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. Reduction of morbidity and mortality of cardiovascular diseases in patients with overt atherosclerosis or diabetes, with normal or elevated cholesterol, as adjunctive therapy when used to correct other risk factors and other therapies to prevent heart disease.
The active metabolite of Simvastatin (beta-hydroxy acid) is an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA). This enzyme catalyzes the conversion of HMG-CoA to mevalonate, i.e. an early reaction and, at the same time, a cholesterol biosynthesis control step. Simvastatin reduces both normal and elevated LDL cholesterol. The mechanism of LDL cholesterol lowering by simvastatin may be a result of both lowering VLDL cholesterol and LDL receptor induction, leading to reduced production and increased catabolism of LDL cholesterol. There is also a significant reduction in apolipoprotein B levels. In addition, simvastatin moderately increases HDL cholesterol and decreases serum triglycerides. After oral administration less than 5% of the dose gets into the systemic circulation as a beta-hydroxy acid. The maximum concentration of active inhibitors in the plasma occurs within approx. 1-2 h after administration. The drug and its metabolites bind to plasma proteins in over 95%. Simvastatin is a substrate for CYP3A4, the major metabolites are: beta-hydroxy acid and 4 other active metabolites. 13% of the dose is excreted in the urine, 60% in the faeces.
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 and nefazodone. Co-administration of gemfibrozil, cyclosporin or danazol. Pregnancy. Breastfeeding period.
Precautions:
Caution in patients with predisposing factors for rhabdomyolysis: in elderly patients (over 70 years), with renal dysfunction, with refractory or untreated hypothyroidism, with hereditary disorders of the muscular system (including family history), in patients who have had muscle or alcohol abuse in the past with statins or fibrates. In these groups of patients, CK activity should be measured before starting treatment - if the CK activity is higher than 5 times the upper limit of normal, do not start treatment. Drug administration must be discontinued if the creatine kinase activity increases (more than 5 times the upper limit of normal); discontinuation of treatment should be considered if the muscle symptoms are significantly increased even when the CK activity is less than 5 times the upper limit of normal. If you suspect myopathy for any other reason, the medicine should be discontinued. If the muscle symptoms go away and the CK values return to normal, re-administration of the statin at the lowest effective dose may be considered with close monitoring of the patient's state of health. Treatment should be discontinued a few days before the planned major surgery or if it is necessary to undergo internist or surgical treatment.Special care should be taken in patients who experience elevated serum transaminases. The drug should be discontinued if persistent elevation of aminotransferases persists, especially if it reaches 3 times the upper limit of normal and will persist. In patients suspected of having interstitial lung disease, treatment with statins should be discontinued. The safety and efficacy of simvastatin in patients aged 10-17 years with familial heterozygous hypercholesterolemia has been evaluated in controlled clinical trials in adolescents: boys on the Tanner scale, phase II and above, and girls at least 1 year after the onset of menarche. Doses greater than 40 mg were not tested in this population. There was no measurable effect on sexual growth or puberty in adolescent boys and girls nor was there any effect on the length of the menstrual cycle in girls. In patients under 18 years, the safety and efficacy of treatment for> 48 weeks have not been studied and the effects of long-term effects on physical, intellectual and sexual maturation are unknown. Simvastatin has not been studied in patients under 10 years of age, nor in sexually immature patients and girls prior to the onset of menarche. The product contains lactose - should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency 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). Frequency unknown: depression, interstitial lung disease, tendinopathy (sometimes complicated by tendon rupture), 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.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. The 10 mg tablet can be divided into halves.
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