Simvastatin

Pharmacological properties

after oral administration, simvastatin, which is an inactive lactone, is hydrolyzed in the liver with the formation of the corresponding β-hydroxy acid derivative having high inhibitory activity against HMG-coa reductase (3-hydroxy-3-methylglutaryl-coa reductase), an enzyme that catalyzes the conversion HMG-COA in Mevalonate, the initial and most significant stage of xc biosynthesis.

It has been proven that simvastatin reduces normal and elevated levels of LDL cholesterol. LDL is formed from VLDL and is catabolized mainly by receptors with high affinity for LDL. The mechanism of the LDL-lowering effect of simvastatin may consist of both a decrease in the concentration of VLDL cholesterol and stimulation of LDL receptors, leading to decreased production and increased catabolism of LDL cholesterol. Apolipoprotein B levels also decrease significantly during treatment with simvastatin. In addition, simvastatin significantly increases HDL cholesterol and reduces the level of TG in blood plasma. As a result of these changes, the ratio of total cholesterol to HDL cholesterol and LDL cholesterol to HDL cholesterol decreases.

Pharmacokinetics Simvastatin is an inactive lactone that readily hydrolyzes, turning in vivo into β-hydroxy acid, a potent inhibitor of HMG-CoA reductase. Hydrolysis occurs mainly in the liver; the rate of hydrolysis in human plasma is very low.

Pharmacokinetic properties were evaluated with the participation of adults. There are no pharmacokinetic data for children and adolescents.

Absorption. In humans, simvastatin is well absorbed and undergoes extensive primary hepatic metabolism. Isolation in the liver depends on blood flow in the liver. The liver is the primary center of action of the active form. It was found that the availability of β-hydroxy acid in the systemic circulation after an oral dose of simvastatin is 5% of the dose. C_max active inhibitors in blood plasma is achieved approximately 1-2 hours after taking simvastatin. Concomitant food intake does not affect absorption. The pharmacokinetics of single and multiple doses of simvastatin demonstrated that drug accumulation after repeated dosing does not occur.

Distribution. The binding of simvastatin and its active metabolite to plasma proteins is 95%.

Simvastatin is a substrate of CYP 3A4 (see CONTRAINDICATIONS, INTERACTIONS). The largest metabolites of simvastatin present in human blood plasma are β-hydroxy acid and 4 additional active metabolites. After administering a human oral dose of radioactive simvastatin for 96 hours, 60% of the labeled drug was excreted in feces and 13% in urine. The amount detected in feces is an equivalent absorbed drug that is excreted in the bile, as well as an unabsorbed drug. After iv injection of a metabolite of β-hydroxy acid of its T_½ averages 1.9 hours. On average, only 0.3% of the dose is excreted in the form of inhibitors with urine.

Simvastatinic acid is actively captured by hepatocytes using the OATP1B1 transporter.

Polymorphism SLCO1B1. Carriers of the p.521TC allele of the SLCO1B1 gene have a reduced activity of the OATP1B1 protein. The average exposure (AUC) of the main active metabolite, simvastatinic acid, is 120% for heterozygous carriers (CT) of the C allele and 221% for homozygous (CC) carriers compared to patients who have the most common genotype (TT). Allele C in the European population is noted with a frequency of 18%, while the homozygous SS genotype is detected with a frequency of 1.5%. In patients with SLCO1B1 gene polymorphism, there is a risk of increased exposure to simvastatinic acid, which can lead to an increased risk of rhabdomyolysis (see SPECIAL INSTRUCTIONS).

Indications

• Hypercholesterolemia.treatment of primary hypercholesterolemia or mixed dyslipidemia as a supplement to the diet, when the response to the diet and other non-drug therapies (e.g. physical exercise, weight loss) are insufficient.

Treatment of homozygous familial hypercholesterolemia as a dietary supplement and other lipid-lowering treatment (for example, apheresis of low-density lipids) or when such treatment methods are inappropriate.

• Cardiovascular prophylaxis. Reducing the risk of mortality in patients with cardiovascular disease and morbidity in patients with obvious atherosclerotic cardiovascular disease or diabetes with normal or elevated levels of cholesterol, as an additional therapy for the correction of other risk factors and other cardioprotective therapy.

Application

The dosage range of the drug is 5–80 mg orally 1 time per day in the evening. if necessary, the selection of the dose of the drug should be carried out at intervals of at least 4 weeks until the maximum daily dose of 80 mg is reached, which should be taken 1 time per day in the evening. A dose of 80 mg is recommended only for patients with severe hypercholesterolemia and a high risk of developing complications from the cardiovascular system, in which the necessary results are not achieved with lower doses, and also when the expected benefits exceed the potential risks (see special instructions).

Hypercholesterolemia. The patient should be prescribed a standard cholesterol lowering diet, which should be followed throughout the course of treatment with simvastatin. Typically, the initial dose is 10–20 mg / day once in the evening. For patients who need a significant (more than 45%) decrease in LDL cholesterol, the initial dose may be 20–40 mg once daily in the evening. Dose selection, if necessary, should be carried out as described above.

Homozygous familial hypercholesterolemia. The recommended initial dose of simvastatin is 40 mg per day once in the evening. Simvastatin should be used as an adjunct to another lipid-lowering treatment (for example, LDL apheresis) or if such treatment is not available.

Cardiovascular prophylaxis. Typically, the dose of simvastatin for patients with a high risk of developing coronary heart disease (in combination with or without hyperlipidemia) is 20–40 mg / day once in the evening. Drug therapy can be prescribed at the same time as diet and exercise. Dose selection, if necessary, should be carried out as described above.

Concomitant therapy. Simvastatin is effective as monotherapy, as well as in combination with bile acid sequestrants. The drug should be used no later than 2 hours before administration or not earlier than 4 hours after administration of bile acid sequestrants.

For patients using simvastatin simultaneously with fibrates, with the exception of gemfibrozil (see CONTRAINDICATIONS), or with fenofibrate, the dose of simvastatin should not exceed 10 mg / day. For patients using simvastatin simultaneously with amiodarone, amlodipine, verapamil, or diltiazem, the daily dose of simvastatin should not exceed 20 mg (see SPECIAL INSTRUCTIONS, INTERACTIONS).

Dosage for renal failure. In patients with moderate renal failure, there is no need to change the dosage. In patients with severe renal failure (creatinine clearance of 30 ml / min), the use of the drug at a dose above 10 mg / day should be carefully considered and, if such a dose is considered necessary, be used with caution.

Use in elderly patients. There is no need for dose adjustment.

Use in children (10-17 years). For children (boys of the Tanner II stage of age II and older and girls who have a menstrual cycle for at least 1 year) aged 10-17 years with heterozygous familial hypercholesterolemia, the recommended starting dose is 10 mg once daily in the evening. Before starting treatment with simvastatin, children should be prescribed a standard cholesterol-lowering diet, which should be followed during treatment with simvastatin.

Recommended doses - 10–40 mg / day; The maximum recommended dose is 40 mg / day. The dose should be selected individually, depending on the purpose of therapy and according to the recommendations of treatment in pediatrics (seeSPECIAL INSTRUCTIONS). Dose selection should be carried out at intervals of 4 weeks or more.

Experience with simvastatin in prepubertal children is limited.

Children. The safety and efficacy of simvastatin in children aged 10-17 years with heterozygous familial hyperlipidemia was evaluated in a controlled clinical trial involving boys of the Tanner II and older stages and girls who have a menstrual cycle for at least 1 year. The adverse reaction profile in patients receiving simvastatin was generally similar to that in patients receiving placebo. The use of doses in excess of 40 mg for this group of patients has not been investigated. In this study, the effect of simvastatin on the growth or puberty of children, as well as on the duration of the menstrual cycle in girls, was not registered (see APPLICATION, SIDE EFFECTS).

Girls should be advised regarding the available contraceptive methods during treatment with simvastatin (see CONTRAINDICATIONS, Use during pregnancy or lactation). In patients under the age of 18, the efficacy and safety of the drug over the treatment periods of more than 48 weeks have not been studied; the long-term consequences of physical, intellectual, and sexual development are unknown.

Simvastatin was not studied in patients under the age of 10 years, in children of prepubertal age, and also in girls before the onset of menstruation.

Contraindications

Hypersensitivity to simvastatin or any component of this drug; acute liver disease or an unclear persistent increase in plasma transaminases; concomitant use of potent cyp 3a4 inhibitors (drugs that increase auc by about 5 times or more), such as itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycinne and tel (see special instructions and interactions); concomitant use of gemfibrozil, cyclosporine or danazole.

Side effects

The frequency of adverse reactions is indicated as very often (1/10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1/1000), very rarely (1/10 000), unknown (impossible to establish from the available data).

On the part of the blood system and lymphatic system: rarely - anemia.

From the psyche: very rarely - insomnia; unknown - depression.

From the nervous system: rarely - headache, paresthesia, dizziness, peripheral neuropathy; very rarely - impaired memory.

From the respiratory tract, chest and mediastinal organs: unknown - interstitial lung disease (see SPECIAL INSTRUCTIONS).

From the digestive system: rarely - constipation, abdominal pain, flatulence, dyspepsia, diarrhea, nausea, vomiting, pancreatitis.

From the hepatobiliary tract: rarely - hepatitis / jaundice; very rarely - fatal and non-lethal liver failure.

On the part of the skin and subcutaneous tissue: rarely - rashes, itching, alopecia.

From the musculoskeletal system and connective tissue: rarely - myopathy (including myositis), rhabdomyolysis with or without acute renal failure (see SPECIAL INSTRUCTIONS), myalgia, muscle cramps; unknown - tendinopathy, sometimes complicated by rupture.

From the reproductive system and mammary glands: unknown - erectile dysfunction.

General disorders and associated with the method of use of the drug: rarely - asthenia.

Hypersensitivity syndrome has rarely been reported, which included the following conditions: angioedema, lupus-like syndrome, polymyalgia rheumatism, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased ESR, arthritis and arthralgia, urticaria, photosensitivity, fever, fever, fever.

Influence on the results of laboratory tests: rarely - an increase in the level of transaminases in blood plasma (AlAT, AsAT and gamma-glutamyl transpeptidases) (see SPECIAL INSTRUCTIONS, Effect on the liver); increased levels of alkaline phosphatase; increased creatine kinase levels (see SPECIAL INSTRUCTIONS).

When using statins, including simvastatin, an increase in fasting Hba1c and plasma glucose levels has been reported.

There have been reports of cognitive impairment (eg, memory loss, forgetfulness, memory impairment, confusion) associated with the use of statins, including simvastatin. In general, the cases were not serious and reversible and disappeared after stopping the use of statin.

Very rarely reported immuno-mediated necrotic myopathy (IONM), an autoimmune myopathy associated with the use of statins. IONM is characterized by weakness of the proximal muscles and an increase in the level of creatine kinase in the blood plasma, which persist despite the cessation of statins; signs of necrotizing myopathy according to the results of muscle biopsy without significant inflammation; improvement after immunosuppressive therapy.

When taking certain statins, these additional side effects have been reported: sleep disorders, including nightmares; sexual dysfunction; diabetes mellitus: the frequency of occurrence depends on the presence or absence of risk factors (fasting blood glucose ≥5.6 mmol / l, body mass index 30 kg / m², an increased level of TG, AH in history).

special instructions

Myopathy / rhabdomyolysis. simvastatin, like other inhibitors of HMG-coa reductase, can cause myopathy in the form of muscle pain, soreness or weakness, accompanied by an increase in creatine kinase activity by more than 10 times compared with the upper limit of normal. myopathy sometimes takes the form of rhabdomyolysis with or without opnea due to myoglobinuria; fatal cases have been very rare. the risk of myopathy is increased due to high levels of inhibitory activity against HMG-coa reductase in the blood plasma.

As with other HMG-CoA reductase inhibitors, the risk of myopathy / rhabdomyolysis is dose-dependent.

In patients using simvastatin at a dose of 80 mg, the risk of myopathy is higher than with other statins with similar effectiveness in lowering LDL cholesterol. Therefore, simvastatin in a dose of 80 mg should be used only in patients with severe hypercholesterolemia and a high risk of cardiovascular complications who have not achieved a therapeutic effect when using lower doses, and also if the expected benefits exceed the potential risk. For patients taking 80 mg simvastatin, who need to prescribe a drug that interacts with simvastatin, use a lower dose of simvastatin or prescribe an alternative drug of the statin group with a less pronounced potential for interaction with other drugs (see Measures to reduce the risk of myopathy due to interaction with drugs).

Reduced function of carrier proteins. With a reduced function of the liver proteins of the OATP family, the systemic exposure of simvastatinic acid may increase and the risk of myopathy and rhabdomyolysis may increase. Decreased function may occur as a result of inhibition of interacting agents (eg cyclosporin) or in patients who are carriers of the SLCO1B1 (p.521T C) genotype.

Patients who carry the SLCO1B1 gene allele (c.521T C), which encodes a less active OATP1B1 protein, have an increased systemic exposure of simvastatinic acid and an increased risk of myopathy. Without reference to genetic testing, the risk of developing myopathy associated with high doses (80 mg) of simvastatin is generally about 1%.

The results of the SEARCH study show that homozygous carriers of the C allele (which are marked as SS), taking 80 mg of simvastatin, have a 15% risk of developing myopathy throughout the year, while this risk in heterozygous carriers of the C (CT) allele is 1.5 %

The corresponding risk indicator in patients with the most common genotype is 0.3% (see Pharmacokinetics). Such specific genotyping is not common in clinical practice. If possible, before prescribing simvastatin in a dose of 80 mg to individual patients, it should be considered appropriate to conduct genotyping for the presence of the C allele in the framework of assessing the benefit-risk ratio and to avoid assigning high doses to those who are carriers of the SS genotype. However, the absence of this gene according to the results of genotyping does not exclude the possibility of the development of myopathy in these patients.

Determination of creatine kinase. The level of creatine kinase should not be determined after intense physical activity or in the presence of any possible alternative reasons for increasing creatine kinase, since this complicates the interpretation of the results. If creatine kinase levels are significantly increased at the beginning (more than 5 times compared with the upper limit of normal), a reanalysis should be performed after 5–7 days to confirm the results.

Before starting treatment. All patients who begin treatment with simvastatin or who are increasing the dose of simvastatin should be informed of the risk of myopathy and the need to immediately consult a doctor in case of muscle pain of unknown etiology, pain or muscle weakness.

Use the drug with caution in patients with predisposing factors for the occurrence of rhabdomyolysis. In order to establish the initial initial value, the level of creatine kinase should be determined before starting treatment in the following situations:

• advanced age (≥65 years);
• female;
• impaired renal function;
• uncontrolled hypothyroidism;
• the presence in a personal or family history of hereditary disorders of the muscular system;
• a history of muscle toxicity with statins or fibrates;
• alcohol abuse.

In such situations, the risk of treatment should be weighed against the potential benefit, and clinical monitoring is recommended. If the patient has previously observed disorders of the muscular system during treatment with fibrates or statins, treatment with various drugs of this class should be started with caution.

If baseline creatine kinase levels are significantly elevated (more than 5-fold compared with the upper limit of normal), treatment should not be initiated.

During treatment. If a patient experiences pain, weakness, or cramping while using statin, creatine kinase levels should be checked. If in the absence of intense physical activity it is established that these levels are significantly increased (more than 5 times compared with the upper limit of normal), treatment should be discontinued. If the symptoms are severe and cause daily discomfort, even if creatine kinase levels are 5 times lower than the upper limit of normal, consideration should be given to stopping treatment. If myopathy is suspected for any other reason, treatment should be discontinued.

If symptoms have disappeared and creatine kinase levels have returned to normal, consideration may be given to restarting the use of a statin or an alternative statin group drug at the lowest dose and under close monitoring.

More often, myopathy is observed in patients who were increased the dose to 80 mg. It is recommended that you periodically check creatine kinase levels, as this can help identify subclinical cases of myopathy. However, such monitoring may not always prevent the development of myopathy.

Simvastatin treatment should be temporarily discontinued a few days before the planned major surgery, as well as after medical or surgical interventions.

Measures to reduce the risk of myopathy due to interactions with drugs (see INTERACTIONS). The risk of developing myopathy and rhabdomyolysis is significantly increased with the simultaneous use of simvastatin with powerful CYP 3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (for example, nelfinrevirone, telofrevavirod, and telofrevavirod, also telofrevavirod,) with gemfibrozil, cyclosporine and danazole. The use of these drugs is contraindicated (see CONTRAINDICATIONS).

The risk of developing myopathy and rhabdomyolysis also increases with the simultaneous use of amiodarone, verapamil or diltiazem with simvastatin in certain doses (see APPLICATION, INTERACTIONS). The risk of developing myopathy, including rhabdomyolysis, may increase with the simultaneous use of fusidic acid and statins (see INTERACTIONS).

Consequently, with respect to CYP 3A4 inhibitors, the use of simvastatin simultaneously with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodium contraindication. If therapy with potent CYP 3A4 inhibitors (drugs that increase AUC by about 5 times or more) cannot be canceled, therapy with simvastatin should be discontinued while taking these drugs (or consider using an alternative drug of the statin group). Moreover, simvastatin should be prescribed with caution in combination with some other less potent CYP 3A4 inhibitors: fluconazole, verapamil, diltiazem (see INTERACTIONS). The simultaneous administration of grapefruit juice and simvastatin should be avoided.

The use of simvastatin with gemfibrozil is contraindicated (see CONTRAINDICATIONS). Due to the increased risk of developing myopathy and rhabdomyolysis, a daily dose of 10 mg should not be exceeded in patients who take simvastatin in combination with fibrates, with the exception of fenofibrate (see APPLICATION). Fenofibrate with simvastatin should be used with caution, since each of these drugs during monotherapy can be the cause of myopathy.

Simvastatin should not be used simultaneously with fusidic acid. There have been reports of rhabdomyolysis (including several fatal cases) in patients who took this combination (see INTERACTIONS). In patients for whom systemic use of fusidic acid is necessary, treatment with simvastatin must be discontinued for the entire period of treatment with fusidic acid. The patient should be advised to see a doctor immediately if any symptoms appear, such as weakness, pain, or muscle soreness. Statin therapy can be resumed 7 days after taking the last dose of fusidic acid. In exceptional cases, when long-term systemic therapy with fusidic acid is necessary, for example, for the treatment of severe infections, the need for the simultaneous use of simvastatin and fusidic acid should be considered only individually and under the close supervision of a doctor.

The combined use of simvastatin in doses exceeding 20 mg / day with amiodarone, amlodipine, verapamil or diltiazem should be avoided (see APPLICATION, INTERACTIONS).

Patients who take other drugs that have a moderate inhibitory effect on CYP 3A4, along with simvastatin, especially with high doses of simvastatin, may have an increased risk of developing myopathy. With the simultaneous use of simvastatin and a moderate inhibitor of CYP 3A4 (drugs that increase the AUC by about 2-5 times), dose adjustment of simvastatin may be required. For some moderate-acting CYP 3A4 inhibitors, such as diltiazem, a maximum dose of simvastatin of 20 mg is recommended (see APPLICATION).

Rare cases of myopathy / rhabdomyolysis are associated with the simultaneous use of HMG-CoA reductase inhibitors and niacin (nicotinic acid) in lipid-modifying doses (≥1 g / day); a separate use of each of these drugs can cause myopathy.

Doctors considering the combination therapy of simvastatin and niacin (nicotinic acid) in lipid-modifying doses (≥1 g / day) or other drugs containing niacin should carefully analyze the potential benefits and risks, and carefully monitor the condition of patients regarding the appearance of such symptoms or symptoms such as pain, soreness, or muscle weakness, especially in the first months of treatment and with an increase in the dose of any of the drugs.

Caution should be exercised in treating patients of Chinese nationality if simvastatin (especially at a dose of 40 mg or higher) is prescribed simultaneously with niacin (nicotinic acid) in lipid-modifying doses (≥1 g / day) or preparations containing niacin. Since the risk of myopathy with the use of statins is dose-dependent, it is not recommended to prescribe Simvastatin at a dose of 80 mg to Chinese patients at the same time as niacin (nicotinic acid) in lipid-modifying doses (≥1 g / day) or niacin-containing drugs. It is not known whether the risk of myopathy in other patients of the Mongoloid race increases when simvastatin is used simultaneously with niacin (nicotinic acid) in lipid-modifying doses (≥1 g / day) or drugs containing niacin.

Effect on the liver. In several adult patients receiving simvastatin, a steady increase in the level of transaminases in the blood serum was observed (more than 3 times compared with the upper limit of normal). Levels of transaminases, as a rule, slowly returned to baseline after a temporary cessation of use of simvastatin or its cancellation.

It is recommended to check liver function indicators before starting treatment and, if clinically indicated, during treatment. Patients who are planning a dose increase to 80 mg / day should perform an additional analysis before increasing the dose, 3 months after increasing the dose to 80 mg and subsequently periodically (for example, once every six months) during the first year of treatment. Particular attention should be given to patients who have increased plasma transaminase levels. In such patients, liver function tests should be repeated immediately and subsequently performed more frequently.

If trasaminase levels continue to rise, in particular 3 times compared with the upper limit of normal, and are persistent, simvastatin should be discontinued. It should be remembered that ALAT levels can vary depending on the state of the muscular system, therefore, an increase in ALAT and creatine kinase may indicate myopathy.

Rarely reported cases of the development of fatal and non-lethal liver failure, which were recorded in patients taking statins, including simvastatin. If treatment with simvastatin causes serious liver damage with clinical symptoms and / or hyperbilirubinemia or jaundice, discontinue therapy immediately. If an alternative etiology is not defined, do not resume the use of the drug.

The drug should be used with caution in patients who abuse alcohol.

As with the use of other drugs that lower lipid levels, moderate (less than 3 times compared with the upper limit of normal) increases in plasma transaminase activity in the treatment with simvastatin were reported. Such changes occurred shortly after the start of treatment, often were temporary, were not accompanied by any symptoms and did not require discontinuation of therapy.

Diabetes.Some evidence suggests that statins as a class increase blood glucose, and in some patients with a high risk of developing diabetes in the future, they can cause an increase in blood glucose, in which treatment for diabetes is recommended. However, over such a risk, the benefits of reducing the risk of developing cardiovascular disease with statins prevail, so this should not be a reason for stopping treatment. There is reason for periodic clinical and biochemical monitoring of glycemia in patients at risk (fasting glucose of 5.6–6.9 mmol / l, body mass index 30 kg / m², increase in the level of TG, AG) according to current recommendations.

Interstitial lung disease. Cases of interstitial lung disease have been reported with some statins, including simvastatin, especially with long-term therapy. Manifestations may include dyspnea, an unproductive cough, and worsening general condition (increased fatigue, weight loss, and fever). If a patient is suspected to have developed interstitial lung disease, treatment with statin should be discontinued.

Ophthalmologic examination. In the absence of any drug treatment, an increase in the area of ​​lens opacification is considered a consequence of the aging process. Currently known data do not indicate the existence of a harmful effect of simvastatin on the lens of the human eye.

Use in elderly patients. The efficacy of simvastatin for the treatment of patients over 65 years of age who received it during controlled clinical trials was evaluated relative to the decrease in the levels of total and LDL cholesterol and turned out to be the same as for the general population. An increase in the frequency of side effects that would be manifested clinically or in laboratory indicators was not noted.

The drug contains lactose. Patients with a rare hereditary form of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption syndrome should not take this drug.

Use during pregnancy or lactation

Pregnancy. Simvastatin is contraindicated during pregnancy, since the safety of the drug in pregnant women has not been established. Controlled clinical trials involving pregnant women have not been conducted. Rarely reported on the development of congenital pathology with intrauterine exposure to HMG-CoA reductase inhibitors. However, when analyzing the data obtained during subsequent observation of about 200 pregnant women who used simvastatin or other similar HMG-CoA reductase inhibitors in the first trimester of pregnancy, it was found that the incidence of congenital pathology was comparable with the frequency in the general population. Observation of such a number of pregnancies was statistically sufficient to exclude an increase in the frequency of congenital anomalies by 2.5 or more times relative to the initial frequency.

Although there is no evidence that the incidence of congenital abnormalities in children of patients who have taken simvastatin or other similar HMG-CoA reductase inhibitors differs from the frequency in the general population, maternal treatment with simvastatin may be accompanied by a decrease in fetal mevalonate levels, which is a precursor of cholesterol biosynthesis. Atherosclerosis is a chronic process, and usually stopping the use of lipid-lowering drugs during pregnancy slightly affects the long-term risk associated with primary hypercholesterolemia. For these reasons, simvastatin should not be prescribed to pregnant women, persons planning a pregnancy, or if pregnancy is suspected. Treatment with simvastatin should be suspended for the period of pregnancy or until the absence of pregnancy is confirmed.

Lactation.It is not known whether simvastatin and its metabolites pass into breast milk. Since a significant amount of the drug passes into breast milk, as well as due to the high risk of serious adverse reactions, women taking simvastatin should not breast-feed.

The ability to influence the reaction rate when driving vehicles or other mechanisms. Simvastatin does not or does not significantly affect the ability to drive vehicles and mechanisms. However, when driving vehicles or working with other mechanisms, it should be borne in mind that dizziness was rarely reported during the post-marketing research period.

Interactions

Interaction studies were conducted only with adults.

Pharmacodynamic interaction

Interactions with lipid-lowering drugs, which can lead to