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 an adjunctive therapy, aimed at correcting other risk factors or supplementing other therapies to prevent heart disease.

1 tabl powl. contains 10 mg, 20 mg or 40 mg of Simvastatin (and respectively 67.92 mg, 135.84 mg or 271.68 mg lactose).

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.

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.

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 useful test to identify subclinical cases of myopathy. However, there is no certainty that this will avoid the development of myopathy. Very rare cases of immunosuppressed necrotic myopathy (IMNM) have been reported during or after treatment with statins. Clinical features of IMNM are persistent weakening of proximal muscles and increased serum creatine kinase activity, which persists despite discontinuation of statin therapy. 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 taking 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. 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 exercised when using simvastatin (especially at a dose of 40 mg or higher) at the same time as niacin or niacin containing preparations at lipid-modifying doses (≥1 g / day) in patients from China; in these patients, simvastatin 80 mg is not recommended together with niacin at lipid-modifying doses (≥1 g / day). It is not known whether the risk of myopathy is increased in other patients of Asian origin who receive simvastatin in this combination. 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. 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 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 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 interstitial lung disease, statin treatment should be stopped. Decreased activity of OATP hepatic uptake transport protein may increase systemic exposure to simvastatin and the risk of myopathy and rhabdomyolysis. Reduced activity may be associated with interactions with drugs that inhibit transport proteins (eg with cyclosporine) or occur in patients with the genotype SLCO1B1 c.521T> C. Patients carrying the allele (c.521T> C) of the SLCO1B1 gene encoding lower OATP1B1 protein activity have increased systemic exposure to simvastatin and an increased risk of myopathy. Generally, without genetic testing, the risk of myopathy associated with high doses of simvastatin (80 mg) is approximately 1%. In CC homozygous patients treated with 80 mg of simvastatin, 15% of the risk of myopathy was found within a year, while in heterozygous carriers of the C (CT) allele, the risk is 1.5%. The corresponding risk in patients with the most common genotype (TT) is 0.3%. Where possible, before initiating administration of simvastatin at a dose of 80 mg, consideration should be given to testing the genotype in individual patients for the presence of the C allele as part of the benefit-risk assessment. Avoid administration of high doses of simvastatin in patients with CC genotype. However, the lack of this gene, found after the genotype test, still does not exclude the possibility of myopathy. The safety and efficacy of simvastatin in patients 10-17 years of age with heterozygous familial hypercholesterolaemia was assessed in a controlled clinical trial of boys in phase II and above according to the Tanner scale and girls who had passed at least 1 year after the first menstrual period. The profile of adverse reactions in patients treated with simvastatin was generally similar to that in patients who received placebo. Doses greater than 40 mg have not been studied in this population. In this limited, controlled study, no detectable effects on sex growth or puberty 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 has not been studied in patients under 10 years of age or in pre-puberty children and 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 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.

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.

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.