Pharmacological properties Lescol XL 80 mg:
Lescol XL fluvastatin, a synthetic agent that reduces cholesterol levels, is a competitive inhibitor of HMG CoA reductase, responsible for the conversion of HMG-CoA to mevalonate, a precursor of sterols, including cholesterol.
Fluvastatin has a major effect in the liver and is a racemate of two eritroenantiomerov, one of which has pharmacological activity. Inhibition of cholesterol biosynthesis reduces its content in liver cells, which stimulates the synthesis of LDL receptors and thereby increases the capture of LDL particles. The net result of these mechanisms is to reduce the concentration of cholesterol in the blood plasma.
Lescol XL reduces total cholesterol, LDL cholesterol, apolipoprotein B (apo B) and TG and increases the number of HDL-C in patients with hypercholesterolemia and mixed dyslipidemia. During the two weeks set a therapeutic effect, and the maximum response is achieved for 4 weeks after initiation of treatment and stabilized during prolonged therapy.
Fluvastatin rapidly and completely (98%) absorbed after oral administration on an empty stomach. After taking the pills Lescol XL, compared with the capsules, the absorption of fluvastatin is 60% slower, while the average residence time of fluvastatin in plasma increased by about 4 hours after ingestion the drug is absorbed more slowly.
Fluvastatin has a major effect in the liver, which is also the main place of its metabolism. The absolute bioavailability (based on concentrations in the blood) is 24%. The apparent volume of distribution – 330 liters. More than 98% of circulating drug binds to plasma proteins (the binding does not affect the concentration of fluvastatin or warfarin or salicylic acid, and glibenclamide).
The main components circulating in the blood are fluvastatin and the pharmacologically inactive metabolite N-dezizopropilpropionovaya acid. Hydroxylated metabolites are pharmacologically active, but do not pass into the systemic circulation. Hepatic metabolic pathway of fluvastatin in humans fully understood. There are various alternatives to the cytochrome P450 (SYR 450) ways of biotransformation of fluvastatin, fluvastatin metabolism and therefore less sensitive to inhibition by SYR 450.
Experimental studies revealed that fluvastatin inhibits the metabolism of a substance, which are metabolized by 2C9 SYR. Despite the possibility of competitive interaction between fluvastatin and compounds that are substrates SYR 2C9, such as diclofenac, phenytoin, tolbutamide and warfarin, the clinical data indicate a small probability of such interaction.
After administration of H3-fluvastatin in healthy volunteers the excretion of the radioactive isotope is 6% in urine and 93% – in the feces, and the fluvastatin – less than 2% of the total radioactivity, which is displayed. Plasma clearance of fluvastatin in humans – 1,8 ± 0,8 l / min. The equilibrium concentration in the blood plasma is not evidence in favor of accumulation of fluvastatin after injection of 80 mg / day. After oral administration of 40 mg fluvastatin, the terminal half-life – 2,3 ± 0,9 hours
Not established significant differences in AUC, when fluvastatin was administered with the evening meal or 4 hours after it.
The concentration of fluvastatin in plasma is independent of sex or age of the patient. Nevertheless, clinical observations have shown the presence of more pronounced effect of the drug in women and elderly patients.
Since fluvastatin is derived mainly from the bile and undergoes first-pass metabolism, it is possible cumulation of the drug in patients with liver failure.
INDICATIONS Lescol XL 80 mg:
Dyslipidemia
Lescol XL is designed as an adjunct to diet to reduce elevated total cholesterol, LDL cholesterol, apo B and triglycerides and to increase HDL cholesterol in adults with primary hypercholesterolemia and mixed dyslipidemia Fredrickson types IIa and IIb and in children older than 9 years and adolescents with heterozygous familial hypercholesterolemia.
Slowing the progression of coronary atherosclerosis in patients with primary hypercholesterolemia
Secondary prevention of major complications of cardiac reactions (sudden cardiac death, nonfatal myocardial infarction and coronary revascularization) in adults with coronary artery disease after transkateteralnoy therapy.
APPLICATION Lescol XL 80 mg:
The drug can be taken once at any time, regardless of the meal. Tablets must be swallowed whole with a glass of water. The maximum lipid-lowering effect of this dose is reached for 4 weeks. Correcting the dose depending on patient response, with an interval of 4 weeks or more. Lescol XL therapeutic effect persists with prolonged use.
Dosage for adults. Before you begin, as well as during treatment with Lescol XL the patient must adhere to a standard diet low in cholesterol.
The recommended starting dose – 80 mg 1 time per day. The initial dose should be individualized according to baseline LDL cholesterol goals and treatment.
For patients with coronary artery disease after treatment transkateteralnoy recommended dose is 80 mg / day.
Dosage for children. Before starting treatment with Lescol XL the patient must adhere to a standard diet low in cholesterol for 6 months. Diet should be continued throughout the treatment period.
The recommended starting dose – 80 mg 1 time per day. The initial dose should be individualized according to baseline LDL levels.
The use of fluvastatin in combination with nicotinic acid, fibrates or kolestiraminom in treating children and adolescents has not been investigated.
The pharmacokinetics of fluvastatin is not changed in patients with renal insufficiency as mild and severe. For such patients, dosage adjustment is needed.
In elderly patients (> 65 years), response to treatment was more pronounced manifestations of reducing the tolerance is not mentioned, so there is no need for dose adjustment.
CONTRAINDICATIONS Lescol XL 80 mg:
Hypersensitivity to fluvastatin or another excipient, liver disease (active form) or the persistent increase in activity of serum transaminases of unknown etiology, pregnancy and breast-feeding up to age 9 years.
SIDE EFFECTS Lescol XL 80 mg:
are based on the frequency and the first effect of this order: very common (≥ 1 / 10), common (≥ 1 / 100,
In most cases, reported minor adverse reactions from the gastrointestinal tract, insomnia and headache.
Blood system: very rare – and thrombocytopenia.
Mental disorders: frequent – insomnia.
Nervous system disorders: frequent – a headache is very rare – paresthesia, dysesthesia, gipestezii for which is also known connection with hyperlipidemic disorders.
Cardio-vascular system: very rare – vasculitis.
Gastrointestinal disorders: frequent – dyspepsia, abdominal pain, nausea, very rarely – pancreatitis.
Of the liver: a very rare – hepatitis.
Skin and subcutaneous tissue is rare – hypersensitivity reactions such as rash, hives, very rarely – other skin reactions (eczema, dermatitis, rash buleznaya), facial edema, angioedema.
With the musculoskeletal system: rarely – myalgia, muscle weakness, myopathy is very rare – rhabdomyolysis, myositis, lyupoidnye (volchankopodobnye) reaction.
From the laboratory parameters. In 1-2% of patients increased transaminase activity, which is more than 3 times the upper limit of normal.
Precautions Lescol XL 80 mg:
As for other lipid drugs before treatment and during 12 weeks of therapy or with increasing dose, and periodically during treatment is recommended for all patients, the determination of liver function. If the levels of AST or ALT of 3 times above the norm and continue to increase, therapy should be discontinued. Very rarely reported hepatitis associated with drug intake, which disappeared after discontinuation of therapy.
Caution should be exercised in the treatment of Lescol XL in patients with liver disease or a history of severe alcoholic liver damage.
Lescol XL is effective when used as monotherapy. Available data confirm the efficacy and safety of fluvastatin in combination with nicotinic acid, fibrates or kolestiraminom.
In the application of fluvastatin in some cases, there myopathy is very rare – myositis and rhabdomyolysis. As for patients with diffuse myalgia of unknown etiology, muscle weakness and / or a significant increase in CK levels, it is necessary to consider the risk of myopathy, myositis or rhabdomyolysis. Patients should be warned about the need to report the appearance of muscle pain, muscle weakness, especially if accompanied by malaise or fever.
There is no reason for the ongoing monitoring of levels in the blood plasma total creatine kinase or other muscle enzymes in patients taking statins, without symptoms. Determine the level of CK is not recommended after intense exercise or if there is any other possible causes of increased CK levels, which could interfere with interpretation of results.
As on all other statins, need to be prescribed with care fluvastatin in patients predisposed to rhabdomyolysis and its complications. Before starting treatment with fluvastatin CPK level should be determined with impaired renal function, hypothyroidism, a history (personal or family) of hereditary muscular disorders, previously established by the toxic effect of statins on muscle, or fibrates, alcohol abuse. You should consider the need for such a determination when it comes to treating older patients (over 70), given that they have other factors that lead to rhabdomyolysis.
If the levels of creatinine clearance significantly increased (5 times or more), the determination should be repeated after 5-7 days to confirm the result. If the levels of creatinine clearance remained significantly higher (5 times or more), treatment should not start.
If patients receiving fluvastatin, there is muscle pain, weakness or cramps, they need to determine the levels of creatinine clearance. Treatment should be discontinued if the level of creatinine clearance significantly increased (5 times).
If muscle symptoms are and cause daily discomfort, even at higher levels of creatinine clearance less than 5 times, you need to consider the need for cessation of treatment.
The risk of myopathy is increased in patients receiving immunosuppressive medication (including cyclosporin), fibrates, nicotinic acid or erythromycin together with other inhibitors of HMG-CoA reductase inhibitors. However, in clinical trials did not report of myopathy in patients treated with fluvastatin in combination with nicotinic acid, fibrates, or cyclosporine. Individual cases of myopathy reported in postmarketing observations while taking fluvastatin with cyclosporine. Lescol XL should be prescribed with care to patients who are referred to simultaneously take drugs.
Homozygous familial hypercholesterolemia
No data on the use of fluvastatin in patients with homozygous familial hypercholesterolemia.
Children
Efficacy and safety of the drug have not been studied in patients younger than 18 years during treatment, which lasted more than 2 years.
The use of fluvastatin was investigated only in children aged 9 years and older with heterozygous familial hypercholesterolemia. The safety profile of fluvastatin in children and adolescents with heterozygous familial hypercholesterolemia was similar to that in adults. All children and adolescents reported normal growth and sexual maturation.
Use during pregnancy or breast-feeding
Since HMG-CoA reductase inhibitors decrease cholesterol synthesis and possibly other biologically active substances that are derived cholesterol, in the application in pregnancy may be dangerous to the fetus. Therefore, the drug is contraindicated during pregnancy and lactation.
No data on the effect of fluvastatin on ability to drive and work with complex arrangements.
INTERACTION Lescol XL 80 mg:
Food. Not identified significant differences in lipid effects of fluvastatin when administered with the evening meal or 4 hours after it. Given the lack of interaction with other substrates fluvastina CYP 3A4, believe that fluvastin does not interact with grapefruit juice.
Fibrates and nicotinic acid. Concomitant administration of fluvastatin with bezafibrate, gemfibrozil, or nicotinic acid tsiprofibratom does not cause clinically significant effect on the bioavailability of fluvastatin or other lipid funds. However, because patients receiving other HMG-CoA reductase inhibitors together with any of these compounds, there is a risk of myopathy, such combinations should be used with caution.
Itraconazole, and erythromycin. Concomitant administration of fluvastatin with potent inhibitors of cytochrome P450 (3A4 SYR) itraconazole and erythromycin has minimal effect on the bioavailability of fluvastatin. Given the minimal involvement of the enzyme in the metabolism of fluvastatin, it is unlikely that other inhibitors SYR 3A4 (ketoconazole, cyclosporine) will affect the bioavailability of fluvastatin.
Fluconazole. The introduction of fluvastatin to healthy volunteers who have previously received fluconazole (an inhibitor of 2C9 SYR), leads to an increase in savings and increased the maximum concentration of fluvastatin in plasma at 84 and 44% respectively. Although there is no clinical evidence that the safety profile of fluvastatin changes in patients previously treated with fluconazole for 4 days, should be used cautiously in conjunction with fluvastatin fluconazole.
Cyclosporine. Study of patients with transplanted kidney shows that the bioavailability of fluvastatin (40 mg / day) does not rise to clinically important values in patients treated with cyclosporine in stable mode. When the drug was administered to patients with transplanted kidney, located in the stable regime of cyclosporine has been shown that the accumulation and the maximum concentration of fluvastatin in plasma increased 2-fold compared to healthy subjects. Although such an increase in the level of fluvastatin was not clinically significant, it should be used with caution in this combination of drugs.
Bile acid sequestrants. Fluvastatin should be entered no earlier than 4 hours after bile acid sequestrants (cholestyramine) to avoid a significant interaction due to binding of the drug.
Rifampicin. The introduction of fluvastatin to healthy volunteers, previously took an rifampicin reduces the bioavailability of fluvastatin by 50%. Although there is no clinical evidence that lipid-lowering efficacy of fluvastatin changes in patients taking rifampicin for a long time (for the treatment of tuberculosis), for a satisfactory reduction in lipid levels may need the appropriate dose adjustment of fluvastatin.
Antagonists of histamine H2-receptor and proton pump inhibitors. Concomitant administration of fluvastatin with cimetidine, ranitidine or omeprazole increases the bioavailability of fluvastatin, which is not clinically significant. Although further studies of these interactions have been conducted, it is unlikely that other antagonists N2-retseptorov/ingibitory proton pump will alter the bioavailability of fluvastatin.
Phenytoin has little effect on the pharmacokinetics of fluvastatin, fluvastatin, so dosage adjustment or combined with phenytoin is not necessary.
Drugs that affect the cardiovascular system. With the simultaneous introduction of fluvastatin with propranolol, digoxin, losartan or amlodipine, there is no clinically significant pharmacokinetic interactions, so the combined use of fluvastatin with these agents clinical observation or dose adjustment is required.
Cyclosporine. Lescol XL does not affect the bioavailability of cyclosporine in the joint application.
Phenytoin. General changes in the pharmacokinetics of phenytoin co-administration of fluvastatin with small and have no clinical significance. Therefore, when combined with the use of fluvastatin fairly routine monitoring of phenytoin levels in blood plasma.
Warfarin and other coumarin derivatives. In healthy volunteers, the use of fluvastatin and warfarin (single dose) did not cause any adverse effect on the level of warfarin in blood plasma and the prothrombin time, compared with the effect of warfarin only. Very rarely reported several episodes of bleeding and / or increased prothrombin time in patients treated with fluvastatin and warfarin at the same time or other coumarin derivatives. It is recommended to monitor the prothrombin time in patients taking warfarin or other coumarin derivatives, and against this background that fluvastatin treatment begin, continue or change its dosage of fluvastatin.
Oral antidiabetic agents. In patients taking oral sulfonylureas (glibenclamide, tolbutamide) for the treatment of insulin dependent diabetes mellitus, administration of fluvastatin does not lead to clinically significant changes in glycemic indices.
Overdose Lescol XL 80 mg:
No specific recommendations for treatment of an overdose. It is shown that symptomatic therapy and all necessary measures to maintain vital body functions.
