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

Clinical and pharmacological group: & nbsp

Statins

Included in the formulation

Lescola® Forte

pills inwards

Novartis Pharma AG Switzerland

АТХ:

C.10.A.A.04 Fluvastatin

Pharmacodynamics:

A hypolipidemic agent from the group of statins, an inhibitor of HMG-CoA reductase. According to the principle of competitive antagonism, the statin molecule binds to that part of the coenzyme A receptor where this enzyme is attached. Another part of the statin molecule inhibits the conversion of hydroxymethylglutarate to mevalonate, an intermediate in the synthesis of the cholesterol molecule. Inhibition of the activity of HMG-CoA reductase results in a series of consecutive reactions that result in a decrease in the intracellular cholesterol content and a compensatory increase in the activity of LDL receptors and, accordingly, acceleration of LDL cholesterol catabolism.

The hypolipidemic effect of statins is associated with a decrease in the total cholesterol level due to LDL cholesterol. The decrease in LDL is dose-dependent and has a non-linear, but an exponential nature.

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 the level of TG is secondary and mediated through their main effects on lowering LDL cholesterol.The moderate decrease in TG levels in statin therapy appears to be due to the expression of the receptor (apo E) receptors on the surface of hepatocytes participating in the catabolism of the disease, which includes approximately 30% TG.

In addition to lipid-lowering effects, statins have a positive effect on endothelial dysfunction (preclinical signs of early atherosclerosis), on the vascular wall, atheroma state, improve the rheological properties of blood, and possess antioxidant, antiproliferative properties.

Pharmacokinetics:

The maximum concentration, systemic exposure and half-life of fluvastatin depend on the dosage form, time taken, the amount of fat in the food, the duration of the drug, and the individual characteristics of the metabolism.

The volume of distribution is 330 liters. Binding to plasma proteins - more than 98%.

It is subjected to intensive metabolism at the first passage through the liver before entering the systemic bloodstream. In patients with hepatic insufficiency, there is a possibility of cumulation of the drug.

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

Indications:

Primary hypercholesterolemia (hypercholesterolemia IIa-IIb) in the absence or inadequate effectiveness of diet therapy.

To slow the progression of coronary atherosclerosis in patients with IHD (as part of a treatment strategy aimed at lowering the levels of total cholesterol and LDL cholesterol). For secondary prevention of serious cardiovascular complications in patients with IHD after percutaneous transluminal balloon angioplasty.

Children and teenagers in combination with diet therapy to lower the levels of total cholesterol, LDL cholesterol, apolipoprotein B in boys and girls (at least 1 year after the first menstruation) at the age of 10-16 years with heterozygous familial hypercholesterolemia who did not have an adequate response to diet therapy,with a baseline LDL ≥ 190 mg / dL, or a baseline LDL ≥ 160 mg / dL, and one or more risk factors for cardiovascular disease (including early coronary heart disease in relatives).

ICD-10

IV.E70-E90.E78.2 Mixed hyperlipidemia

IX.I20-I25.I25.1 Atherosclerotic Heart Disease

Contraindications:

Hypersensitivity.
Acute liver disease, increased activity of transaminases.
Pregnancy, breast-feeding.
Children under 18 years of age (efficacy and safety of use not established).

Carefully:Use with caution in patients with liver disease, with a predisposedto rhabdomyolysis, chronic alcoholism, diffuse myalgia, epilepsy, renal insufficiency.

Pregnancy and lactation:

Contraindicated in pregnancy. There are no data on the use of fluvastatin sodium in pregnant women. However, there are rare reports of congenital anomalies accompanying the intrauterine effect of other HMG-CoA reductase inhibitors.

Action category for the fetus by FDA - X.

Contraindicated in breastfeeding (in preclinical studies it is shown that fluvastatin is present in breast milk, the fluvastatin ratio in milk and plasma is 2: 1)

Dosing and Administration:

Inside, regardless of food intake. Patients who need to lower LDL cholesterol to ≥ 25% - an initial dose of 40 mg (1 capsule) or 80 mg (1 tablet retard, covered with a shell) once a day in the evening or 80 mg in 2 divided doses (capsules 40 mg twice a day). Patients who need to lower LDL cholesterol to <25%, an initial dose of 20 mg. The recommended level of doses is 20-80 mg per day. After the maximum decrease in the level of LDL cholesterol (observed after 4 weeks of treatment), the level of lipids is periodically determined and the dose of fluvastatin is adjusted. The therapeutic effect of fluvastatin persists with its long-term use.

Patients with impaired renal function from mild to moderate severity are not required to adjust the dose, since fluvastatin is excreted by the liver and only <6% of the dose is excreted by urine.

For children: the recommended initial dose is 20 mg.

Before starting treatment, the patient is transferred to a standard hypocholesterol diet, which is observed throughout the course of therapy.

Side effects:Myalgia, myositis, acute necrosis of skeletal muscles (fever, muscle pain, unusual fatigue or weakness), kidney failure, joint pain. Increased incidence of respiratory infections, urinary tract infection. Diarrhea, pain in the stomach, constipation, flatulence, heartburn, nausea, increased activity of transaminases. Headache, dizziness, weakness. Impotence, sleep disturbance, skin rash.

Overdose:

Fluvastatin was administered to healthy volunteers at a maximum single dose of 80 mg (in capsule form), with no clinically significant side effects. With the appointment of fluvastatin in the prolonged form, the maximum dose was 640 mg for 2 weeks. In this case, the tolerability of the drug was not very good, there were various complaints of the gastrointestinal tract and an increase in the plasma levels of transaminases (AST, ALT).

Treatment: symptomatic, carrying out the necessary supportive measures. At present, it is not known whether fluvastatin and its metabolites to dialysis.

Interaction:

Amprenavir. Against the background of amprenavir (blocks biotransformation) the concentration of fluvastatin inblood, activity and the risk of toxicity.

Bezafibrate. Use this combination with caution.

Warfarin. In healthy volunteers, when taking a single dose of fluvastatin and warfarin, there was no adverse effect on the concentration of warfarin in the blood plasma and on prothrombin time. However, there are very few reports of bleeding and / or an increase prothrombin time, noted in patients who are on treatment with fluvastatin, while prescribing warfarin. Therefore, in patients who are on warfarin therapy, it is recommended to monitor prothrombin time in the case of the initiation or withdrawal of fluvastatin therapy, as well as in the case of a change in its dose.

Kolestyramin. Fluvastatin should be prescribed no earlier than 4 hours after receiving kolestiramina, to avoid its binding.

Colchicine. When fluvastatin was used together with colchicine, in some cases, myopathy developed (muscle pain, muscle weakness and rhabdomyolysis).

A nicotinic acid. With the simultaneous administration of fluvastatin with nicotinic acid, no clinically significant changes in the bioavailability of fluvastatin or nicotinic acid have been observed.However, since the simultaneous use of other HMG-CoA reductase inhibitors with nicotinic acid has been associated with an increased risk of myopathy, this combination should be used with caution.

Rifampicin. When fluvastatin is prescribed to healthy volunteers who have previously received rifampicin, a decrease in the bioavailability of fluvastatin by about 50% was noted. Although the change in the activity of fluvastatin has not been proven for patients receiving long-term treatment with rifampicin (for example, in tuberculosis), nevertheless, appropriate fluvastatin dose adjustment may be required to achieve the desired hypolipidemic effect.

Fenofibrate. Increases (mutually) the risk of rhabdomyolysis, myopathy and acute renal failure; combined use is not recommended.

Fluconazole. Although no clinical evidence of a change in the safety profile of fluvastatin has been obtained in patients receiving the previous 4-day treatment with fluconazole, caution should be exercised when they are used together.

Fluconazole.With the simultaneous use of fluconazole with the HMG-CoA reductase inhibitor fluvastatin metabolized by the isoenzyme CYP2D6, the risk of developing myopathy and rhabdomyolysis increases. If simultaneous therapy with these drugs is necessary, caution should be observed, patients should be observed to detect symptoms of myopathy and rhabdomyolysis, and control the concentration of creatinine kinase. In the case of a significant increase in the concentration of creatinine kinase or if there is a diagnosis or suspected development of myopathy or rhabdomyolysis, fluvastatin therapy should be discontinued.

Holina fenofibrate. With simultaneous use of fenofibrate choline with fluvastatin, 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 damage to the muscles.

Cyclosporine. Despite the fact that an increase in systemic exposure and maximum concentration of fluvastatin was not clinically significant, caution should be exercised when using this combination.With simultaneous application of fluvastatin in a dose of 80 mg with cyclosporine, the bioavailability of the latter was not noted.

Ciprofibrate. With the simultaneous administration of fluvastatin with ciprofibrate, no clinically significant changes in the bioavailability of fluvastatin or ciprofibrate have been observed. However, since simultaneous use of other HMG-CoA reductase inhibitors with ciprofibrate has been associated with an increased risk of myopathy, this combination should be used with caution.

Etravirine. The simultaneous use of fluvastatin (metabolized by the isoenzyme CYP2C9) with etravirine can lead to an increase in plasma concentrations of fluvastatin (it may need to adjust its dose).

Special instructions:

Therapy with lipid-altering agents can only be considered after excluding secondary cases of hyperlipidemia, such as poorly controlled diabetes mellitus, hypothyroidism, nephrotic syndrome, dysproteinemia, obstructive liver disease, other medication therapy, or alcoholism. Before starting treatment with fluvastatin sodium, you need to determine the lipid profile (total cholesterol, HDL cholesterol and triglycerides).For patients with triglyceride levels <400 mg / dL (<4.5 mmol / L), the LDL cholesterol level is determined by the formula: Cholesterol LDL = Total cholesterol - HDL cholesterol - 1/5 Triglycerides. For patients with triglyceride levels> 400 mg / dl (> 4.5 mmol / L), this equation is less accurate, and the concentration of LDL cholesterol is determined by ultracentrifugation. In many patients with hypertriglyceridemia, the content of LDL cholesterol may be lower or normal, despite the elevated level of total cholesterol. In such cases fluvastatin not indicated for treatment.

Determination of lipid content should be carried out for at least 4 weeks, and the dose is prescribed in accordance with the patient's response to therapy.

If the triglyceride content is still ≥200 mg / dL after reaching the required LDL cholesterol level, then therapy should be continued to achieve the appropriate cholesterol level of non-HDL cholesterol (total cholesterol-HDL cholesterol). The goal of therapy for each risk group is to achieve a non-HDL cholesterol level of 30 mg / dL higher than LDL cholesterol.

When combined with bile acid-binding resins (for example, colestramine), fluvastatin appoint at night, at least 2 hours after taking the resin in order to avoid significant interaction.

It is not recommended to share with other HMG-CoA reductase inhibitors.

Impact on the ability to drive vehicles and manage mechanisms.

Data on the effect of fluvastatin on the ability to drive and work with mechanisms are not available.

Instructions

Fluvastatin (Fluvastatinum)