hypercholesterolemia. Treatment of primary hypercholesterolemia or mixed dyslipidemia, as a dietary supplement, when the response to diet or other nonpharmacological treatment (eg physical exercise, weight loss) is insufficient. Treatment of familial homozygous hypercholesterolemia as a supplement to diet and other lipid-lowering therapy (eg LDL apheresis) or if such treatment is inappropriate or unavailable.Prevention of events from the cardiovascular system. Reduction of morbidity and mortality of cardiovascular diseases in patients with overt atherosclerosis or diabetes, with normal or elevated cholesterol, as adjunctive therapy to correct other risk factors or supplement other treatments to prevent heart disease.
Inhibitor of HMG-CoA reductase, an enzyme that determines the rate of conversion of 3-hydroxy-3-methylglutaryl-coenzyme A to mevalonate, a precursor to cholesterol. The drug reduces LDL-cholesterol (LDL-C): it decreases production and increases catabolism of LDL-C. It decreases the concentration of apolipoprotein B. In addition, it causes a slight increase in HDL-C concentration and a decrease in plasma TG concentration. As a result, the ratio of total cholesterol to HDL-C and LDL to HDL-C is reduced. Simvastatin is an inactive lactone thatin vivo it is easily hydrolysed to the β-hydroxy acid, a potent HMG-CoA reductase inhibitor. The hydrolysis process takes place mainly in the liver. Simvastatin is well absorbed from the digestive tract and significant uptake occurs in the liver (first-pass effect). The liver is the main site of the active form. After oral administration of Simvastatin, the absorption of β-hydroxy acid into the systemic circulation is less than 5% of the dose. The maximum concentration in the blood of the active inhibitor is reached about 1-2 hours after administration of simvastatin. Simvastatin and its active metabolites to a large extent (> 95%) bind to proteins. Simvastatin is a substrate for CYP3A4. The main metabolites are β-hydroxy acid and other four active metabolites. Within 96 hours, 13% of the dose is excreted in the urine and 60% of the dose. T0,5 The β-hydroxy acid is on average 1.9 h.
Contraindications:
Hypersensitivity to the active substance or to any of the excipients. Active liver disease or persistent, unexplained elevation of blood transaminases. Concomitant use of strong CYP3A4 inhibitors (drugs that increase simvastatin AUC approximately 5-fold or more) such as Itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (eg nelfinavir), boceprevir, telaprevir, Erythromycin, Clarithromycin, telithromycin , nefazodone and medicines containing cobicistat. Co-administration of gemfibrozil, cyclosporin or danazol. Patients with homozygous familial hypercholesterolaemia taking lomitapide are contra-indicated with the use of simvastatin> 40 mg daily. Pregnancy. Breastfeeding period.
Precautions:
Before using simvastatin, or if the dose is increased, inform the patient about the risk of myopathy and recommend that you report to your doctor promptly if you experience difficult-to-explain muscle pains, oversensitivity or weakness. The drug should be used with caution in patients with predisposing factors for rhabdomyolysis, such as: older age (> 65 years), female gender, renal dysfunction, refractory or untreated hypothyroidism, individual or family history of systemic hereditary disorders muscular, occurring in the past toxic effects of statins or fibrates on the muscles, addiction to alcohol. The risk of myopathy may be increased also when interacting with simvastatin with other drugs (pharmacokinetic or pharmacodynamic interactions, see also contraindications and interactions).In patients with an increased risk of myopathy, creatine kinase (CK) should be measured before starting treatment, the risk and possible benefits of treatment should be considered, and the patient monitored during treatment. If CK activity is significantly increased (> 5 x ULN - upper limit of normal), follow-up should be carried out after 5-7 days. Treatment should not be initiated if the control CK> 5 x ULN. If unexplained muscle pain, muscular weakness or muscle cramps occur during treatment, CK activity should be determined. Treatment should be discontinued if the patient who has not been on strenuous exercise is significantly increased (> 5 times ULN) or if the muscle symptoms are severe and cause symptoms during daily activities (even if CK activity ≤5 times ULN). If myopathy is suspected for any reason, the medicine should be discontinued. After the clinical symptoms have resolved and CK levels are reduced to normal, re-use of the statin at the lowest dose may be considered, with close observation of the patient. The risk of myopathy is higher in patients taking simvastatin 80 mg, so the 80 mg dose should only be used in patients with severe hypercholesterolaemia and with a high risk of cardiovascular complications whose treatment goal has not been achieved with lower doses and for which the expected benefit outweighs potential risk. Patients taking simvastatin 80 mg requiring the administration of another interacting drug should use a lower dose of simvastatin or an alternate therapy regimen based on a statin with less potential for interaction. It is recommended to periodically determine CK concentration as a test useful for the identification of subclinical cases of myopathy; however, there is no certainty that this will avoid the development of myopathy. Treatment with simvastatin should be discontinued a few days before the planned major surgery or if it is necessary to undergo internist or surgical treatment. It is recommended to perform liver function tests in all patients prior to initiating simvastatin and then when clinically indicated. Patients who require simvastatin 80 mg should be given an additional test before changing the dosage, 3 months after changing the dose to 80 mg, and then periodically (eg every six months) in the first year of treatment. Special attention should be paid to patients who have elevated aminotransferases. In these patients, the tests should be repeated immediately and then carried out more frequently. If there is a further increase in transaminase levels, especially up to> 3 x ULN and persists, simvastatin should be discontinued. It should be noted that AIAT activity may be derived from muscle tissue, so an increase in ALT with increasing CK activity may indicate myopathy. If severe liver damage resulting in clinical signs and / or hyperbilirubinemia or jaundice occurs during treatment with simvastatin, treatment should be discontinued immediately. If another cause of the disorder can not be identified, simvastatin treatment should not be restarted. The drug should be used with caution in people who consume significant amounts of alcohol. Statins can cause an increase in blood Glucose and in some patients at risk for developing diabetes can cause hyperglycaemia, which requires proper diabetes care. However, this risk should not be a reason for discontinuation of statin therapy, because the benefits of reducing the risk of vascular disorders due to the use of statins are greater. Patients at risk (with a fasting glucose level of 5.6-6.9 mmol / l, BMI> 30 kg / m2, increased triglycerides, hypertension) should be monitored both clinically and biochemically in accordance with national guidelines. If the patient is suspected of developing interstitial lung disease (manifested by dyspnoea, dry cough, general deterioration of health - fatigue, weight loss, fever), statin therapy should be discontinued. In a controlled clinical trial in patients aged 10-17 years (boys in phase II and above according to the Tanner scale, and girls who were at least 1 year old) who received simvastatin, no detectable effects on growth or maturation were found in boys and girls or any effect on the length of the menstrual cycle in girls. The girls should be informed about appropriate methods of contraception during treatment with simvastatin. Patients <18 years of age have not been screened for efficacy or safety over the treatment period> 48 weeks and the long-term effect on the physical, mental and genital maturation is unknown.The use of simvastatin in patients <10 years of age or pre-puberty children and girls before the first menstrual period has not been studied. Due to the lactose content, the drug should not be used in patients with rare hereditary galactose intolerance, lactase deficiency (Lapp type) or malabsorption of glucose-galactose.
Pregnancy and lactation:
Do not use in pregnant women, those planning pregnancy or those who are suspected of being pregnant, as mother's treatment with simvastatin may reduce the fetus concentration of mevalonate, which is a precursor to cholesterol biosynthesis. It is not known whether simvastatin or its metabolites are excreted in human milk - do not use during breast-feeding due to the possibility of serious side effects in the infant.
Side effects:
Rare: anemia, headache, paresthesia, dizziness, peripheral neuropathy, constipation, abdominal pain, flatulence, indigestion, diarrhea, nausea, vomiting, pancreatitis, hepatitis, jaundice, rash, pruritus, alopecia, myopathy after 80 mg (including myositis), rhabdomyolysis (with or without acute renal failure), muscle pain, muscle spasms, weakness, symptoms of hypersensitivity syndrome (angioneurotic edema, lupus-like syndrome, rheumatoid type muscle pain, dermatomyositis, inflammation vasculitis, thrombocytopenia, eosinophilia, accelerated OB, arthritis, arthralgia, urticaria, hypersensitivity to light, fever, redness, difficulty in breathing, malaise), increase in blood transaminases (ALAT, AST, GGT), increase in ALP, increase in CK activity in the blood. Very rare: insomnia, impaired memory, liver failure (fatal and fatal). Not known: depression, interstitial lung disease, tendinopathy (sometimes complicated by tendon rupture), immunosensory necrotic myopathy, erectile dysfunction. Patients taking statins, including simvastatin, have reported increases in HbA1c and fasting blood glucose. Rare cases of cognitive dysfunctions have also been observed (eg memory loss, poor memory, amnesia, memory impairment, confusion) in patients receiving statins, including simvastatin; the reporting disorders were generally mild and resolved after discontinuation of statin therapy; a variable time to onset (from 1 day to several years) and resolution of symptoms (median 3 weeks) were observed. Side effects characteristic of statins: sleep disorders (including nightmares), sexual dysfunction, diabetes (frequency depends on the presence or absence of risk factors, i.e. fasting blood glucose ≥ 5,6 mmol / l, BMI> 30 kg / m2, increased triglycerides, history of hypertension). The long-term effect of simvastatin is not known for the physical and intellectual development and sexual maturation of children and adolescents.
Dosage:
Orally. The dose range is 5-80 mg / day. If necessary, the dose should be adjusted at intervals of at least 4 weeks to a maximum of 80 mg / day. A dose of 80 mg per day is only recommended for patients with severe hypercholesterolaemia and a high risk of cardiovascular complications who have not achieved the goals of treatment with a lower dose. The patient should use a standard low-cholesterol diet, which should be continued during treatment.hypercholesterolemia10-20 mg once a day; if it is necessary to reduce the LDL-cholesterol> 45%, the initial dose may be 20-40 mg once a day.Homozygous familial hypercholesterolaemia: 40 mg once a day.Prevention of cardiovascular diseases20-40 mg once a day.Combination treatment with other medicines: simvastatin should be taken not less than 2 hours before or not less than 4 hours after administration of bile acid sequestrants. In the case of simultaneous treatment with fibrates (except gemfibrozil - contraindicated or fenofibrate) the simvastatin dose can not be> 10 mg / day. Patients taking simvastatin concomitantly with Amiodarone, Verapamil, diltiazem or Amlodipine must not receive simvastatin> 20 mg / day. Patients who are taking concomitant livetapide with simvastatin must not receive simvastatin> 40 mg / day.Special groups of patients. In patients with severe renal impairment (CCr <30 ml / min), simvastatin> 10 mg / day should be carefully considered and, if necessary, very cautiously start treatment. No dosage adjustment is necessary in patients with mild or moderate renal impairment or in elderly patients.Children and teenagers 10-17 years(boys ≥12 on the Tanner scale and girls at least one year from the first menstruation) with heterozygous familial hypercholesterolaemia: the recommended starting dose is 10 mg per day. The recommended dose range is 10-40 mg / day. The largest recommended dose is 40 mg per day. Doses should be adjusted individually according to the recommended goal of therapy according to the recommendations for treatment of children and adolescents. The dose should be adjusted at intervals of at least 4 weeks. The appropriate diet should be used. There is limited experience in the use of simvastatin in pre-pubertal children.Way of giving. The drug should be taken once a day, in the evening.
(C)
