Apextatin (Tablets) Instructions for Use

ATC Code

C10AA02 (Lovastatin)

Active Substance

Lovastatin (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Hypolipidemic agent – HMG-CoA reductase inhibitor

Pharmacological Action

A hypolipidemic agent from the group of statins, an inhibitor of HMG-CoA reductase. It is a prodrug because it has a closed lactone ring in its structure, which is hydrolyzed after entering the body.

The lactone ring of statins is structurally similar to a part of the HMG-CoA reductase enzyme. By the principle of competitive antagonism, the statin molecule binds to the part of the coenzyme A receptor where this enzyme attaches. Another part of the statin molecule inhibits the process of converting hydroxymethylglutarate into mevalonate, an intermediate product in the synthesis of the cholesterol molecule. Inhibition of HMG-CoA reductase activity leads to a series of sequential reactions, resulting in a decrease in intracellular cholesterol content and a compensatory increase in LDL receptor activity and, accordingly, an acceleration of LDL cholesterol (C) catabolism.

The hypolipidemic effect of statins is associated with a decrease in total C levels due to LDL-C. The decrease in LDL levels is dose-dependent and has an exponential, not linear, character.

Statins do not affect the activity of lipoprotein and hepatic lipases, do not significantly affect the synthesis and catabolism of free fatty acids, so their effect on TG levels is secondary and mediated through their main effects of lowering LDL-C levels. The moderate decrease in TG levels during treatment with statins is apparently associated with the expression of remnant (apo E) receptors on the surface of hepatocytes involved in the catabolism of IDL, which contain approximately 30% TG.

According to controlled studies, Lovastatin increases HDL-C levels by up to 10%.

In addition to the hypolipidemic effect, statins have a positive effect on endothelial dysfunction (a preclinical sign of early atherosclerosis), on the vascular wall, the state of the atheroma, improve the rheological properties of blood, and have antioxidant and antiproliferative properties.

Pharmacokinetics

When taken orally, Lovastatin is slowly and incompletely (about 30% of the dose taken) absorbed from the gastrointestinal tract. Taking on an empty stomach reduces absorption by 1/3. C_max is reached within 2-4 hours, then the plasma level decreases rapidly, amounting to 10% of the maximum after 24 hours. Plasma protein binding is 95%. The C_ss of lovastatin and its active metabolites with a single dose at night is reached on the 2nd-3rd day of therapy and is 1.5 times higher than after a single dose.

Lovastatin penetrates the blood-brain barrier and the placental barrier. It undergoes intensive metabolism during the “first pass” through the liver, oxidized to a beta-hydroxy acid, its 6-oxy derivative and other metabolites, some of which are pharmacologically active (block 3-hydroxy-3-methylglutaryl-coenzyme A reductase). T_1/2 is 3 hours. 83% is excreted through the intestines, 10% by the kidneys.

Indications

Primary hypercholesterolemias (hyperlipoproteinemias types IIa and IIb) with high LDL content (when diet therapy is ineffective in patients with an increased risk of coronary atherosclerosis), combined hypercholesterolemia and hypertriglyceridemia, atherosclerosis.

ICD codes

Dosage Regimen

Take Apextatin orally, with the evening meal, to enhance bioavailability.

Initiate therapy at a starting dose of 20 mg once daily.

Adjust the dosage at intervals of at least 4 weeks based on patient response and tolerability.

The usual maintenance dose range is 10-80 mg per day, administered in a single evening dose or in two divided doses.

Do not exceed the maximum recommended daily dose of 80 mg.

For patients requiring only a moderate reduction in LDL-C, a starting dose of 10 mg may be considered.

For severe hypercholesterolemia (LDL-C >190 mg/dL), initiate at 40 mg/day.

When co-administering with drugs like danazol, diltiazem, or verapamil, the maximum daily dose must not exceed 20 mg.

When co-administering with amiodarone, do not exceed a maximum daily dose of 40 mg.

Adhere to a standard cholesterol-lowering diet throughout treatment.

Prior to initiation, exclude secondary causes of hyperlipidemia.

Assess liver function tests before commencing therapy and monitor periodically thereafter.

If a dose is missed, take it as soon as remembered. If it is near the time for the next dose, skip the missed dose and resume the usual schedule. Do not double the dose.

Adverse Reactions

From the digestive system heartburn, nausea, diarrhea, constipation, flatulence, vomiting, dryness of the oral mucosa, abdominal pain, taste disturbance, anorexia, gastralgia, cholestatic jaundice, hepatitis, impaired liver function, acute pancreatitis.

From the musculoskeletal system myalgia, myopathy, myositis, rhabdomyolysis (with simultaneous use of cyclosporine, gemfibrozil or nicotinic acid), arthralgia; frequency unknown – occurrence or exacerbation of myasthenia.

From the nervous system dizziness, headache, general weakness, convulsions, insomnia, paresthesia, peripheral neuropathy, memory loss, mental disorders (including anxiety).

From the organ of vision: blurred vision, lens opacity, cataract, optic nerve atrophy; frequency unknown – ocular myasthenia.

From the hematopoietic system hemolytic anemia, leukopenia, thrombocytopenia.

Allergic reactions skin rash, itching; in isolated cases – urticaria, angioedema, toxic epidermal necrolysis.

From laboratory parameters increased activity of liver transaminases, increased activity of creatine phosphokinase (CPK), bilirubin.

Other decreased potency; acute renal failure (caused by rhabdomyolysis), chest pain, palpitations.

Contraindications

Hypersensitivity to lovastatin; active liver disease; increased activity of liver transaminases (of unclear etiology); use in women of reproductive age not using reliable methods of contraception; pregnancy or pregnancy planning; breastfeeding period; general severe condition of the patient; age under 18 years (safety and efficacy of use have not been established); simultaneous use of potent inhibitors of the CYP3A4 isoenzyme (including itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone); simultaneous use of gemfibrozil, cyclosporine ; grapefruit juice – more than 1 liter/day.

With caution history of liver disease; alcohol abuse; patients after organ transplantation receiving immunosuppressive therapy (increased risk of rhabdomyolysis and renal failure); surgical interventions (including dental); with simultaneous use with gemfibrozil and other fibrates, nicotinic acid in lipid-lowering doses (more than 1 g/day) due to the risk of myopathy.

Use in Pregnancy and Lactation

Lovastatin is contraindicated for use during pregnancy or its planning, during lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in acute liver diseases. Use with caution in patients with a history of liver disease.

Use in Renal Impairment

Should be used with caution in patients with severe renal impairment.

Pediatric Use

Contraindicated for use in children and adolescents under 18 years of age (safety and efficacy of use have not been established).

Special Precautions

During treatment, patients should adhere to a special diet low in cholesterol.

Patients should be warned that if unexplained muscle pain, muscle tenderness and weakness occur (especially in combination with fever), they should consult a doctor.

Treatment with lovastatin may cause an increase in the activity of liver transaminases and CPK. With long-term therapy, biochemical monitoring of liver function is indicated. The activity of liver transaminases is determined before the start of treatment, every 8 weeks during the first year of therapy and then – at least once every 6 months. If the activity of liver transaminases and CPK increases more than 3 times relative to the upper limit of normal, Lovastatin should be discontinued.

The use of statins can lead to the development of hyperglycemia in patients with diabetes mellitus.

Lovastatin therapy can lead to the development of myopathy with rhabdomyolysis and renal failure. The risk of this pathology increases with simultaneous use with immunosuppressants, gemfibrozil, nicotinic acid in lipid-lowering doses (more than 1 g/day), cyclosporine, erythromycin and antifungal drugs of the azole group (itraconazole, etc.).

If the patient is in a generally severe condition due to any disease, lovastatin therapy should be discontinued.

Lovastatin is contraindicated for use in women of reproductive age not using reliable methods of contraception.

In case of missing the current dose of Lovastatin, it must be taken as soon as possible. If it is time for the next dose, the dose should not be increased.

Effect on the ability to drive vehicles and mechanisms

During the treatment period, patients should exercise caution when driving vehicles and engaging in other activities that require high concentration and speed of psychomotor reactions.

Drug Interactions

Immunosuppressants, potent inhibitors of the CYP3A4 isoenzyme (including itraconazole, ketoconazole, posaconazole, HIV protease inhibitors, boceprevir, telaprevir, erythromycin, clarithromycin, telithromycin and nefazodone), gemfibrozil, cyclosporine, nicotinic acid in lipid-lowering doses (more than 1 g/day), colchicine, ranolazine and drugs affecting the concentration of endogenous steroid hormones increase the risk of developing myopathy with rhabdomyolysis and acute renal failure.

With simultaneous use with anticoagulants, coumarin and indandione derivatives, increased bleeding and increased prothrombin time are noted. Regular monitoring of prothrombin time is necessary.

With simultaneous use with oral contraceptives, Lovastatin may prevent hyperlipidemia caused by taking hormonal contraceptives.

It is believed that a decrease in the hypolipidemic effect of lovastatin is possible with simultaneous use of “loop” and thiazide diuretics.

Diltiazem, verapamil, isradipine inhibit the CYP3A4 isoenzyme, which is involved in the metabolism of lovastatin, so with simultaneous use, an increase in the concentration of lovastatin in the blood plasma and an increased risk of myopathy are possible.

There are reports of the development of acute rhabdomyolysis and hepatotoxicity with simultaneous use with itraconazole.

A case of severe hyperkalemia in a patient with diabetes mellitus with simultaneous use of lisinopril has been described.

With simultaneous administration with danazol, diltiazem, verapamil, the maximum daily dose of lovastatin should not exceed 20 mg, with amiodarone – 40 mg.

Cholestyramine and colestipol reduce bioavailability (lovastatin can be taken 4 hours after taking the above drugs).

Cyclosporine may increase the plasma level of metabolites.

Large amounts of grapefruit juice (more than 1 liter/day) increase the C_max and AUC of lovastatin and increase the risk of myopathies (simultaneous use is not recommended).

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.