Indications

Primary hypercholesterolemia and mixed dyslipidemia (type IIa and IIb according to the Fredrickson classification) in combination with diet therapy; coronary atherosclerosis in patients with coronary artery disease and primary hypercholesterolemia, including mild (to slow the progression of the disease); secondary prevention of major serious cardiovascular events (sudden death from cardiovascular pathology, past myocardial infarction and coronary revascularization) in patients with coronary artery disease after percutaneous transluminal balloon angioplasty.

Children and adolescents over 9 years old: heterozygous familial hypercholesterolemia in combination with diet therapy.

ICD codes

Dosage Regimen

Determine the dose individually based on the indication, therapeutic goal, and patient response.

Initiate therapy with a starting dose of 20 mg or 40 mg once daily, taken in the evening.

For patients requiring a more intensive LDL-cholesterol reduction, use the 40 mg tablet as the initial dose.

Adjust the dose at intervals of no less than 4 weeks based on lipid level response.

The maximum recommended daily dose is 80 mg.

Administer the 80 mg daily dose as a single 80 mg extended-release tablet in the evening, or as 40 mg twice daily.

For pediatric patients (children and adolescents 9-16 years old) with heterozygous familial hypercholesterolemia, the recommended starting dose is 20 mg once daily in the evening.

In pediatric patients, titrate the dose to a maximum of 80 mg daily (as 20 mg, 40 mg, or 80 mg extended-release tablet) based on response and tolerability.

Take tablets and capsules with a glass of water, with or without food.

Swallow tablets and capsules whole; do not crush or chew.

For patients taking bile acid sequestrants (e.g., cholestyramine), administer fluvastatin at least 4 hours after the resin.

Before initiating treatment, place the patient on a standard cholesterol-lowering diet.

In patients with renal impairment (creatinine clearance less than 30 mL/min), use with caution and consider a starting dose of 20 mg.

In patients with mild to moderate hepatic impairment, use with caution; fluvastatin is contraindicated in patients with active liver disease.

Periodically monitor lipid levels to assess therapeutic response and adjust the dose accordingly.

Adverse Reactions

From the hematopoietic system: very rarely – thrombocytopenia.

From the immune system: rarely – hypersensitivity reactions (skin rash, urticaria); very rarely – anaphylactic reactions.

From the nervous system: often – headache, insomnia; very rarely – paresthesia, dysesthesia, hypesthesia, possibly related to the underlying disease.

From the vascular system: very rarely – vasculitis.

From the digestive system: often – nausea, abdominal pain, dyspepsia; very rarely – pancreatitis.

From the liver and biliary tract: very rarely – hepatitis.

From the skin and subcutaneous tissues: very rarely – angioedema, facial edema, eczema, dermatitis, bullous exanthema.

From the musculoskeletal system: rarely – myalgia, muscle weakness, myopathy; very rarely – rhabdomyolysis, lupus-like syndrome, myositis; frequency unknown – occurrence or exacerbation of myasthenia.

From the organ of vision: frequency unknown – ocular myasthenia.

From laboratory parameters: increased activity of liver transaminases, CPK, ALP.

Contraindications

Hypersensitivity to fluvastatin; active pathological process in the liver, persistent increase in the level of liver transaminases in the blood; pregnancy, lactation (breastfeeding) period; age under 18 years, except for the indication: heterozygous familial hypercholesterolemia in combination with diet therapy – age under 9 years.

With caution

When using fluvastatin in patients with a history of liver disease or alcohol abuse; when used in patients predisposed to rhabdomyolysis; when used in patients with renal failure (creatinine clearance less than 30 ml/min or serum creatinine content more than 250 µmol/L), with impaired muscle tone of unclear etiology, increased CPK activity, as well as with hereditary muscle diseases, immune-mediated necrotizing myopathy, and a history of muscle toxicity with the use of other hypolipidemic agents.

Use in Pregnancy and Lactation

Fluvastatin is contraindicated for use during pregnancy and lactation (breastfeeding).

Women of childbearing age during therapy with fluvastatin must use reliable methods of contraception. If pregnancy occurs in a patient receiving fluvastatin therapy, treatment should be discontinued.

Since HMG-CoA reductase inhibitors reduce the synthesis of cholesterol and probably other biologically active substances – cholesterol derivatives, when these drugs are prescribed to pregnant women, they can harm the fetus.

Use in Hepatic Impairment

Contraindicated for use in active pathological processes in the liver, persistent increase in the level of liver transaminases in the blood. Use with caution in patients with liver diseases.

Use in Renal Impairment

Should be used with caution in renal failure (creatinine clearance less than 30 ml/min or serum creatinine content more than 250 µmol/L), in patients with moderate renal failure.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age, except for the indication “heterozygous familial hypercholesterolemia in combination with diet therapy” – for this indication, it is contraindicated in children under 9 years of age.

Geriatric Use

In elderly patients (over 65 years of age), the need to determine CPK activity should be assessed in the presence of other factors predisposing to rhabdomyolysis. The ratio of the expected benefit of therapy and the risk of adverse events in this category of patients should be assessed and they should be carefully monitored when using fluvastatin.

Special Precautions

Before starting treatment with fluvastatin, the patient should be switched to a standard hypocholesterolemic diet. The diet must be followed throughout the entire treatment period.

It is recommended to evaluate liver function in all patients before starting treatment with fluvastatin, 12 weeks after starting treatment or increasing the dose, and periodically during treatment. If AST or ALT activity exceeds the upper limit of normal (ULN) by 3 times and persistently remains at this level, treatment should be discontinued. There are reports of rare cases of hepatitis (possibly drug-induced) that resolved after discontinuation of therapy.

Patients should be advised to immediately report any potential symptoms or signs of liver failure (including nausea, vomiting, loss of appetite, jaundice, impaired brain function, tendency to bruise, bleeding) with subsequent consideration of discontinuing therapy.

If patients complain of unexplained diffuse myalgias, muscle weakness or soreness and/or a significant increase in CPK activity is detected, myopathy, myositis, or rhabdomyolysis should be suspected. Patients should be advised to immediately report muscle pain of unknown etiology, muscle soreness or weakness, especially if accompanied by general malaise or fever.

Before starting treatment, it is recommended to determine CPK activity in the following cases: impaired renal function, hypothyroidism, hereditary muscle diseases (personal or family history), manifestations of muscle toxicity with the use of statins and fibrates in the anamnesis, alcohol abuse, sepsis, arterial hypotension, trauma, extensive surgery, severe metabolic, endocrine or water-electrolyte disturbances, uncontrolled epilepsy. In elderly patients (over 65 years of age), the need to determine CPK activity should be assessed in the presence of other factors predisposing to rhabdomyolysis. In the listed cases, the ratio of the expected benefit of therapy and the risk of adverse events should be assessed and patients should be carefully monitored. If CPK activity is significantly increased by 5 times or more before starting fluvastatin therapy compared to ULN, a repeat measurement should be performed after 5-7 days to confirm the result. If there is a persistent significant increase in CPK activity (> 5 ULN), treatment with fluvastatin should not be started.

During treatment with fluvastatin, if muscle symptoms (pain, weakness, cramps) occur, CPK activity should be determined. Treatment should be discontinued if there is a significant increase in CPK activity (> 5 ULN). In case of severe muscle symptoms causing constant discomfort, even if the increase in CPK activity is ≤ 5 ULN, the issue of discontinuing therapy should be considered.

If muscle pain, weakness, cramps cease and CPK activity normalizes, resumption of treatment with fluvastatin or any other HMG-CoA reductase inhibitor should be started with the minimum dose and under careful medical supervision.

Drug Interactions

With simultaneous use of fluvastatin with warfarin, the anticoagulant effect of the latter is enhanced.

With simultaneous use with cholestyramine, the bioavailability of fluvastatin decreases, while the overall hypolipidemic effect is enhanced.

With simultaneous use with rifampicin, the concentration of fluvastatin in the blood plasma decreases, apparently due to increased metabolism in the liver under the influence of rifampicin, which is an inducer of liver microsomal enzymes.

With simultaneous use with cyclosporine, cases of myalgia and increased CPK activity have been reported.

With simultaneous use with cimetidine, ranitidine, omeprazole, an increase in the absorption of fluvastatin is possible.

When using fluvastatin simultaneously with colchicine, cases of myopathy (muscle pain, muscle weakness and rhabdomyolysis) have been reported.

With simultaneous use of fluvastatin with bezafibrate, gemfibrozil, ciprofibrate or nicotinic acid in lipid-lowering doses (≥1 g/day), no clinically significant changes in the bioavailability of fluvastatin or other hypolipidemic agents were noted. However, since with simultaneous use of other HMG-CoA reductase inhibitors with any of the above drugs, an increased risk of myopathy was noted, such combinations should be used with caution.

Fluvastatin should be used no earlier than 4 hours after taking resins (e.g., cholestyramine) to avoid binding of fluvastatin.

No clinically significant pharmacokinetic interactions were observed with the simultaneous use of fluvastatin with propranolol, digoxin, losartan, clopidogrel or amlodipine, therefore, when using such combinations, monitoring of the concentration of these drugs in the blood plasma and correction of their doses is not required.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°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.