Simvastatin 40 ananta: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT SIMVASTATIN 20 ANANTA SIMVASTAT 40 ANANTA (SIMVASTATIN 20 ANANTA SIMVASTATIN 40 ANANTA)

Composition:

Active substance: simvastatin;

1 tablet contains simvastatin EP 20 mg or 40 mg;

Excipients: lactose monohydrate; microcrystalline cellulose; pregelatinized starch; butylhydroxyanisole (E 320); ascorbic acid (E 300); anhydrous citric acid (E 330); ethanol 96 %; purified water; colloidal anhydrous silicon dioxide; talc; magnesium stearate;

Film coating: hypromellose, iron oxide red (E 172), iron oxide yellow (E 172), triethyl citrate, titanium dioxide (E 171), talc, povidone, purified water.

Pharmaceutical form. Film-coated tablets.

Main physicochemical properties:

SIMVASTATIN 20 ANANTA: film-coated, oval, biconvex tablets of beige to yellow-brown color.

SIMVASTATIN 40 ANANTA: film-coated, oval, biconvex tablets of peach to red-brown color.

Pharmacotherapeutic group.

Lipid-lowering agents, single component. HMG-CoA reductase inhibitors. ATC code C10AA01.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action.

Simvastatin, an inactive lactone, is hydrolyzed in the liver to the corresponding beta-hydroxyacid form after oral administration. This form is a potent inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, the enzyme that catalyzes the conversion of HMG-CoA to mevalonate, the initial and rate-limiting step in cholesterol biosynthesis.

Simvastatin has been shown to reduce both normal and elevated levels of low-density lipoprotein cholesterol (LDL-C). Low-density lipoproteins (LDL) are derived from very-low-density lipoproteins (VLDL) and are primarily catabolized by high-affinity LDL receptors. The LDL-lowering effect of simvastatin may be due to both a reduction in VLDL-cholesterol (VLDL-C) levels and an upregulation of LDL receptors, leading to decreased production and increased catabolism of LDL-C. Simvastatin also significantly reduces apolipoprotein B levels. In addition, simvastatin moderately increases high-density lipoprotein cholesterol (HDL-C) and reduces plasma triglyceride levels. As a result of these changes, the ratios of total cholesterol to HDL-C and LDL-C to HDL-C are reduced.

Clinical efficacy and safety.

High risk of ischemic heart disease (IHD) or existing ischemic heart disease.

In the Heart Protection Study (HPS), the efficacy of simvastatin treatment was evaluated in 20,536 patients (aged 40–80 years) with or without hyperlipidemia who were at high risk of developing ischemic heart disease due to other occlusive arterial diseases or diabetes mellitus. In this study, 10,269 patients received simvastatin 40 mg daily and 10,267 patients received placebo; the mean duration of treatment was 5 years. At baseline, LDL-C levels were below 116 mg/dL in 6,793 patients (33%), between 116–135 mg/dL in 5,063 patients (25%), and above 135 mg/dL in 8,680 patients (42%).

Treatment with simvastatin 40 mg daily significantly reduced the risk of all-cause mortality compared to placebo (1,328 [12.9%] in the simvastatin group vs. 1,507 [14.7%] in the placebo group; p = 0.0003), due to an 18% reduction in coronary mortality (587 [5.7%] vs. 707 [6.9%]; p = 0.0005; absolute risk reduction of 1.2%). The reduction in non-coronary mortality was not statistically significant. Simvastatin also reduced the risk of major coronary events (a composite endpoint of non-fatal myocardial infarction [MI] or death from IHD) by 27% (p < 0.0001).

Simvastatin reduced the need for coronary revascularization procedures (including coronary artery bypass grafting or percutaneous transluminal coronary angioplasty), peripheral and other non-coronary revascularization procedures by 30% (p < 0.0001) and 16% (p = 0.006), respectively. Simvastatin reduced the risk of stroke by 25% (p < 0.0001), primarily due to a 30% reduction in ischemic stroke (p < 0.0001). In the subgroup of patients with diabetes mellitus, simvastatin reduced the risk of macrovascular complications, including peripheral revascularization procedures (surgery or angioplasty), lower limb amputations, or leg ulcers, by 21% (p = 0.0293). The proportional reduction in event rates was similar across all patient subgroups, including those without IHD but with cerebrovascular or peripheral arterial disease, both men and women, patients aged under or over 70 years at study entry, those with or without hypertension, and particularly in those with baseline LDL-C levels below 3.0 mmol/L.

In the Scandinavian Simvastatin Survival Study (4S), the effect of simvastatin therapy on total mortality was evaluated in 4,444 patients with IHD and baseline total cholesterol levels of 212–309 mg/dL (5.5–8.0 mmol/L). This multicenter, randomized, double-blind, placebo-controlled study included patients with angina or prior myocardial infarction (MI) who received diet, standard therapy, and either simvastatin 20–40 mg daily (n = 2,221) or placebo (n = 2,223); the mean treatment duration was 5.4 years. Simvastatin reduced the risk of death by 30% (absolute risk reduction of 3.3%). The risk of death from IHD decreased by 42% (absolute risk reduction of 3.5%). Simvastatin also reduced the incidence of major coronary events (fatal IHD and clinically confirmed non-fatal MI) by 34%. Additionally, simvastatin significantly reduced the risk of fatal and non-fatal cerebrovascular events (stroke, transient ischemic attack) by 28%. No statistically significant differences were observed between treatment groups regarding non-cardiovascular mortality.

The Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) compared the effects of simvastatin 80 mg versus 20 mg (mean follow-up period 6.7 years) on major vascular events (defined as fatal IHD, non-fatal MI, coronary revascularization procedures, non-fatal stroke or fatal stroke, peripheral revascularization procedures) in 12,064 patients with prior MI. No significant difference between the two groups was observed: 20 mg simvastatin (n = 1,553; 25.7%) vs. 80 mg simvastatin (n = 1,477; 24.5%); OR 0.94, 95% CI: 0.88–1.01. The absolute difference in LDL-C levels between the two groups during the study was 0.35 ± 0.01 mmol/L. The safety profile was similar in both treatment groups, except for the incidence of myopathy, which was approximately 1.0% in patients receiving 80 mg simvastatin compared to 0.02% in those receiving 20 mg simvastatin. About half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy in subsequent years was approximately 0.1%.

Primary hypercholesterolemia and combined hyperlipidemia.

In studies comparing the efficacy and safety of simvastatin at doses of 10, 20, 40, and 80 mg daily in patients with hypercholesterolemia, the mean reduction in LDL-C levels was 30%, 38%, 41%, and 47%, respectively. In studies of patients with combined (mixed) hyperlipidemia receiving simvastatin at 40 mg and 80 mg, the mean reduction in triglycerides was 28% and 33% (placebo: 2%), respectively, and the mean increase in HDL-C was 13% and 16% (placebo: 3%), respectively.

Clinical studies in adolescents aged 10–17 years.

In a double-blind, placebo-controlled study, 175 patients (99 boys at Tanner stage II or higher and 76 girls with at least one year of menstrual cycles) aged 10–17 years (mean age 14.1 years) with heterozygous familial hypercholesterolemia were randomized to receive simvastatin or placebo for 24 weeks (core study). Eligibility required an LDL-C level of 160–400 mg/dL and at least one parent with an LDL-C level >189 mg/dL. The simvastatin dose was 10 mg once daily in the evening for the first 8 weeks, 20 mg for the next 8 weeks, and then 40 mg. A total of 144 patients participated in a 24-week extension study receiving either 40 mg simvastatin or placebo.

Simvastatin significantly reduced plasma levels of LDL-C, triglycerides, and apolipoprotein B. Results at 48 weeks were compared with those from the core study.

After 24 weeks of treatment, the mean LDL-C level was 124.9 mg/dL (range 64.0–289.0 mg/dL) in the simvastatin 40 mg group compared to 207.8 mg/dL (range 128.0–334.0 mg/dL) in the placebo group.

After 24 weeks of treatment with simvastatin (with dose escalation from 10 to 20 to 40 mg daily at 8-week intervals), the mean reductions from baseline were 36.8% for LDL-C (placebo: +1.1%), 32.4% for apolipoprotein B (placebo: +0.5%), and 7.9% for triglycerides (placebo: +3.2%), with an 8.3% increase in HDL-C (placebo: +3.6%). The long-term effect of simvastatin treatment on cardiovascular events in children with heterozygous familial hypercholesterolemia is unknown.

The safety and efficacy of doses exceeding 40 mg daily in children and adolescents with heterozygous familial hypercholesterolemia have not been studied. The long-term effect of simvastatin treatment in children on reducing morbidity and mortality in adulthood has not been investigated.

Pharmacokinetics.

Simvastatin is an inactive lactone that is readily hydrolyzed in vivo to the corresponding beta-hydroxyacid, a potent inhibitor of HMG-CoA reductase. Hydrolysis occurs primarily in the liver; the rate of hydrolysis in human plasma is very low.

Pharmacokinetic properties were evaluated in adults.

Pharmacokinetic data in children and adolescents are lacking.

Absorption.

In humans, simvastatin is well absorbed and undergoes extensive first-pass hepatic metabolism. Hepatic uptake depends on hepatic blood flow. The liver is the primary site of action of the active form. The systemic bioavailability of the beta-hydroxyacid after oral administration of simvastatin is less than 5% of the dose. Maximum concentrations of active inhibitors in plasma are reached approximately 1–2 hours after simvastatin administration. Food intake does not affect absorption. Pharmacokinetics of single and repeated doses of simvastatin showed no accumulation of the drug after repeated dosing.

Distribution.

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

Elimination.

Simvastatin is a substrate of CYP3A4. The main metabolites present in plasma are the beta-hydroxyacid and four additional active metabolites. After oral administration of radiolabeled simvastatin in humans, 13% was excreted in urine and 60% in feces within 96 hours. The amount recovered in feces represents both absorbed drug excreted in bile and unabsorbed drug. After intravenous administration of the beta-hydroxyacid metabolite, the mean elimination half-life was 1.9 hours. On average, only 0.3% of the intravenous dose was excreted in urine as inhibitors.

Simvastatin acid is actively taken up by hepatocytes via the OATP1B1 transporter.

Simvastatin is a substrate of the efflux transporter breast cancer resistance protein (BCRP).

SLCO1B1 polymorphism.

Carriers of the c.521T > C allele of the SLCO1B1 gene exhibit reduced OATP1B1 transporter activity. The mean exposure (AUC) of the main active metabolite—simvastatin acid—is 120% higher in heterozygous carriers (CT) and 221% higher in homozygous carriers (CC) compared to patients with the most common genotype (TT). The C allele occurs with a frequency of 18% in the European population, and the homozygous CC genotype is found in 1.5% of individuals. Patients with SLCO1B1 polymorphism are at increased risk of elevated simvastatin acid exposure, which increases the risk of rhabdomyolysis (see section "Special precautions for use").

Preclinical data.

Based on traditional animal studies of pharmacodynamics, repeat-dose toxicity, genotoxicity, and carcinogenicity, no additional risks were observed in patients beyond those expected from the pharmacological mechanisms of simvastatin. At the maximum tolerated dose in rats and rabbits, simvastatin did not cause fetal developmental abnormalities and had no effect on fertility, reproduction, or neonatal development.

Clinical characteristics.

Indications.

Hypercholesterolemia.

Treatment of primary hypercholesterolemia or mixed dyslipidemia, as an adjunct to diet, when response to diet and other nonpharmacological treatments (e.g., exercise, weight reduction) is inadequate.

Treatment of homozygous familial hypercholesterolemia as an adjunct to diet and other lipid-lowering therapies (e.g., low-density lipoprotein apheresis) or when such treatment modalities are not suitable.

Cardiovascular prevention.

Reduction of cardiovascular mortality and morbidity in patients with established atherosclerotic cardiovascular disease or diabetes, with normal or elevated cholesterol levels, as an additional therapy to correct other risk factors and alongside other cardioprotective therapies (see section "Pharmacological properties, Pharmacodynamics").

Contraindications.

Hypersensitivity to simvastatin or to any component of the medicinal product.
Active liver disease or unexplained and persistent elevations in serum transaminase levels.
Pregnancy or breastfeeding (see section "Use in pregnancy or breastfeeding").
Concomitant use of strong CYP3A4 inhibitors (agents that increase AUC by approximately 5-fold or more), such as itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, and nefazodone, and medicinal products containing cobicistat (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interactions").
Concomitant use of gemfibrozil, cyclosporine, or danazol (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interactions").
Contraindicated in patients with homozygous familial hypercholesterolemia receiving lomitapide and simvastatin in doses exceeding 40 mg (see sections "Special precautions for use", "Interaction with other medicinal products and other forms of interactions", and "Dosage and administration").

Interaction with other medicinal products and other forms of interactions.

Several mechanisms may contribute to interactions with HMG-CoA reductase inhibitors. Medicinal products or herbal preparations that inhibit certain enzyme pathways (e.g., CYP3A4) and/or transporters (e.g., OATP1B1) may increase plasma concentrations of simvastatin and simvastatin acid, leading to myopathy/rhabdomyolysis.

It is necessary to consult the instructions for medical use of concomitantly administered medicinal products to obtain additional information on their potential interaction with simvastatin, changes in enzymes or transporters, and possible dose adjustments and treatment regimens.

Interaction studies have been conducted only in adults.

Pharmacodynamic interaction.

Interactions with lipid-lowering medicinal products that may cause myopathy when used individually.

The risk of myopathy, including rhabdomyolysis, increases when administered concomitantly with fibrates. In addition, a pharmacokinetic interaction with gemfibrozil occurs, resulting in increased plasma levels of simvastatin (see subsection "Pharmacokinetic interaction" below and sections "Contraindications" and "Special precautions for use"). Regarding the combination of simvastatin and fenofibrate, there is no evidence that the risk of myopathy exceeds the sum of risks associated with each individual agent. Adequate data from pharmacovigilance and pharmacokinetic studies for other fibrates are lacking.

Occasionally, cases of myopathy/rhabdomyolysis have been associated with concomitant use of simvastatin and lipid-modifying doses (≥1 g/day) of niacin (see section "Special precautions for use").

Pharmacokinetic interaction.

Recommendations for concomitant administration of medicinal products interacting with simvastatin are summarized in the table below (see sections "Dosage and administration", "Contraindications", "Special precautions for use").

Interaction with other medicinal products associated with an increased risk of myopathy/rhabdomyolysis
Interacting medicinal products	Appropriate recommendations
Potent CYP3A4 inhibitors, for example: Itraconazole Ketoconazole Posaconazole Voriconazole Erythromycin Clarithromycin Telithromycin HIV protease inhibitors (e.g., nelfinavir) Boceprevir Telaprevir Nefazodone Cobicistat Cyclosporine Danazol Gemfibrozil	Contraindicated with simvastatin
Other fibrates (except fenofibrate)	Do not exceed 10 mg of simvastatin daily
Fusidic acid	Not recommended with simvastatin
Niacin (nicotinic acid) (≥ 1 g/day)	Not recommended to administer together with simvastatin to Asian patients
Amiodarone Amlodipine Verapamil Diltiazem Elbasvir Grazoprevir	Do not exceed 20 mg of simvastatin daily
Lomitapide	In patients with homozygous familial hypercholesterolemia (HoFH), simvastatin should be administered at doses not exceeding 40 mg daily.
Daptomycin	Consider temporary discontinuation of simvastatin in patients receiving daptomycin if benefit does not outweigh risk (see section "Special warnings and precautions for use").
Ticagrelor	Doses exceeding 40 mg of simvastatin daily are not recommended
Grapefruit juice	Avoid consumption of grapefruit juice when taking simvastatin

Effects of other medicinal products on simvastatin

Interaction with CYP3A4 inhibitors

Simvastatin is a substrate of cytochrome P450 3A4. Potent inhibitors of cytochrome P450 3A4 increase the risk of myopathy and rhabdomyolysis due to elevated plasma concentrations of HMG-CoA reductase inhibitory activity during simvastatin therapy. Such inhibitors include itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, nefazodone, and medicinal products containing cobicistat. Concomitant administration of itraconazole resulted in more than a 10-fold increase in exposure to simvastatin acid (the active beta-hydroxyacid metabolite). Telithromycin led to an 11-fold increase in exposure to simvastatin acid.

Combination with itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat, as well as with gemfibrozil, cyclosporine, and danazol, is contraindicated (see section "Contraindications").

If therapy with potent CYP3A4 inhibitors (agents increasing AUC approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be suspended (and consideration given to using an alternative statin) during such treatment. Caution is advised when combining simvastatin with other, less potent CYP3A4 inhibitors: fluconazole, verapamil, or diltiazem (see sections "Dosage and administration" and "Special precautions").

Fluconazole

Rare cases of rhabdomyolysis associated with concomitant use of simvastatin and fluconazole have been reported (see section "Special precautions").

Cyclosporine

The risk of developing myopathy/rhabdomyolysis increases when cyclosporine is co-administered with simvastatin; therefore, combination with cyclosporine is contraindicated (see sections "Contraindications" and "Special precautions"). Although the mechanism of action is not fully understood, it has been demonstrated that cyclosporine increases the AUC of HMG-CoA reductase inhibitors. The increase in simvastatin AUC occurs primarily partly through inhibition of CYP3A4 and/or the OATP1B1 transporter protein.

Danazol

The risk of developing myopathy and rhabdomyolysis increases with concomitant administration of danazol and simvastatin; therefore, combination with danazol is contraindicated (see sections "Contraindications" and "Special precautions").

Gemfibrozil

Gemfibrozil increases the AUC of simvastatin acid by 1.9-fold, possibly due to inhibition of the glucuronidation pathway and/or the OATP1B1 transporter protein (see sections "Contraindications" and "Special precautions"). Concomitant use with gemfibrozil is contraindicated.

Fusidic acid

The risk of myopathy, including rhabdomyolysis, increases during concomitant use of systemic fusidic acid and statins. The mechanism of this interaction (pharmacodynamic, pharmacokinetic, or both) is not yet known. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients receiving this combination. If systemic treatment with fusidic acid is required, simvastatin therapy should be discontinued during this period (see section "Special precautions"). Use of this combination may lead to increased plasma concentrations of both agents.

Amiodarone

The risk of developing myopathy and rhabdomyolysis increases during concomitant use of simvastatin and amiodarone (see section "Special precautions"). In a clinical study, myopathy was reported in 6% of patients receiving simvastatin 80 mg and amiodarone. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients taking this drug concomitantly with amiodarone.

Calcium channel blockers

Verapamil: The risk of developing myopathy and rhabdomyolysis increases when verapamil is used concomitantly with simvastatin 40 mg or 80 mg (see section "Special precautions"). Concomitant use with verapamil is known to result in a 2.3-fold increase in exposure to simvastatin acid, primarily partly due to CYP3A4 inhibition. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving verapamil concomitantly.
Diltiazem: The risk of developing myopathy and rhabdomyolysis increases when diltiazem is used concomitantly with simvastatin 80 mg (see section "Special precautions"). Concomitant use with diltiazem is known to result in a 2.7-fold increase in exposure to simvastatin acid, primarily partly due to CYP3A4 inhibition. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving diltiazem concomitantly.
Amlodipine: Patients taking amlodipine concomitantly with simvastatin have an increased risk of developing myopathy. Concomitant use with amlodipine is known to result in a 1.6-fold increase in exposure to simvastatin acid. Therefore, the dose of simvastatin should not exceed 20 mg daily in patients receiving amlodipine concomitantly.
Lomitapide*

The risk of myopathy and rhabdomyolysis increases when lomitapide is used concomitantly with simvastatin (see sections "Dosage and administration", "Contraindications", and "Special precautions"). Therefore, in patients with HoFH receiving concomitant lomitapide, the dose of simvastatin should not exceed 40 mg daily.

Moderate CYP3A4 inhibitors

Patients taking other medicinal products that moderately inhibit CYP3A4 concomitantly with simvastatin, especially with high doses of simvastatin, have an increased risk of developing myopathy (see section "Special precautions").

Inhibitors of the OATP1B1 transporter protein

Simvastatin acid is a substrate of the OATP1B1 transporter protein. Concomitant administration of medicinal products that are inhibitors of the OATP1B1 transporter protein may lead to increased plasma concentrations of simvastatin acid and development of myopathy (see sections "Contraindications" and "Special precautions").

Inhibitors of breast cancer resistance protein (BCRP)

Concomitant use with BCRP inhibitors (including medicinal products containing elbasvir or grazoprevir) may lead to increased plasma concentrations of simvastatin and development of myopathy (see sections "Dosage and administration" and "Special precautions").

Niacin (nicotinic acid)

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant use of lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid). In a pharmacokinetic study, concomitant administration of a single 2 g dose of extended-release niacin with simvastatin 20 mg resulted in a moderate increase in AUC of simvastatin and simvastatin acid, as well as in Cmax of simvastatin acid in plasma.

Ticagrelor*

Concomitant use of ticagrelor with simvastatin increased Cmax of simvastatin by 81% and AUC by 56%, and increased Cmax of simvastatin acid by 64% and AUC by 52% (in individual cases, increases of 2–3 times were observed). Concomitant use of ticagrelor with simvastatin at doses exceeding 40 mg daily may cause simvastatin-related adverse effects, which should be weighed against the potential benefit. No effect of simvastatin on plasma levels of ticagrelor was observed. Ticagrelor may have a similar effect on lovastatin. Concomitant use of ticagrelor with simvastatin at doses exceeding 40 mg daily is not recommended.

Grapefruit juice

Grapefruit juice inhibits cytochrome P450 3A4. Concomitant intake of large quantities (more than 1 litre per day) of grapefruit juice and simvastatin resulted in a sevenfold increase in drug activity. Consumption of 240 ml of grapefruit juice in the morning with evening simvastatin also led to a 1.9-fold increase in effect. Therefore, grapefruit juice should be avoided during simvastatin treatment.

Colchicine

Cases of myopathy and rhabdomyolysis have been reported with concomitant use of colchicine and simvastatin in patients with renal impairment. Careful clinical monitoring of patients receiving this combination is recommended.

Daptomycin

The risk of developing myopathy and/or rhabdomyolysis may be increased with concomitant use of HMG-CoA reductase inhibitors (e.g., simvastatin) and daptomycin (see section "Special precautions").

Rifampicin

Since rifampicin is a potent inducer of CYP3A4, loss of efficacy of simvastatin may occur in patients undergoing long-term rifampicin therapy (e.g., for tuberculosis treatment). In a pharmacokinetic study in healthy volunteers, the area under the concentration-time curve (AUC) of simvastatin acid decreased by 93% with concomitant administration of rifampicin.

Effect of simvastatin on the pharmacokinetics of other medicinal products.

Simvastatin does not have an inhibitory effect on cytochrome P450 3A4. Therefore, it is not expected that simvastatin will affect plasma concentrations of substances metabolized by cytochrome P450 3A4.

Oral anticoagulants

In two clinical studies, one involving healthy volunteers and the other involving patients with hypercholesterolemia, simvastatin at doses of 20–40 mg/day moderately increased the effect of coumarin anticoagulants: prothrombin time, measured as the international normalized ratio (INR), increased from a baseline value of 1.7 to 1.8 and from 2.6 to 3.4 in healthy volunteers and patients, respectively. Very rare cases of elevated INR values have been observed. In patients receiving coumarin anticoagulants, prothrombin time should be determined before starting simvastatin therapy and frequently monitored at the beginning of treatment to ensure no significant change in prothrombin time has occurred. Once a stable prothrombin time level is achieved, monitoring should continue at intervals normally recommended for patients receiving coumarin anticoagulant therapy. Prothrombin time should also be monitored when changing or discontinuing simvastatin dosage. Simvastatin therapy is not associated with bleeding or changes in prothrombin time in patients not taking anticoagulants.

Special precautions for use.

Myopathy/rhabdomyolysis.

Simvastatin, like other HMG-CoA reductase inhibitors, may cause myopathy, which is manifested by muscle pain, tenderness or weakness and is accompanied by an increase in creatine phosphokinase activity more than 10 times above the upper limit of normal (ULN). Myopathy sometimes progresses to rhabdomyolysis with or without acute renal failure caused by myoglobinuria, and very rarely leads to fatal outcomes. The risk of developing myopathy increases with high levels of HMG-CoA reductase inhibitory activity in plasma (elevated plasma levels of simvastatin and simvastatin acid), which may be partially related to interactions with medicinal products that interfere with the metabolism and/or transport of simvastatin (see section "Interaction with other medicinal products and other types of interactions").

As with other HMG-CoA reductase inhibitors, the risk of developing myopathy/rhabdomyolysis depends on the dose of the drug. In the clinical trial database, where 41,413 patients received simvastatin, of whom 24,747 (approximately 60%) were enrolled in studies with a mean observation period of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08%, and 0.61% at doses of 20, 40, and 80 mg daily, respectively. During these trials, patients were closely monitored, and certain concomitantly used medicinal products with potential interactions were excluded.

In a clinical trial where patients with a history of myocardial infarction received simvastatin 80 mg daily (mean observation period of 6.7 years), the incidence of myopathy was approximately 1.0% compared to 0.02% in patients receiving simvastatin 20 mg daily. Approximately half of these cases of myopathy were observed during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1% (see sections "Pharmacological properties" and "Adverse reactions").

The risk of myopathy is higher in patients receiving 80 mg simvastatin compared to patients receiving other statins with similar efficacy in lowering LDL-C. Therefore, the 80 mg dose of simvastatin should only be used in patients with severe hypercholesterolemia and a high risk of cardiovascular complications who have not achieved treatment goals at lower doses, and when the expected benefit outweighs the potential risks. For patients taking simvastatin 80 mg who require a drug that interacts, a lower dose of simvastatin or an alternative statin with a lower potential for interaction with other medicinal products should be used (see below "Measures to reduce the risk of myopathy caused by interaction with other medicinal products," as well as sections "Contraindications," "Interaction with other medicinal products and other types of interactions," and "Dosage and administration").

In a clinical trial where patients at high risk of cardiovascular disease received simvastatin 40 mg daily (median observation period of 3.9 years), the incidence of myopathy was approximately 0.05% in non-Chinese patients (n=7,367) compared to 0.24% in Chinese patients (n=5,468). Although the Asian population in this clinical trial was represented only by Chinese patients, simvastatin should be used with caution in patients of Asian origin, prescribing the lowest dose.

In isolated cases, statins have been reported to induce de novo or exacerbate existing myasthenia gravis or ocular myasthenia (see section "Adverse reactions"). If symptoms worsen, simvastatin should be discontinued. Recurrences have been reported upon re-administration of the same or another statin.

Reduced function of transporter proteins.

Reduced function of hepatic transporter proteins of the OATP family may increase systemic exposure to simvastatin acid and increase the risk of myopathy and rhabdomyolysis. Reduced function may result from inhibition by interacting agents (e.g., cyclosporine) or in patients who are carriers of the SLCO1B1 (c.521T > C) genotype.

In patients carrying the SLCO1B1 (c.521T > C) allele, which encodes a less active OATP1B1 protein, increased systemic exposure to simvastatin acid and an increased risk of myopathy have been observed. Regardless of genetic testing, the overall risk of developing myopathy associated with high doses (80 mg) of simvastatin is approximately 1%. Results from the SEARCH study show that homozygous carriers of the C allele (designated CC) taking simvastatin 80 mg have a 15% risk of developing myopathy within one year, whereas the risk in heterozygous carriers of the C allele (CT) is 1.5%. The corresponding risk in patients with the most common genotype (TT) is 0.3% (see section "Pharmacokinetics"). Where possible, genotyping for the presence of the C allele should be performed before prescribing simvastatin 80 mg to individual patients as part of a benefit/risk assessment, and high doses should be avoided in those found to be CC genotype carriers. However, the absence of this gene by genotyping does not exclude the possibility of developing myopathy in these patients.

Measurement of creatine kinase.

Creatine kinase levels should not be measured after strenuous physical exercise or in the presence of any likely alternative cause of elevated creatine kinase, as this complicates interpretation of results. In cases of significant elevation of creatine kinase levels at baseline (more than 5 times ULN), levels should be re-measured after 5–7 days to confirm results.

Prior to treatment.

All patients initiating simvastatin therapy, as well as those whose simvastatin dose has been increased, should be warned about the possibility of developing myopathy and the need to seek immediate medical attention if any unexplained muscle pain, muscle tenderness, or muscle weakness occurs.

Caution should be exercised in patients with predisposing factors for rhabdomyolysis. To establish an appropriate baseline value, creatine kinase levels should be measured before starting treatment in the following situations:

advanced age (age ≥ 65 years);
female sex;
impaired renal function;
uncontrolled hypothyroidism;
personal or family history of inherited muscle disorders;
history of muscle toxicity due to 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 a patient previously experienced muscle disorders while taking a fibrate or statin, treatment with another agent of this class should be initiated with caution. Treatment should not be initiated if there is a significant initial elevation of creatine kinase levels (more than 5 times ULN).

During treatment.

If pain, weakness, or cramps occur during statin use, creatine kinase levels should be measured. If these levels are significantly elevated (> 5 times ULN) in the absence of strenuous physical exertion, treatment should be discontinued. If muscle symptoms are severe and cause daily discomfort, even if creatine kinase levels are < 5 times ULN, discontinuation of treatment may be considered. If myopathy is suspected for any other reason, treatment should be discontinued.

Very rare cases of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy occurring during or after statin treatment, have been reported. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels, which do not resolve despite discontinuation of statin use (see section "Adverse reactions").

If symptoms resolve and creatine kinase levels return to normal, re-initiation of the same statin or an alternative statin at a low dose with close monitoring should be considered.

A higher percentage of myopathy was observed in patients whose dose was increased to 80 mg (see section "Pharmacodynamics"). Periodic measurement of creatine kinase levels is recommended, as it may help detect subclinical cases of myopathy. However, there are no reliable data indicating that such monitoring can prevent the development of myopathy.

Simvastatin therapy should be temporarily discontinued in patients several days before elective major surgical procedures, as well as after medical or surgical interventions.

Measures to reduce the risk of myopathy caused by interaction with other medicinal products (see section "Interaction with other medicinal products and other types of interactions").

The risk of developing myopathy and rhabdomyolysis is significantly increased when simvastatin is co-administered with potent CYP3A4 inhibitors such as itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, nefazodone, medicinal products containing cobicistat, as well as with gemfibrozil, cyclosporine, and danazol. Concomitant use of these medicinal products is contraindicated (see section "Contraindications").

The risk of developing myopathy and rhabdomyolysis is also increased when amiodarone, amlodipine, verapamil, or diltiazem are co-administered with certain doses of simvastatin (see sections "Interaction with other medicinal products and other types of interactions" and "Dosage and administration"). The risk of developing myopathy, including rhabdomyolysis, increases when fusidic acid is co-administered with statins (see section "Interaction with other medicinal products and other types of interactions"). In patients with HoFH, this risk increases when lomitapide and simvastatin are used concomitantly.

Thus, concomitant use of simvastatin with CYP3A4 inhibitors, itraconazole, ketoconazole, posaconazole, voriconazole, HIV protease inhibitors (e.g., nelfinavir), boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin, nefazodone, and medicinal products containing cobicistat is contraindicated (see sections "Contraindications" and "Interaction with other medicinal products and other types of interactions"). If therapy with potent CYP3A4 inhibitors (drugs that increase AUC approximately 5-fold or more) cannot be discontinued, simvastatin therapy should be stopped during the administration of these drugs (and consideration should be given to using an alternative statin). Additionally, simvastatin should be used with caution when co-administered with certain less potent CYP3A4 inhibitors: fluconazole, verapamil, diltiazem (see sections "Interaction with other medicinal products and other types of interactions" and "Dosage and administration"). Grapefruit juice should be avoided during simvastatin use.

Concomitant use of simvastatin with gemfibrozil is contraindicated (see section "Contraindications"). Due to the increased risk of developing myopathy and rhabdomyolysis, the simvastatin dose should not exceed 10 mg daily for patients taking simvastatin with other fibrates except fenofibrate (see sections "Interaction with other medicinal products and other types of interactions" and "Dosage and administration"). Fenofibrate should be prescribed with caution together with simvastatin, as each of these drugs may cause myopathy.

Simvastatin should not be taken simultaneously with systemic preparations containing fusidic acid or within 7 days after discontinuation of fusidic acid. If fusidic acid is necessary, statin therapy should be discontinued for the entire duration of fusidic acid use. Cases of rhabdomyolysis (including several fatal cases) have been reported in patients taking the combination of fusidic acid and statins (see section "Interaction with other medicinal products and other types of interactions"). Patients should be advised to seek immediate medical attention if they experience symptoms of weakness, muscle pain, or other pain. Statin therapy may be resumed 7 days after the last dose of fusidic acid. In exceptional cases, when long-term systemic treatment with fusidic acid is necessary, e.g., for severe infections, concomitant use of simvastatin and fusidic acid may only be possible under strict medical supervision.

Concomitant use of simvastatin in doses exceeding 20 mg daily with amiodarone, amlodipine, verapamil, or diltiazem should be avoided. Concomitant use of lomitapide and simvastatin in doses exceeding 40 mg daily is contraindicated in patients with HoFH (see sections "Contraindications," "Interaction with other medicinal products and other types of interactions," and "Dosage and administration").

Patients taking other medicinal products with a moderate inhibitory effect on CYP3A4 concomitantly with simvastatin, especially with high doses of simvastatin, have an increased risk of developing myopathy. Dose adjustment of simvastatin may be required when co-administered with a moderate CYP3A4 inhibitor (drugs that increase AUC approximately 2–5 times). With co-administration of certain moderate CYP3A4 inhibitors, e.g., diltiazem, a maximum dose of 20 mg simvastatin is recommended (see section "Dosage and administration").

Simvastatin is a substrate of the breast cancer resistance protein (BCRP) efflux transporter. Concomitant use with BCRP inhibitors (e.g., elbasvir and grazoprevir) may lead to increased plasma concentrations of simvastatin and an increased risk of developing myopathy; dose adjustment of simvastatin should be considered depending on the dose of BCRP inhibitors prescribed. Concomitant use of elbasvir and grazoprevir with simvastatin has not been studied, but the daily dose of simvastatin should not exceed 20 mg for patients receiving concomitant therapy with medicinal products containing elbasvir or grazoprevir (see section "Interaction with other medicinal products and other types of interactions").

Rare cases of myopathy/rhabdomyolysis have been associated with concomitant use of HMG-CoA reductase inhibitors and lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid); each of these drugs may cause myopathy.

In a clinical trial (median observation period of 3.9 years) involving patients at high risk of cardiovascular disease with well-controlled LDL-C levels while receiving simvastatin 40 mg daily with or without ezetimibe 10 mg, no additional cardiovascular benefit was observed with the addition of lipid-modifying doses (≥1 g daily) of niacin (nicotinic acid). Physicians considering combined therapy of simvastatin with lipid-modifying doses (≥ 1 g/day) of niacin (nicotinic acid) or niacin-containing preparations should carefully weigh the potential benefits and risks. Patients should be closely monitored for the development of muscle pain, tenderness, or weakness, especially during the first months of therapy and when increasing the dose of any of these medicinal products.

In the study, the incidence of myopathy was approximately 0.24% among Chinese patients taking simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg, compared to 1.24% of Chinese patients receiving simvastatin 40 mg or ezetimibe/simvastatin 10/40 mg together with a combination medicinal product of modified-release niacin/laropiprant 2000 mg/40 mg. Although the Asian population in this clinical trial was represented only by Chinese patients, since the incidence of myopathy among Chinese patients is higher than among non-Chinese patients, concomitant use of simvastatin and lipid-modifying doses (≥ 1 g daily) of niacin (nicotinic acid) is not recommended in patients of Asian origin. Acipimox is structurally similar to niacin. Although acipimox has not been studied, the risk of developing muscle toxic effects may be similar to that with niacin.

Daptomycin.

Cases of myopathy and/or rhabdomyolysis have been reported with concomitant use of HMG-CoA reductase inhibitors and daptomycin. Caution should be exercised when prescribing HMG-CoA reductase inhibitors with daptomycin, as either agent may cause myopathy and/or rhabdomyolysis when used alone. Consideration should be given to temporarily discontinuing simvastatin in patients taking daptomycin if the benefit of concomitant use does not outweigh the risk. Information on daptomycin prescribing should be consulted for additional information on this potential interaction with HMG-CoA reductase inhibitors (e.g., simvastatin), as well as for further monitoring (see section "Interaction with other medicinal products and other types of interactions").

Liver effects.

Data indicate that in several adult patients receiving simvastatin, persistent elevations in serum transaminase levels (> 3 times ULN) were observed. Upon interruption or discontinuation of simvastatin in these patients, transaminase activity usually gradually returned to baseline levels.

Liver function tests are recommended for all patients before starting treatment and subsequently as clinically indicated. For patients whose simvastatin dose is planned to be increased to 80 mg daily, additional liver function tests should be performed before starting titration, then 3 months after reaching the 80 mg daily dose, followed by periodic repeat testing (e.g., once every 6 months) during the first year of treatment. Particular attention should be paid to patients with elevated serum transaminase levels. These patients should have liver function tests repeated immediately and more frequently thereafter. If transaminase levels increase, especially with persistent elevations exceeding ULN by 3 times, the drug should be discontinued. Alanine aminotransferase may originate from muscle tissue; therefore, elevations in alanine aminotransferase and creatine kinase may indicate myopathy (see above "Myopathy/rhabdomyolysis").

In the post-marketing period, rare cases of fatal and non-fatal liver failure have been reported in patients taking statins, including simvastatin. If serious liver injury with clinical symptoms of hyperbilirubinemia or jaundice occurs during treatment, therapy should be immediately discontinued. If no alternative etiology is identified, re-initiation of the drug should not be attempted.

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

With treatment with simvastatin, as with other lipid-lowering agents, mild (< 3 ULN) increases in serum transaminase activity have been reported. These changes occurred soon after the start of treatment, were often transient, were asymptomatic, and did not require discontinuation of therapy.

Diabetes mellitus.

Certain evidence indicates that statins as a class increase blood glucose levels and in some patients at high risk of developing diabetes in the future may cause hyperglycemia levels at which initiation of diabetes treatment is recommended. However, the benefit of statins in reducing vascular risk outweighs this risk, and therefore this should not be a reason for discontinuing statin therapy. The condition of patients at risk of developing diabetes (fasting glucose 5.6–6.9 mmol/L, BMI > 30 kg/m², elevated triglyceride levels, arterial hypertension) should be monitored both clinically and biochemically according to national guidelines.

Interstitial lung disease.

Cases of interstitial lung disease have been reported with the use of some statins, particularly with long-term therapy (see section "Adverse reactions"). Symptoms may include dyspnea, non-productive cough, and worsening general health (fatigue, weight loss, and fever). If interstitial lung disease is suspected in a patient, statin therapy should be discontinued.

Excipients.

The medicinal product contains lactose. Patients with established intolerance to certain sugars should consult their physician before taking this medicinal product.

The medicinal product contains a small amount of ethanol (alcohol), less than 100 mg per dose.

Use during pregnancy or breastfeeding.

Pregnancy.

The drug is contraindicated in pregnant women (see section "Dosage and administration").

The safety of the drug for pregnant women has not been established. No controlled clinical trials of simvastatin in pregnant women have been conducted. Rare reports of congenital anomalies after in utero exposure to HMG-CoA reductase inhibitors have been received. However, a prospective analysis of approximately 200 pregnancies with exposure to simvastatin or another similar HMG-CoA reductase inhibitor during the first trimester showed a rate of congenital anomalies comparable to that in the general population. This number of pregnancy cases was statistically sufficient to exclude an increase in congenital anomalies by 2.5 times or more compared to the general population. Although there is no evidence that the rate of congenital anomalies in offspring of patients who took simvastatin or another similar HMG-CoA reductase inhibitor differs from that observed in the general population, maternal treatment with simvastatin may reduce fetal levels of mevalonate, a precursor in cholesterol biosynthesis. Atherosclerosis is a chronic process, and discontinuation of lipid-lowering agents during pregnancy usually has minimal impact on the long-term risk associated with primary hypercholesterolemia. For these reasons, the drug should not be prescribed to pregnant women or to women attempting to become pregnant or suspected of being pregnant. Drug intake should be suspended for the entire duration of pregnancy or until pregnancy is ruled out (see sections "Contraindications" and "Preclinical data").

Breastfeeding.

It is unknown whether simvastatin or its metabolites pass into breast milk. Since a significant number of drugs pass into breast milk and due to the high risk of serious adverse reactions, women taking the drug should refrain from breastfeeding (see section "Dosage and administration").

Fertility.

There are no data from clinical studies on the effect of simvastatin on human fertility. Simvastatin did not affect fertility in male and female rats (see section "Preclinical data").

Ability to affect reaction speed when driving vehicles or operating machinery.

The medicinal product has no effect or a negligible effect on the ability to drive vehicles and operate machinery. However, when driving vehicles or operating other machinery, it should be considered that during the post-marketing use of simvastatin, rare cases of dizziness have been reported.

Method of Administration and Dosage.

Method of Administration.

The drug is administered orally. The drug may be taken once daily in the evening.

Dosage.

The daily dose of simvastatin ranges from 5 mg (use the drug at the corresponding dosage) to 80 mg orally once daily in the evening.

Dose adjustments, if necessary, should be made at intervals of no less than 4 weeks until the maximum daily dose of 80 mg is reached, taken once daily in the evening. The 80 mg dose is recommended only for patients with severe hypercholesterolemia and a high risk of cardiovascular complications who have not achieved treatment goals with lower doses and when the expected benefit outweighs potential risks (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use").

Hypercholesterolemia.

Patients should be placed on a standard cholesterol-lowering diet, which should be maintained throughout the course of simvastatin treatment. The usual initial dose is 10–20 mg once daily in the evening. For patients requiring a substantial reduction in LDL-C levels (more than 45%), the initial dose may be 20–40 mg once daily in the evening. Dose adjustments, if necessary, should be performed as described above.

Homogeneous Familial Hypercholesterolemia.

Based on results of a controlled clinical study, the recommended initial dose is 40 mg once daily in the evening. The drug should be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) or when such treatment is unavailable.

For patients concurrently taking lomitapide with simvastatin, the simvastatin dose should not exceed 40 mg/day (see sections "Contraindications", "Special Warnings and Precautions for Use", and "Interaction with Other Medicinal Products and Other Forms of Interaction").

Cardiovascular Prevention.

The usual dose of simvastatin for patients at high risk of developing ischemic heart disease (with or without hyperlipidemia) is 20–40 mg once daily in the evening. Pharmacological therapy may be initiated simultaneously with diet and physical exercise. Dose adjustments, if necessary, should be performed as described above.

Concomitant Therapy.

Simvastatin is effective as monotherapy and in combination with bile acid sequestrants. The dose should be administered more than 2 hours before or more than 4 hours after taking medicinal products that enhance bile acid excretion.

For patients taking simvastatin concomitantly with fibrates other than gemfibrozil (see section "Contraindications") or with fenofibrate, the simvastatin dose should not exceed 10 mg daily (use the drug at the corresponding dosage). For patients taking simvastatin concomitantly with amiodarone, amlodipine, verapamil, diltiazem, or products containing elbasvir or grazoprevir, the daily dose of simvastatin should not exceed 20 mg (see sections "Interaction with Other Medicinal Products and Other Forms of Interaction" and "Special Warnings and Precautions for Use").

Renal Impairment.

Patients with moderate renal impairment do not require dose adjustment. In patients with severe renal impairment (creatinine clearance < 30 mL/min), the benefit-risk balance of initiating treatment with a dose of 10 mg daily (use the drug at the corresponding dosage) should be carefully considered, and if such dosage is deemed necessary, the drug should be administered with caution.

Use in Elderly Patients.

No dose adjustment is required.

Use in Children and Adolescents (10–17 years).

For children and adolescents (boys at Tanner stage II or higher and girls who have had menstruation for at least 1 year) aged 10–17 years with heterozygous familial hypercholesterolemia, the recommended usual initial dose is 10 mg once daily in the evening (use the drug at the corresponding dosage). Prior to initiating simvastatin therapy, children and adolescents should be placed on a standard cholesterol-lowering diet, which should be maintained during treatment. Recommended doses are 10–40 mg daily; the maximum recommended daily dose is 40 mg. The dose should be individualized according to treatment goals and in accordance with pediatric treatment guidelines (see sections "Pharmacodynamics" and "Special Warnings and Precautions for Use"). Dose titration should be performed at intervals of 4 weeks or longer.

Experience with simvastatin in prepubertal children is limited.

Children.

Data on the safety and efficacy of simvastatin are available for children (girls who have had menstruation for at least 1 year and boys at Tanner stage II or higher) aged 10–17 years with heterozygous familial hyperlipidemia. The adverse effect profile in patients taking simvastatin was similar to that in patients receiving placebo. Doses higher than 40 mg have not been studied in this patient group. During the study, no effects of simvastatin on growth, sexual development, or menstrual cycle duration in girls were observed (see sections "Pharmacodynamics", "Method of Administration and Dosage", and "Adverse Reactions").

Girls should be counseled regarding contraception methods when using simvastatin (see sections "Contraindications" and "Use During Pregnancy or Breastfeeding").

In patients under 18 years of age, efficacy and safety have not been studied for treatment periods longer than 48 weeks; the long-term effects on physical, cognitive, and sexual development are unknown.

Simvastatin has not been studied in patients under 10 years of age, prepubertal children, or girls who have not yet started menstruation.

Overdose.

Several cases of overdose are known to date. The maximum ingested dose was 3.6 g. All patients recovered without sequelae. There is no specific antidote for simvastatin overdose. In case of overdose, symptomatic and supportive measures should be employed.

Adverse Reactions

The frequency of the adverse reactions listed below, reported during clinical trials and/or in the post-marketing period, has been classified based on their incidence observed in large, long-term, placebo-controlled clinical studies, including HPS and 4S, involving 20,536 and 4,444 patients, respectively (see section "Pharmacodynamics").

In HPS, only serious adverse reactions, as well as myalgia, elevated serum transaminases, and creatine kinase were recorded. In 4S, all the adverse reactions listed below were documented. If the incidence during these studies was lower or similar with simvastatin compared to placebo, and spontaneous reports of events with a reasonable causal relationship were similar, such adverse reactions were classified as rare.

In the HPS study (see section "Pharmacodynamics"), involving 20,536 patients receiving 40 mg/day simvastatin (n=10,269) or placebo (n=10,267), the safety profiles were comparable between patients receiving simvastatin 40 mg and those receiving placebo over a mean study duration of 5 years. Rates of discontinuation due to adverse reactions were similar (4.8% in patients receiving simvastatin 40 mg versus 5.1% in those receiving placebo). The incidence of myopathy was <0.1% in patients receiving simvastatin 40 mg. Elevated transaminases (>3 times the upper limit of normal, confirmed by repeat testing) occurred in 0.21% (n=21) of patients receiving simvastatin 40 mg, compared to 0.09% (n=9) of patients receiving placebo.

Frequency of adverse reactions: very common (> 1/10), common (≥ 1/100, < 1/10), uncommon (≥ 1/1,000, < 1/100), rare (≥ 1/10,000, < 1/1,000), very rare (< 1/10,000), unknown (cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare – anaemia.

Immune system disorders:

Very rare – anaphylaxis.

Psychiatric disorders:

Very rare – insomnia.

Unknown – depression.

Nervous system disorders:

Uncommon – headache, paraesthesia, dizziness, peripheral neuropathy;

Very rare – memory impairment.

Unknown – myasthenia gravis.

Eye disorders:

Uncommon – blurred vision, worsening of vision.

Unknown – ocular myasthenia.

Respiratory, thoracic and mediastinal disorders:

Unknown – interstitial lung disease (see section "Special precautions for use").

Gastrointestinal disorders:

Uncommon – constipation, abdominal pain, flatulence, dyspepsia, diarrhoea, nausea, vomiting, pancreatitis.

Hepatobiliary disorders:

Uncommon – hepatitis/jaundice.

Very rare – fatal and non-fatal hepatic failure.

Skin and subcutaneous tissue disorders:

Uncommon – rash, pruritus, alopecia.

Very rare – lichenoid skin reactions.

Musculoskeletal and connective tissue disorders:

Uncommon – myopathy* (including myositis), rhabdomyolysis with acute renal failure (see section "Special precautions for use"), myalgia, muscle spasms.

* Myopathy occurred more frequently in patients receiving simvastatin 80 mg daily compared to those receiving 20 mg daily (0.1% vs. 0.02%, respectively) (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Very rare – muscle rupture.

Unknown – tendonopathy, sometimes complicated by rupture, immune-mediated necrotizing myopathy**.

** Very rare cases of immune-mediated necrotizing myopathy (IMNM), an autoimmune myopathy, have been observed during or after statin therapy. IMNM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels, which do not resolve despite discontinuation of statins, necrotizing myopathy features on muscle biopsy without significant inflammation, and improvement with immunosuppressive therapy (see section "Special precautions for use").

Reproductive system and breast disorders:

Very rare – gynaecomastia.

Unknown – erectile dysfunction.

General disorders:

Uncommon – asthenia.

Occasionally reported is a hypersensitivity syndrome including: angioneurotic oedema, lupus-like syndrome, polymyalgia rheumatica, dermatomyositis, vasculitis, thrombocytopenia, eosinophilia, increased erythrocyte sedimentation rate (ESR), arthritis and arthralgia, urticaria, photosensitivity, fever, flushing, dyspnoea, and weakness.

Investigations:

Uncommon – increased serum transaminases (alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase) (see section "Special precautions for use. Effect on the liver"); increased alkaline phosphatase; increased serum creatine kinase levels (see section "Special precautions for use").

With statin use, increases in HbA1c and fasting plasma glucose levels have been reported. During the post-marketing period, rare reports of cognitive impairment (e.g., memory loss, forgetfulness, amnesia, memory impairment, confusion) associated with statin use, including simvastatin, have been received. Overall, these cases were non-serious and reversible upon discontinuation of the statin; the time to onset of symptoms (from 1 day to several years) and resolution (on average 3 weeks) varied.

With some statins, the following additional adverse reactions have been reported:

Sleep disorders, including nightmares;
Sexual dysfunction;
Diabetes mellitus: frequency of occurrence depends on the presence or absence of risk factors (fasting plasma glucose ≥ 5.6 mmol/L, body mass index > 30 kg/m², elevated triglycerides, history of hypertension).

Children and adolescents (aged 10–17 years)

In a 48-week study involving children and adolescents (boys at Tanner stage II or higher and girls with at least one year of menstrual history), aged 10–17 years, with heterozygous familial hypercholesterolaemia (n = 175), the safety and tolerability profile in patients receiving simvastatin was generally similar to that in patients receiving placebo. Long-term effects on physical, intellectual, and sexual development are unknown. There is insufficient data beyond one year of treatment (see sections "Pharmacodynamics", "Dosage and administration", and "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after a medicinal product is authorised is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, or their legal representatives should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua

Shelf life. 3 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 30 °C. Keep out of the reach of children.

Packaging.

SIMVASTATIN 20 ANANTA – 14 tablets in a blister, 2 blisters in a cardboard box.

SIMVASTATIN 40 ANANTA – 14 tablets in a blister, 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. Marcksons Pharma Ltd.

Manufacturer’s address and place of business.

Plot No. L-82, L-83, Verna Industrial Estate, Verna Goa, IN – 403 722, India.

Marketing Authorisation Holder. Ananta Medicares Ltd.

Address of the Marketing Authorisation Holder.

Suite 1, 2 Station Court, Imperial Wharf, Townmead Road, Fulham, London, United Kingdom.