Simvastatin tablets 10 mg

Instructions for use for Simvastatin tablets 10 mg

Brand Name: Simvastatin

International Nonproprietary Name: Simvastatin

Dosage Form: Film-coated tablets

Composition per one tablet:

Description:

Round, biconvex, film-coated tablets, pink in color. A cross-section shows a core ranging from white to almost white with a yellowish tint.

Pharmacotherapeutic group: Hypolipidemic agent - HMG-CoA reductase inhibitor.

ATC Code: C10AA01

Pharmacological properties

The drug Simvastatin is a hypolipidemic drug obtained synthetically from a fermentation product of Aspergillus terreus.

Pharmacodynamics:

After oral administration, simvastatin, which is an inactive lactone, is hydrolyzed in the liver to form the corresponding β-hydroxyacid of simvastatin, the primary metabolite and a potent inhibitor of HMG-CoA (3-hydroxy-3-methylglutaryl-coenzyme A) reductase, the enzyme that catalyzes the initial, rate-limiting step in cholesterol biosynthesis. Clinical studies have demonstrated the efficacy of simvastatin in reducing plasma concentrations of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and very-low-density lipoprotein cholesterol (VLDL-C), as well as increasing high-density lipoprotein cholesterol (HDL-C) in patients with heterozygous familial and non-familial hypercholesterolemia or mixed hyperlipidemia when elevated cholesterol is a risk factor and diet alone is insufficient. A noticeable therapeutic effect is observed within 2 weeks, with the maximum therapeutic effect occurring within 4-6 weeks. The effect is maintained during continued therapy. Discontinuation of simvastatin returns cholesterol levels to pre-treatment baseline.

The active metabolite of simvastatin is a specific inhibitor of HMG-CoA reductase. However, therapeutic doses do not lead to complete inhibition, allowing for the production of biologically necessary amounts of mevalonate. As the conversion of HMG-CoA to mevalonate is an early step, the use of simvastatin is not expected to cause accumulation of potentially toxic sterols. HMG-CoA is also rapidly metabolized back to acetyl-CoA, which participates in many biosynthetic processes.

No clinical impact on steroidogenesis has been observed. Simvastatin does not increase the lithogenicity of bile, making an increase in the incidence of cholelithiasis unlikely.

Simvastatin reduces both elevated and normal LDL-C concentrations. LDL is formed from very-low-density lipoproteins (VLDL). The catabolism of LDL occurs predominantly via high-affinity LDL receptors. The mechanism of LDL-C reduction involves both a reduction in VLDL-C concentration and activation of LDL receptors, leading to reduced formation and increased catabolism of LDL-C. Therapy with simvastatin also significantly reduces apolipoprotein B (apo B) levels. Furthermore, simvastatin increases HDL-C and reduces plasma TG, thereby improving the TC/HDL-C and LDL-C/HDL-C ratios.

Major clinical trials (e.g., 4S, HPS) have demonstrated that simvastatin reduces the risk of total mortality, coronary heart disease (CHD) mortality, major vascular and coronary events (non-fatal MI, coronary death, stroke), and the need for coronary and non-coronary revascularization procedures in high-risk patients, including those with CHD, diabetes, or cerebrovascular disease. It also slows the progression of coronary atherosclerosis.

Pharmacokinetics:

Metabolism

Simvastatin is an inactive lactone that is rapidly hydrolyzed to its active β-hydroxyacid form. Peak plasma concentrations of active metabolites are reached 1.3-2.4 hours after oral administration. Absorption is high (~85%), and food intake does not affect the pharmacokinetic profile. Simvastatin undergoes extensive first-pass metabolism in the liver; thus, concentrations of unchanged simvastatin in systemic circulation are low (<5% of the dose). It is highly bound to plasma proteins (>95%).

Elimination

Excretion is mainly via bile (60% in feces), with renal excretion accounting for about 13% of the dose. The half-life is approximately 1-2 hours for the active metabolites.

Special patient groups

Plasma concentrations of active metabolites are approximately doubled in patients with severe renal impairment (creatinine clearance <30 mL/min). Pharmacokinetics may be influenced by genetic polymorphisms in the OATP1B1 transporter and by drugs that inhibit CYP3A4 (e.g., cyclosporine, diltiazem, amlodipine), leading to increased exposure and risk of myopathy.

Indications for use:

Patients with coronary heart disease or at high risk of CHD

In patients at high risk of developing CHD (with or without hyperlipidemia), for example, patients with diabetes, patients with a history of stroke or other cerebrovascular diseases, patients with peripheral vascular disease, or patients with CHD or a predisposition to CHD, the drug Simvastatin is indicated for:

• Reducing the risk of total mortality by reducing mortality from CHD.
• Reducing the risk of major vascular and coronary complications:

1. non-fatal myocardial infarction,
2. coronary death,
3. stroke,
4. revascularization procedures.

• Reducing the risk of needing surgical interventions to restore coronary blood flow (such as coronary artery bypass grafting and percutaneous transluminal coronary angioplasty).
• Reducing the risk of needing surgical interventions to restore peripheral blood flow and other types of non-coronary revascularization.
• Reducing the risk of hospitalization due to angina attacks.

Hyperlipidemia

• As an adjunct to diet, when the use of diet and other non-drug treatments in patients with primary hypercholesterolemia, including heterozygous familial hypercholesterolemia (Fredrickson type IIa), or mixed hypercholesterolemia (Fredrickson type IIb) is insufficient for:

1. reducing elevated concentrations of TC, LDL-C, TG, apolipoprotein B (apo B);
2. increasing the concentration of HDL-C;
3. reducing the LDL-C/HDL-C and TC/HDL-C ratios.

• Hypertriglyceridemia (Fredrickson type IV).
• As an adjunct to diet and other treatments for patients with homozygous familial hypercholesterolemia to reduce elevated concentrations of TC, LDL-C and apo B.
• Primary dysbetalipoproteinemia (Fredrickson type III).

Use in children and adolescents with heterozygous familial hypercholesterolemia

Use of the drug Simvastatin concomitantly with diet is indicated to reduce elevated concentrations of TC, LDL-C, TG, apo B in boys 10-17 years and in girls 10-17 years at least 1 year post-menarche with heterozygous familial hypercholesterolemia.

Contraindications:

• Hypersensitivity to any component of the drug.
• Active liver disease or persistent elevation of serum transaminases of unclear etiology.
• Pregnancy or breastfeeding period.
• Age under 18 years (except children and adolescents 10-17 years with heterozygous familial hypercholesterolemia).
• Lactose intolerance, lactase deficiency, or glucose-galactose malabsorption.
• Concomitant treatment with potent CYP3A4 inhibitors (e.g., itraconazole, ketoconazole, HIV protease inhibitors, erythromycin, clarithromycin).
• Concomitant treatment with gemfibrozil, cyclosporine, or danazol.

Precautions:

Severe renal impairment (CrCl <30 mL/min); history of liver disease; alcohol abuse; history of muscular disease/statin myopathy; uncontrolled hypothyroidism; planned surgical interventions; concomitant use with fibrates (except fenofibrate), niacin in lipid-lowering doses (>1 g/day), amiodarone, amlodipine, verapamil, diltiazem; diabetes; use in patients of Asian descent; elderly age (over 65 years, especially women).

Use in pregnancy and lactation:

Pregnancy

The drug Simvastatin is contraindicated in pregnant women. Discontinue immediately if pregnancy occurs. Treatment with Simvastatin should be suspended for the duration of pregnancy.

Breastfeeding

Discontinue the drug while breastfeeding.

Dosage and administration:

Before starting treatment with Simvastatin, the patient should be prescribed a standard cholesterol-lowering diet, which must be followed throughout the course of treatment.

Recommended doses of Simvastatin are from 5 to 80 mg per day. The drug should be taken once daily in the evening. If necessary, the dose can be increased at intervals of at least 4 weeks up to a maximum of 80 mg once daily in the evening. The 80 mg daily dose is recommended only for patients with a high risk of cardiovascular complications if treatment with lower doses has not achieved lipid targets and the expected benefit of therapy outweighs the potential risk.

Patients with coronary heart disease or high risk of developing CHD

The standard initial dose of Simvastatin for patients with a high risk of developing CHD with or without hyperlipidemia is 40 mg once daily in the evening.

Patients with hyperlipidemia, without the above risk factors

The standard initial dose of Simvastatin is 20 mg once daily in the evening.

Patients with homozygous familial hypercholesterolemia

Simvastatin is recommended at a dose of 40 mg per day, taken once in the evening.

Concomitant therapy

In patients taking Simvastatin simultaneously with fibrates (other than gemfibrozil) or fenofibrate, the maximum recommended dose of Simvastatin is 10 mg per day.

For patients taking amiodarone, verapamil, diltiazem, or amlodipine simultaneously with Simvastatin, the daily dose of Simvastatin should not exceed 20 mg.

Renal impairment

In patients with severe renal insufficiency (CrCl <30 mL/min), doses exceeding 10 mg/day should be carefully considered and used with caution.

Use in children and adolescents 10-17 years with heterozygous familial hypercholesterolemia

The recommended initial dose is 10 mg once daily in the evening. The recommended dosing range is 10-40 mg per day.

Adverse reactions:

Simvastatin is generally well tolerated. Most side effects are mild and transient.

Common (>1/100 to <1/10): Headache, abdominal pain, constipation.

Uncommon (>1/1000 to <1/100): Dizziness, asthenia, nausea, dyspepsia.

Rare (>1/10,000 to <1/1000): Myalgia, peripheral neuropathy, pancreatitis, hepatitis, rash, pruritus, hypersensitivity reactions.

Very Rare (<1/10,000): Rhabdomyolysis, liver failure, immune-mediated necrotizing myopathy.

Frequency Unknown: Depression, memory impairment, sleep disturbances, erectile dysfunction, increased HbA1c and fasting blood glucose.

Overdose:

Several cases reported (max 3.6 g) with no specific sequelae. General supportive and symptomatic measures recommended.

Pharmaceutical form:

Film-coated tablets, 10 mg.

10 tablets in a blister pack made of polyvinyl chloride film and printed lacquered aluminum foil.

2, 3, 4, 6, or 9 blister packs along with the package insert are placed in a cardboard carton.

Storage conditions:

Store in a dry place, protected from light, at a temperature not exceeding 25°C. Keep out of reach of children.

Shelf life:

2 years. Do not use after the expiration date printed on the packaging.

Regulatory status:

Prescription only.

Marketing Authorization Holder / Organization for claims:

JSC "AVVA RUS", Russia, 121614, Moscow, Krylatskie Kholmy St., 30, building 9.

Tel/Fax: +7 (495) 956-75-54.

avva.com.ru

Manufacturing address:

JSC "AVVA RUS", Russia, 610044, Kirov Region, Kirov, Luganskaya St., 53a.

Tel: +7 (8332) 25-12-29; +7 (495) 956-75-54.