Index of drugs

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, along with corrective measures for other risk factors and other methods of therapy to prevent heart disease.

1 tabl powl. contains 10 mg or 20 mg of simvastatin. The preparation contains lactose.

The active metabolite of Simvastatin (beta-hydroxy acid) is a potent inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG-CoA). This enzyme catalyses the conversion of HMG-CoA to mevalonate, an early stage of transformation leading to the formation of cholesterol. The limitation of this process has an impact on the rate of cholesterol synthesis. Simvastatin reduces both normal and elevated LDL-cholesterol (LDL-C). The mechanism of lowering LDL cholesterol may be the result of both lowering VLDL cholesterol (VLDL-C) and LDL receptor induction, which leads to reduced production and increased LDL-C catabolism. There is also a significant reduction in apolipoprotein B levels. In addition, simvastatin moderately increases HDL-C levels and decreases serum triglycerides (TG). Hydrolysis of simvastatin to the active metabolite occurs mainly in the liver (in human plasma this process is very slow). After oral administration less than 5% of the dose gets into the systemic circulation as a beta-hydroxy acid. Maximum plasma concentrations of active inhibitors occur 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 main 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 persistent, unexplained increase in serum transaminases. Pregnancy. Breastfeeding period. Concomitant administration of strong CYP3A4 inhibitors - substances that cause approximately at least 5-fold increase in AUC (eg 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 contraindicated in doses above 40 mg per day.

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 reference baseline, CK activity should be measured prior to initiation of treatment in the following cases: old age (≥ 65 years); female; kidney problems; refractory or untreated hypothyroidism; an individual or family history of hereditary disorders of the muscular system; patients with a history of toxic effects of statins or muscle fibrates; alcohol addiction.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 the CK activity significantly exceeds the upper limit of the value considered normal (GGN) - 5-fold above ULN, simvastatin treatment should not be initiated. If muscle pain, muscle weakness or cramps occur during treatment, CK activity should be determined. Administration of simvastatin 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. Patients with a dose of simvastatin up to 80 mg had a higher incidence of myopathy. Periodic CK determination is recommended as a test useful for identifying subclinical cases of myopathy. There is no certainty that doing so 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. The risk of myopathy is higher in patients taking simvastatin 80 mg compared with other statin-based treatments with similar efficacy in lowering LDL cholesterol. Therefore, simvastatin 80 mg should only be used in patients with severe hypercholesterolaemia and a high risk of cardiovascular complications whose treatment goal has not been achieved with lower doses and whose expected benefit outweighs the potential risk. Patients receiving simvastatin 80 mg requiring administration of an interacting drug should use a lower dose of simvastatin or an alternate therapy regimen based on a statin with less potential for interaction. Due to the increased risk of myopathy, caution should be exercised when prescribing simvastatin to patients of Asian descent and use the lowest necessary dose. Decreased activity of hepatic organic anion transporting proteins (OATP) may increase systemic exposure to simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Decreased activity may be the result of inhibition by interacting drugs (eg cyclosporine) or occur in patients who are carriers of the S.5O1.51 c.521T> C genotype. In patients with the allele (c.521T> C) of the SLCO1B1 gene that encodes the OATP1B1 protein with less activity, there is an increased systemic exposure to simvastatin acid and an increased risk of myopathy. Without genetic testing, the risk of myopathy associated with high doses of simvastatin (80 mg) is approximately 1% in the general population. In homozygous carriers of the C allele (called CC) treated with simvastatin 80 mg, the risk of myopathy is 15% in 1 year, while in heterozygous carriers of the C (CT) allele, the risk is 1.5%. The risk for patients with the most common genotype (TT) is 0.3%. If possible, the possibility of genetic testing for the C allele should be considered to assess the benefit / risk ratio before prescribing 80 mg of simvastatin to the patient and avoid high-dose prescribing to patients with the CC genotype. Nevertheless, the absence of these alleles during genotyping does not exclude myopathy. 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 there is a further increase in transaminases, especially up to 3-fold greater than ULN, and persists, the drug should be discontinued. It should be noted that ALT activity may be derived from muscle tissue, therefore an increase in ALT with increased CK activity may indicate myopathy. If severe liver damage resulting in clinical signs and / or hyperbilirubinemia or jaundice occurs during treatment with the preparation, treatment should be discontinued immediately. If another cause of the disorder can not be identified, the treatment should not be resumed. The drug should be used with caution in people who consume significant amounts of alcohol. Statins can increase blood Glucose levels; in some patients who are at high risk of developing diabetes in the future, they may cause hyperglycaemia at a level that requires the administration of antidiabetic agents. However, this risk is offset by the ability of statins to reduce the risk of vascular disease, so it should not be a reason for stopping statin therapy. In patients at risk (fasting glucose 5.6-6.9 mmol / l, BMI> 30 kg / m², elevated triglycerides, hypertension), clinical observation and biochemical parameters should be monitored according to local guidelines. If you suspect or have interstitial lung disease, you should stop statin treatment. The safety and efficacy of simvastatin in patients aged 10-17 years with heterozygous familial hypercholesterolaemia was assessed in a controlled clinical trial including boys who achieved at least phase II Tanner and girls who had a minimum of one year from the first period. The profile of adverse reactions in patients treated with simvastatin and placebo was similar. No doses greater than 40 mg / day have been studied in this population. During this limited clinical trial, it was not found that the treatment had a detectable effect on the growth and sexual maturation of the boys and girls participating in it, nor would it affect the length of the menstrual cycle in girls. Girls should be informed of appropriate methods of contraception during treatment with simvastatin. In patients <18 years, efficacy and safety studies with respect to the treatment period> 48 weeks have not been performed - the long-term effect on the physical, mental and sexual maturation is unknown. There are no studies on the use of simvastatin in children under 10 years, pre-pubertal children, girls before the first menstrual period. The product contains lactose - should not be used in patients with rare hereditary lactose intolerance, Lapp lactase deficiency or malabsorption of glucose-galactose.

Do not use the drug in pregnant women who plan to become pregnant in the near future or those who are suspected of being pregnant. 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.

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 - 1% of patients) including muscle inflammation, rhabdomyolysis (with or without acute renal failure), muscle pain, muscle spasms, asthenia, hypersensitivity syndrome (angioneurotic edema, lupus-like syndrome, rheumatoid type muscle pain, myositis and dermatitis) , vasculitis, thrombocytopenia, eosinophilia, increased OB, arthritis, arthralgia, urticaria, photosensitivity, fever, flushing, shortness of breath, malaise), increase in blood transaminases (ALAT, AST, GGT), increase in ALP , increase in serum CK activity. Very rare: insomnia, impaired memory, liver failure (no fatal or fatal outcome).Frequency unknown: depression, interstitial lung disease, tendinopathy (sometimes complicated by tendon rupture), immunoreceptor myelopathy - IMNM (characterized by proximal muscle weakness and increased serum creatine kinase activity, persisting despite discontinuation of statin therapy; muscle biopsy shows necrotic myopathy without significant inflammation, improvement occurs through the use of immunosuppressive drugs), erectile dysfunction. Statistically, increases in HbA1c and fasting plasma glucose have been reported in patients taking statins, including simvastatin. Rare cases of cognitive dysfunction (eg memory loss, poor memory, amnesia, memory impairment, confusion) have been reported in post-marketing period in patients taking statins, including simvastatin. The reported problems were generally mild and resolved after discontinuation of statin therapy. A variable time to onset (from 1 day to several years) and resolution (median 3 weeks) of symptoms were observed. In addition, the following side effects have been reported when using some statins: sleep disorders, including nightmares; sexual dysfunction; diabetes mellitus: frequency depends on the presence or absence of risk factors (glucose level, fasting ≥5,6 mmol / l, BMI> 30 kg / m², elevated triglyceride levels, a history of hypertension). In a 48-week study in which children and adolescents participated (boys in phase II and above according to the Tanner scale and girls who have had at least one year from the first menstruation) from 10 to 17 years of age with heterozygous familial hypercholesterolemia, safety profile and tolerability of the treatment group in the simvastatin group was generally similar to that observed in the placebo group. The long-term effect of the drug on physical, mental and sexual maturation is unknown. There are currently no adequate data for the treatment with simvastatin for over a year.

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.hypercholesterolemia: initial dose - 10-20 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. If a dose adjustment is necessary, it must be carried out as described above.Homozygous familial hypercholesterolaemia: 40 mg once a day in the evening. In this patient group, simvastatin should be used as a supplement to other lipid-lowering treatments (eg LDL apheresis), or if such treatment is not available or not appropriate. In patients taking lomitapide concomitantly with Simvastatin, the simvastatin dose should not exceed 40 mg daily.Prevention of cardiovascular diseases20-40 mg once a day, in the evening. If a dose adjustment is necessary, it must be carried out as described above.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. Patients taking fibrates together with the preparation, with the exception of gemfibrozil or fenofibrate, must not take a daily dose of simvastatin greater than 10 mg daily. Patients taking Amiodarone, Amlodipine, Verapamil or diltiazem concomitantly with the concomitant administration must not receive a simvastatin dose of 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.