Index of drugs

Treatment of primary hypercholesterolemia or mixed dyslipidemia, in combination with diet, when the response to diet or non-pharmacological treatments (eg, exercise, weight loss) is insufficient. Treatment of familial homozygous hypercholesterolemia, in combination with diet and other treatments leading to a reduction in lipids (eg LDL apheresis) or when other treatments can not be used. Decrease of morbidity and mortality of cardiovascular diseases in patients with overt atherosclerosis or diabetes, with normal or elevated cholesterol, combined with correction of other risk factors and with other methods of cardioprotective treatment.

1 tabl powl. contains 20 mg or 40 mg simvastatin. The preparation contains lactose.

The active metabolite of Simvastatin (beta-hydroxy acid) is an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA). This enzyme catalyses the conversion of HMG-CoA to mevalonate, i.e. the early stage of cholesterol biosynthesis. Simvastatin reduces both normal and elevated LDL cholesterol. The mechanism of LDL cholesterol lowering by simvastatin may be the 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 causes a small increase in HDL cholesterol and decreases serum triglycerides. After oral administration, the absorption of beta-hydroxy acid into the systemic circulation was less than 5% of the dose. The maximum concentration of the active inhibitor in the plasma is reached within about 1-2 hours 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.

Hypersensitivity to the active substance or to any of the excipients. Active liver disease or unexplained, persistent increase in serum transaminases. Pregnancy and lactation. Concomitant use of strong CYP3A4 inhibitors (eg Itraconazole, ketoconazole, posaconazole, HIV protease inhibitors (eg nelfinavir), Erythromycin, Clarithromycin, telithromycin and nefazodone). Co-administration of gemfibrozil, cyclosporin or danazol.

Because of the dose-dependent risk of myopathy and / or rhabdomyolysis before starting the treatment or if the dose is increased, all patients should be informed of the risk of myopathy and recommended to report promptly to the physician if they experience difficult-to-explain muscle pains, excessive sensitivity to touch or weakness. The drug should be used with caution in patients with predisposing factors for rhabdomyolysis. To establish a baseline reference value, CK activity should be measured prior to initiating treatment in the following cases: elderly (> 65 years), women, patients with impaired renal function, patients with refractory or untreated hypothyroidism, patients with an individual or family history an interview that proves hereditary disorders of the muscular system, patients who have had a history of toxic effects of statins or muscle fibrates, patients addicted to alcohol. In these cases, the expected benefits of treatment and the associated risks should be considered. Monitoring the patient's health is recommended. If the patient has had a harmful effect of statins or fibrates on the muscle in the past, the treatment should be started very carefully. If CK activity is significantly above ULN (5 times above ULN), simvastatin therapy should not be initiated. If muscle pain, muscle weakness or cramps occur during treatment, CK activity should be determined.Administration of a statin should be discontinued if the CK activity studied in a patient who was not after strenuous exercise is significantly elevated (more than 5 times above ULN). Discontinuation of simvastatin should be considered, even if the CK activity does not exceed 5 times ULN, but unwanted muscle symptoms are exacerbated and cause daily discomfort. If myopathy is suspected for any reason, the medicine should be discontinued. If the muscle symptoms have disappeared and the CK value has returned 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. The higher incidence of myopathy was observed in patients in whom the simvastatin dose was increased to 80 mg / day. Periodic CPK monitoring is recommended as this examination may be helpful in diagnosing subclinical cases of myopathy. However, there is no certainty that such controls will prevent 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. Due to the increased risk of myopathy, caution should be used in Chinese patients using simvastatin (especially at a dose of 40 mg or higher) together with niacin or niacin containing preparations at lipid-modifying doses (≥ 1 g / day); the use of simvastatin 80 mg in this combination is not recommended in Chinese patients (it is not known whether the increased risk of developing myopathy affects other patients of Asian origin). Statins can increase blood Glucose levels and in some patients with a high risk of developing diabetes in the future, they can cause hyperglycemia of an intensity requiring appropriate diabetes care. This risk is however outweighed by the benefit of reducing the risk of developing vascular disease, so statin therapy should not be discontinued. Patients at risk (patients with fasting glucose 5,6-6,9 mmol / l, BMI> 30 kg / m², with elevated triglycerides, hypertension) should be subjected to clinical and biochemical monitoring according to local guidelines. It is recommended to perform liver function tests in all patients before starting treatment, 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 the aminotransferases increase further, especially up to 3 times higher than ULN and persist, the drug should be discontinued. The drug should be used with caution in people who consume significant amounts of alcohol. If during treatment there is a suspicion that the patient has developed interstitial lung disease, the statin treatment should be stopped. The efficacy and safety of simvastatin administration in patients aged 10-17 years, with heterozygous familial hypercholesterolaemia were evaluated in a controlled clinical trial in boys from Phase II. Tanner and girls who have been menstruating for at least a year. The profile of adverse reactions in patients treated with simvastatin was generally similar to that seen in the placebo group. In this population, the effects of doses higher than 40 mg / day were not studied. In this limited, controlled study, no measurable effects on the growth or sexual maturation of teenage boys or girls, or any effect on the length of the menstrual cycle in girls were demonstrated. Teenage girls should be informed about the need to take appropriate contraception measures during treatment with simvastatin. In patients under 18 years, the efficacy and safety of the drug have not been studied longer than 48 weeks, therefore the long-term effect of treatment on physical, intellectual and sexual maturation is unknown. Simvastatin has not been studied in patients less than 10 years of age, pre-pubertal children, or girls prior to the first menstrual period.The product contains lactose - should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency or malabsorption of glucose-galactose.

The product should not be used in pregnant women, in women who are planning to become pregnant or who are suspected of being pregnant. Women who take simvastatin must not breastfeed because of the possibility of serious side effects in the child.

Rare: anemia, headache, paresthesia, dizziness, peripheral neuropathy, constipation, abdominal pain, flatulence, indigestion, diarrhea, nausea, vomiting, pancreatitis, hepatitis, jaundice, rash, pruritus, alopecia, myopathy (in including myositis) - more frequently in patients treated with 80 mg / day compared to patients treated with 20 mg / day, rhabdomyolysis with or without acute renal failure, myalgia, muscle cramps, myositis, polymyositis, asthenia, transaminase elevation (ALAT, AST, GGT), increased alkaline phosphatase, increased serum CK activity. Very rare: insomnia, memory deterioration, liver failure. Frequency unknown: depression, interstitial lung disease, tendon rupture (sometimes complicated by tendon rupture), erectile dysfunction. In rare cases, symptoms of hypersensitivity syndrome with one or more of the following symptoms have been reported, such as: angioneurotic edema, rheumatoid type muscle pain, myositis and dermatitis, vasculitis, thrombocytopenia, eosinophilia, elevated OB, arthritis, arthralgia, urticaria, hypersensitivity to light, fever, hot flashes, shortness of breath, feeling unwell. The following adverse events have also been reported with the use of some of the statins: sleep disorders (including nightmares), memory loss, sexual dysfunction, diabetes: the incidence depends on the presence or absence of risk factors (blood Glucose, fasting ≥5,6 mmol / L, BMI> 30 kg / m², increased triglyceride levels, a history of hypertension).

Orally. Adults. The dose range is 5-80 mg per day. Dose adjustments, if necessary, should be made at intervals of not less than 4 weeks. The dose may be increased up to a maximum dose of 80 mg administered once a day, in the evening. The 80 mg dose is only recommended for patients with severe hypercholesterolaemia and a high risk of cardiovascular complications who have not achieved their goals of treatment with lower doses where the expected benefit outweighs the potential risk.hypercholesterolemiaA typical starting dose is 10-20 mg once a day, in the evening. In patients who require a significant reduction in LDL cholesterol (by over 45%), treatment can be started with a 20-40 mg dose given once a day, in the evening.Homozygous familial hypercholesterolaemia: 40 mg daily in the evening. Simvastatin should be used in these patients in addition to other lipid-lowering treatments (eg LDL apheresis) or when other methods of such treatment are not available.Prevention of events from the cardiovascular systemA typical dose of simvastatin is 20-40 mg / day in a single daily dose, in the evening, in patients at high risk for coronary heart disease (with or without hyperlipidemia). Pharmacological treatment can be started simultaneously with diet and exercise.Simultaneous use with other drugs. Simvastatin is effective in monotherapy or in combination therapy with bile acid sequestrants. Simvastatin should be administered either> 2 h before or> 4 h after treatment with bile acid sequestrants. For patients who are taking fibrates other than gemfibrozil or fenofibrates with Simvastatin, the simvastatin dose should not exceed 10 mg daily. In patients taking simvastatin concomitantly with Amiodarone, Amlodipine, Verapamil or diltiazem, the dose of simvastatin should not exceed 20 mg per day. There is no need to modify the dosage in patients with moderate renal impairment. In patients with severe renal impairment (creatinine clearance <30 ml / min), the need for doses exceeding 10 mg per day should be carefully considered. If these doses are necessary, they should be used with caution.There is no need to modify the dosage in elderly patients.Children and adolescents (10-17 years). For children and adolescents (boys from the second phase according to Tanner and girls at least one year after the first menstruation, aged 10-17 years) with heterozygous familial hypercholesterolemia, the recommended starting dose is 10 mg once a day, in the evening. Before starting treatment with simvastatin, children and adolescents should remain on a standard cholesterol-lowering diet; The diet should be maintained throughout the therapy. The recommended dose range is 10-40 mg / day; the maximum recommended daily dose is 40 mg. Doses should be selected individually, according to the recommended therapeutic goal set out in the pediatric guidelines. Dose modification should be made at intervals of not less than 4 weeks.