Zovatin (Tablets) Instructions for Use

Marketing Authorization Holder

Eczacibasi Ilac Sanayi ve Ticaret, A.S. (Turkey)

ATC Code

C10AA01 (Simvastatin)

Active Substance

Simvastatin (Rec.INN registered by WHO)

Dosage Forms

	Zovatin	Film-coated tablets, 10 mg: 30 pcs.
		Film-coated tablets, 20 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets pale pink in color, oval, biconvex, with a score on one side; white or almost white on the fracture.

Excipients: lactose monohydrate, corn starch, butylated hydroxyanisole, ascorbic acid, citric acid monohydrate, microcrystalline cellulose, magnesium stearate, hypromellose, hydroxypropyl cellulose, titanium dioxide, talc, iron oxide red.

10 pcs. – blisters (3) – cardboard packs.

Film-coated tablets light yellow in color, oval, biconvex; white or almost white on the fracture.

Excipients: lactose monohydrate, corn starch, butylated hydroxyanisole, ascorbic acid, citric acid monohydrate, microcrystalline cellulose, magnesium stearate, hypromellose, hydroxypropyl cellulose, titanium dioxide, talc, iron oxide yellow.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

A drug that corrects lipid metabolism. An inhibitor of HMG-CoA reductase, obtained synthetically from a fermentation product of Aspergillus terreus. It is a prodrug (an inactive lactone), which is hydrolyzed in the body to form an active metabolite. The active metabolite inhibits HMG-CoA reductase, the enzyme that catalyzes the initial reaction of mevalonate formation from HMG-CoA.

Since the conversion of HMG-CoA to mevalonate is an early stage of cholesterol synthesis, the use of simvastatin does not cause the accumulation of potentially toxic sterols in the body. HMG-CoA is easily metabolized to acetyl-CoA, which is involved in many synthesis processes in the body.

It reduces the content of triglycerides (TG), low-density lipoproteins (LDL), very low-density lipoproteins (VLDL) and total cholesterol in plasma (in heterozygous familial and non-familial forms of hypercholesterolemia, in mixed hyperlipidemia, when elevated cholesterol is a risk factor). It increases the content of high-density lipoproteins (HDL) and reduces the LDL/HDL ratio and total cholesterol/HDL.

The onset of the drug’s action is noted after 2 weeks of administration, the maximum therapeutic effect develops after 4-6 weeks and persists throughout the entire period of drug administration. When therapy is discontinued, the cholesterol level returns to the initial (before treatment) level.

Pharmacokinetics

Absorption and Distribution

After oral administration, Simvastatin is highly absorbed from the gastrointestinal tract, C_max in blood plasma is reached after 1.3-2.4 hours and decreases by 90% after 12 hours. Plasma protein binding is 95%.

Metabolism and Excretion

Simvastatin undergoes a first-pass effect through the liver with the formation of the main active metabolite (beta-hydroxy acid), other active and inactive metabolites have also been detected.

T_1/2 of active metabolites is 1.9 hours. It is mainly (up to 60%) excreted in the feces as metabolites, about 10-15% – by the kidneys in an inactive form.

Indications

• Primary hypercholesterolemia (type IIa and IIb according to the Fredrickson classification) when diet therapy is ineffective in patients with an increased risk of coronary atherosclerosis;
• Combined hypercholesterolemia and hypertriglyceridemia (when a special diet and physical exercise are ineffective);
• Hyperlipoproteinemia (not amenable to correction by a special diet and physical exercise);
• Prevention of myocardial infarction (to slow the progression of coronary atherosclerosis), stroke and transient ischemic attacks.

ICD codes

Dosage Regimen

For mild or moderate hypercholesterolemia, the initial dose of Zovatin is 5 mg.

For severe hypercholesterolemia, the drug is prescribed at an initial dose of 10 mg/day. If necessary, after 4 weeks of therapy, the dose may be increased. The maximum daily dose is 80 mg.

For coronary heart disease, the initial dose is 20 mg. If necessary, it is gradually increased every 4 weeks to 40 mg.

If the LDL content is less than 75 mg/dL (1.94 mmol/L), and the total cholesterol content is less than 140 mg/dL (3.6 mmol/L), the drug dose should be reduced.

In patients with chronic renal failure with a creatinine clearance of less than 30 ml/min or with simultaneous use of cyclosporine, fibrates, nicotinamide, the initial dose of the drug is 5 mg, the maximum daily dose is 10 mg.

If a dose is missed, the drug should be taken as soon as possible. If it is time for the next dose, the dose should not be doubled.

The tablets are taken once a day in the evening.

Adverse Reactions

From the digestive system: nausea, vomiting, gastralgia, abdominal pain, constipation, diarrhea, flatulence, hepatitis, jaundice, increased activity of liver transaminases, alkaline phosphatase and creatine phosphokinase; rarely – acute pancreatitis.

From the central and peripheral nervous system: asthenic syndrome, dizziness, headache, insomnia, convulsions, paresthesia, peripheral neuropathy, blurred vision, taste disturbance.

From the musculoskeletal system: myopathy, myalgia, muscle weakness, arthritis, arthralgia; rarely – rhabdomyolysis.

Dermatological reactions: skin rash, itching, alopecia.

Allergic reactions: angioedema, lupus-like syndrome, polymyalgia rheumatica, vasculitis, increased ESR, urticaria, photosensitivity, fever, skin hyperemia, dyspnea.

From the hematopoietic system: anemia, thrombocytopenia, eosinophilia,

Other: palpitations, acute renal failure (due to rhabdomyolysis), decreased potency, hot flashes.

Contraindications

• Hepatic insufficiency;
• Acute liver diseases;
• Increased activity of liver transaminases of unclear etiology;
• Pregnancy;
• Lactation (breastfeeding);
• Children and adolescents under 18 years of age (because safety and efficacy have not been established);
• Hypersensitivity to the components of the drug and other HMG-CoA reductase inhibitors in history.

With caution, the drug should be prescribed to patients who abuse alcohol and/or have a history of liver disease; to patients after organ transplantation taking immunosuppressants (due to an increased risk of rhabdomyolysis and renal failure); in conditions that may lead to the development of severe renal impairment, such as arterial hypotension, severe acute infectious diseases, severe metabolic and endocrine disorders, water-electrolyte imbalance, surgical interventions (including dental) or trauma; to patients with decreased or increased skeletal muscle tone of unclear etiology; with epilepsy.

Use in Pregnancy and Lactation

The drug is contraindicated for use during pregnancy and lactation. During the use of the drug, women of reproductive age should avoid conception.

It should be borne in mind that the withdrawal of hypolipidemic agents during pregnancy does not significantly affect the results of long-term treatment of primary hypercholesterolemia. Since HMG-CoA reductase inhibitors inhibit cholesterol synthesis, and cholesterol and its synthesis products play a significant role in fetal development (including the synthesis of steroids and cell membranes), Simvastatin may have an adverse effect on the fetus. If pregnancy occurs during treatment, the drug should be discontinued, and the woman should be warned about the possible danger to the fetus.

Use in Hepatic Impairment

The drug is contraindicated in hepatic insufficiency, acute liver diseases, and with increased activity of liver transaminases of unclear etiology.

Use in Renal Impairment

In patients with chronic renal failure with a creatinine clearance of less than 30 ml/min or with simultaneous use of cyclosporine, fibrates, nicotinamide, the initial dose of the drug is 5 mg, the maximum daily dose is 10 mg.

Pediatric Use

The efficacy and safety of the drug in children under 18 years of age have not been established.

Special Precautions

Before and during therapy, the patient should be on a hypocholesterolemic diet.

Before starting the drug, liver function tests should be performed (monitoring the activity of liver transaminases every 6 weeks for the first 3 months, then every 8 weeks for the remaining first year and then once every six months). In patients receiving Zovatin at a daily dose of 80 mg, liver function is monitored once every 3 months. If the activity of liver transaminases increases (exceeding the upper limit of normal by 3 times), the drug should be discontinued.

In patients with impaired renal function, therapy can be carried out only with careful monitoring of the patient’s condition (primarily renal function).

If myalgia, muscle weakness and/or a significant increase in creatine phosphokinase activity appear, the drug should be discontinued.

Zovatin (like other HMG-CoA reductase inhibitors) should not be used if there is an increased risk of rhabdomyolysis and renal failure (due to severe acute infection, arterial hypotension, major surgery, trauma, severe metabolic disorders).

Zovatin is not indicated for hypertriglyceridemia types I, IV and V.

The drug is effective both as monotherapy and in combination with bile acid sequestrants.

Patients should be warned about the need to immediately inform the doctor about the appearance of unexplained muscle pain, lethargy or weakness, especially if this is accompanied by general malaise or fever.

Overdose

Treatment: artificial vomiting, activated charcoal; if necessary, symptomatic therapy is carried out. Liver and kidney functions, serum creatine phosphokinase concentration should be monitored.

Drug Interactions

When used concomitantly, Simvastatin enhances the effect of indirect anticoagulants and increases the risk of bleeding.

When used concomitantly with simvastatin, cytostatics, antifungal drugs (ketoconazole, itraconazole), fibrates, nicotinic acid (in high doses), immunosuppressants, erythromycin, clarithromycin, protease inhibitors increase the risk of rhabdomyolysis.

When used concomitantly, Simvastatin increases the plasma concentration of digoxin.

Cholestyramine and colestipol reduce the bioavailability of simvastatin (the drug can be taken 4 hours after taking these drugs, while an additive effect is noted).

Storage Conditions

List B. The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

Shelf life – 2 years.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.