Allesta

Allesta is a hypolipidemic monocomponent drug from a subgroup of substances that inhibit the effect exerted by HMG-CoA reductase.

Simvastatin is an inactive lactone that is readily hydrolyzed and subsequently transformed in vivo into a β-hydroxy acid (which significantly inhibits the activity of HMG-CoA reductase). The hydrolysis that occurs is primarily intrahepatic; its plasma rate is very low. [ 1 ]

It has been determined that simvastatin reduces normal and, at the same time, elevated LDL-C levels. LDL elements are formed from VLDL; their catabolism occurs mainly with the participation of endings that have a significant affinity for LDL elements.

Indications Allesta

Hypercholesterolemia.

It is used for primary hypercholesterolemia or mixed dyslipidemia - as a supplement to the diet, in cases where the response to the diet and other non-drug therapies (for example, weight loss and exercise) is not effective enough.

It can be used in cases of familial hypercholesterolemia (homozygous form) – to complement diet and other lipid-lowering therapies (this includes LDL-apheresis) or in situations where these treatments do not help.

Prescribed for prevention of problems with the functioning of the cardiovascular system.

Allows to reduce the probability of death in people with cardiovascular diseases, as well as morbidity in people with severe atherosclerotic lesions of the cardiovascular system or diabetes mellitus (with standard or increased cholesterol values) - additional treatment that helps to correct other risk factors and other cardioprotective procedures.

Release form

The medicinal substance is released in tablets of 10 and 20 mg (10 pieces inside a cell package; 3 packages inside a pack), as well as 40 mg (15 pieces inside a blister pack; 2 packs inside a box).

Pharmacodynamics

The principle of the LDL-lowering effect of simvastatin may include a decrease in VLDL-C levels, as well as stimulation of LDL-terminal activity, causing a decrease in the production and an increase in the catabolism of LDL-C. Apolipoprotein B values are also significantly reduced during the use of simvastatin.

Simvastatin also significantly increases HDL-C levels and decreases intraplasmic triglyceride levels. Such changes cause a decrease in the proportions of systemic cholesterol to HDL-C, and, along with this, LDL-C to HDL-C.

Pharmacokinetics

Suction.

Simvastatin absorption in humans is quite good, with primary extensive intrahepatic metabolic processes. Secretion of the drug into the liver is determined by the intensity of hepatic blood circulation. The main activity of the drug develops inside the liver. It has been determined that the level of availability of β-hydroxy acid for passage into the systemic circulation with oral administration of simvastatin is less than 5% of the dosage.

The Cmax values of inhibitors with activity in blood plasma are determined approximately after 1-2 hours from the moment of drug administration. Food intake does not change the absorption processes. Pharmacokinetic characteristics of the substance when administered in single and multiple doses show that the drug does not accumulate in the case of multiple administration.

Distribution processes.

In blood plasma, simvastatin and its metabolic element (which has therapeutic activity) are synthesized with protein by >95%.

Excretion.

Simvastatin is a substrate of CYP3A4. The major metabolic products of simvastatin in human plasma are β-hydroxy acid and 4 additional metabolic products with activity.

After oral administration of a portion of the radioactive active element of the drug, 60% of the labeled substance was excreted with feces and another 13% with urine over a period of 96 hours. The volume found in the feces is equivalent to the absorbed substance secreted with bile, plus the unabsorbed element.

When the β-hydroxy acid metabolite was administered intravenously, its half-life averaged 1.9 hours. On average, only 0.3% of the dose was excreted in the urine as inhibitors.

Dosing and administration

The medication is taken orally, once a day, in the evening; the range of portion sizes fluctuates between 5-80 mg. The dosage is selected at minimum 1-month intervals until the maximum daily dose of 80 mg is obtained (it is administered in the evening, once a day). The dosage of 80 mg is used only in people with severe hypercholesterolemia and a very high probability of complications in the work of the cardiovascular system, who do not develop the desired effect when using lower doses (also in cases where the probable benefits are more expected than the risks of negative consequences).

Hypercholesterolemia.

A standard diet aimed at reducing the level of cholesterol is carried out (it must be followed throughout the entire period of therapy with the introduction of simvastatin). Basically, the size of the initial dosage is 10-20 mg per day (1-time intake in the evening). For people who need a significant (over 45%) reduction in LDL-C, the starting dose can be 20-40 mg with 1-time intake in the evening. If dosage adjustment is required, it is carried out according to the above scheme.

Familial form of hypercholesterolemia (homozygous).

At first, it is necessary to use 40 mg of the substance once a day (in the evening). Simvastatin is used as an addition to other lipid-lowering therapy (for example, performing LDL apheresis) or when such therapy cannot be performed.

Prevention of diseases associated with the function of the cardiovascular system.

Often, people with a high probability of developing coronary heart disease (in combination with hyperlipidemia or not) are given 20-40 mg of the drug once in the evening. Treatment with drugs can be combined with physical exercise and diet. If dosage adjustment is required, it is carried out according to the scheme described above.

Additional treatment.

Simvastatin demonstrates good efficacy as monotherapy, and also in combination with bile acid sequestrants. The drug should be taken at least 2 hours before the administration of sequestrants or at least 4 hours after their use.

For people taking Allesta with fibrates (except gemfibrozil) or fenofibrate, the dose of simvastatin is a maximum of 10 mg per day. For people taking the drug in combination with verapamil, amiodarone, diltiazem or amlodipine, this dosage per day is no more than 20 mg.

Serving sizes for renal impairment.

In people with severe renal failure, the drug is used with extreme caution - no more than 10 mg per day.

Use in pediatrics (10-17 years of age).

For children aged 10-17 years with a familial type of hypercholesterolemia (heterozygous nature), a dose of 10 mg is initially used with 1-time evening use per day. Before starting therapy, the child is prescribed a standard diet aimed at lowering the cholesterol level (it must be followed throughout the entire period of the treatment course).

Daily doses in the range of 10-40 mg are usually used; 40 mg is the highest dose per day. Dosage selections are made individually, taking into account the treatment goal and therapy recommendations for the pediatric group. Dosages are selected at intervals of at least 1 month.

• Application for children

Therapeutic efficacy and safety indicators of simvastatin use in individuals aged 10-17 years with familial hyperlipidemia (heterozygous nature) were studied during controlled clinical trials, which involved boys (age Tanner phase 2 and above) and girls who had been menstruating for at least 1 year. Statistics of adverse events in individuals who used simvastatin, in general, did not differ from those in people who used placebo. The introduction of doses greater than 40 mg in this category of patients was not tested. During this testing, no effect of simvastatin on puberty and growth in children, as well as on the duration of the menstrual cycle, was found.

Girls should be advised about the use of contraception during therapy with Allesta. The safety and efficacy of the drug in patients under 18 years of age have not been studied beyond 48 weeks; there is no information on possible long-term effects related to physical, sexual and mental development.

The effects of the drug have not been studied in individuals under 10 years of age, premenstrual girls, and prepubertal children.

Use Allesta during pregnancy

Simvastatin should not be used during pregnancy because there is no proven information regarding its safety during this period - controlled clinical trials involving pregnant women have not been performed. There have been rare reports of congenital anomalies in cases of intrauterine exposure to HMG-CoA reductase inhibitors. However, an analysis of information obtained during observations of approximately 200 pregnant women who used simvastatin or other similar HMG-CoA reductase inhibitors in the first trimester showed that the incidence of congenital anomalies is approximately the same as that observed in the general population.

However, it should be taken into account that when using simvastatin, a decrease in mevalonate levels (a precursor of cholesterol biosynthesis) in the fetus may be observed. Atherosclerosis is a chronic process, so often the cancellation of lipid-lowering medications during pregnancy has some effect on the long-term risks associated with primary hypercholesterolemia. For this reason, simvastatin is prohibited for use in pregnant women, if there is a suspicion of pregnancy, as well as when planning it. Therapy using this substance should be stopped for the period of gestation or until pregnancy is completely excluded.

There is no information on whether the drug is excreted in breast milk. Because many medications can be excreted in milk, and because of the high likelihood of severe side effects in women using simvastatin, breastfeeding should be discontinued during treatment.

Contraindications

Main contraindications:

• severe intolerance associated with simvastatin or other components of the drug;
• liver pathologies in the active phase or persistent increase in serum transaminase values of unknown origin;
• administration together with potent inhibitors of CYP3A4 action (medicines that increase the AUC level approximately fivefold or more). Among them are ketoconazole and voriconazole with itraconazole and posaconazole, boceprevir and clarithromycin together with nefazodone; the list also includes erythromycin, telaprevir with telithromycin and agents that inhibit the activity of HIV protease (among them nelfinavir);
• use in combination with cyclosporine or gemfibrozil, as well as danazol.

Side effects Allesta

Side effects include:

• Disorders associated with the blood and lymphatic system: anemia occasionally occurs;
• problems affecting the psyche: insomnia appears occasionally. Depression may develop;
• disorders of the nervous system: paresthesia, headaches, polyneuropathy and dizziness are occasionally observed. Memory disorders develop isolated cases;
• lesions associated with the organs of the mediastinum and sternum or with the respiratory system: the development of interstitial lung disease is possible;
• gastrointestinal disorders: occasionally there is bloating, diarrhea, abdominal pain, constipation, vomiting, dyspepsia, pancreatitis and nausea;
• problems with hepatobiliary function: jaundice or hepatitis occasionally occur. Isolated cases – liver failure (possibly fatal);
• lesions of the epidermis with the subcutaneous layer: occasionally itching, rash or alopecia appear;
• disorders of the functioning of connective tissues and the structure of muscles with the skeleton: myopathy (may include myositis), myalgia, rhabdomyolysis (with or without acute renal failure) and muscle spasms are occasionally observed. Tendinopathy may develop, which is sometimes complicated by rupture;
• problems affecting the mammary glands and reproductive function: impotence may occur;
• systemic manifestations: asthenia is occasionally observed;
• severe intolerance syndrome: occasionally, dermatomyositis, eosinophilia, Quincke's edema, polymyalgia of rheumatic origin, thrombocytopenia, lupus-like syndrome, urticaria, arthralgia, hot flashes, increased ESR, and also arthritis, fever, malaise, photosensitivity and dyspnea may occur;
• changes in test results: occasionally there is an increase in serum transaminase values (AST, ALT, and GGT), creatine kinase and alkaline phosphatase levels.

The use of statins, including simvastatin, may cause an increase in Hba1c levels, as well as serum glucose when administered on an empty stomach.

There are reports of cognitive dysfunction (eg, forgetfulness, confusion, memory loss or impairment) associated with statin use (including simvastatin). These events were usually mild and reversible, disappearing after discontinuation of statin use.

There have been isolated reports of the development of IONM, an autoimmune myopathy caused by statin use. IONM is characterized by proximal muscle weakness and an increase in serum creatine kinase levels (this process persists even after statin administration is discontinued), and in addition, symptoms of necrotizing myopathy develop on muscle biopsy (without severe inflammation) and improve with immunosuppressant treatment.

The use of certain statins may cause the following additional adverse effects:

• sleep disorders, including nightmares;
• sexual dysfunction;
• diabetes mellitus: the likelihood of its development is determined by the absence or presence of risk factors (fasting blood glucose levels ≥5.6 mmol/l, BMI >30 kg/m2, history of high blood pressure and elevated triglyceride levels).

Overdose

At present, there are several cases of Allesta poisoning. The highest dose taken was 3600 mg. All such patients recovered without any negative consequences.

There is no specific therapy for intoxication; supportive and symptomatic measures are taken.

Interactions with other drugs

Pharmacodynamic parameters of interaction.

The risk of myopathy (including rhabdomyolysis) increases when the drug is combined with fibrates. In addition, interaction with gemfibrozil occurs, causing an increase in plasma levels of simvastatin.

In some cases, rhabdomyolysis or myopathy develops due to the combination of the drug with lipid-modifying doses (≥1 g per day) of niacin.

Pharmacokinetic characteristics of interaction.

Use in combination with substances that have a strong inhibitory effect on CYP3A4 activity (including voriconazole and itraconazole with posaconazole and ketoconazole, as well as clarithromycin and erythromycin with telithromycin), as well as with boceprevir, cyclosporine, telaprevir and danazol, as well as with gemifibrozil, nefazodone and agents that inhibit HIV protease (including nelfinavir) is prohibited.

When combined with other fibrates (except fenofibrate), no more than 10 mg of simvastatin can be used per day.

It is prohibited to use the medicine together with fusidic acid.

When prescribed in combination with amlodipine, diltiazem, as well as amiodarone and verapamil, the daily dosage of the drug should be a maximum of 20 mg.

During treatment with Allesta, you should not drink grapefruit juice.

Storage conditions

Allesta should be stored in a place closed to small children. Temperature level – maximum 25°C.

Shelf life

Allesta can be used within 24 months from the date of manufacture of the medicinal substance.

Analogues

Analogues of the drug are Zocor, Vazilip, Simvatin with Vasostat, and also Simvastatin and Simvastat.