Inegy^® (Tablets) Instructions for Use

Marketing Authorization Holder

Organon, LLC (Russia)

Manufactured By

Merck Sharp & Dohme, Ltd. (United Kingdom)

Or

MSD International GmbH (Singapore Branch) (Singapore)

Packaging and Quality Control Release

MERCK SHARP & DOHME, B.V. (Netherlands)

ATC Code

C10BA02 (Simvastatin and Ezetimibe)

Active Substances

Simvastatin (Rec.INN registered by WHO)

Ezetimibe (Rec.INN registered by WHO)

Dosage Forms

	Inegy®	Tablets 20 mg+10 mg: 10, 14, 20, 28, 30, 42, 50, 70, 100 or 140 pcs.
		Tablets 40 mg+10 mg: 10, 14, 20, 28, 30, 42, 50, 70, 100 or 140 pcs.
		Tablets 80 mg+10 mg: 10, 14, 20, 28, 30, 42, 50, 70, 100 or 140 pcs.

Dosage Form, Packaging, and Composition

Tablets from white to almost white, capsule-shaped, biconvex, engraved with “312” on one side and smooth on the other.

Excipients: lactose monohydrate – 126.5 mg, microcrystalline cellulose – 30 mg, hypromellose 2910 6 cps – 4 mg, croscarmellose sodium – 6 mg, citric acid monohydrate – 0.5 mg, butylated hydroxyanisole – 0.04 mg, propyl gallate – 0.01 mg, magnesium stearate – 3 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (5) – cardboard packs.
14 pcs. – blisters (10) – cardboard packs.

Tablets from white to almost white, capsule-shaped, biconvex, engraved with “313” on one side and smooth on the other.

Excipients: lactose monohydrate – 262.9 mg, microcrystalline cellulose – 60 mg, hypromellose 2910 6 cps – 8 mg, croscarmellose sodium – 12 mg, citric acid monohydrate – 1 mg, butylated hydroxyanisole – 0.08 mg, propyl gallate – 0.02 mg, magnesium stearate – 6 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (5) – cardboard packs.
14 pcs. – blisters (10) – cardboard packs.

Tablets from white to almost white, capsule-shaped, biconvex, engraved with “315” on one side and smooth on the other.

Excipients: lactose monohydrate – 535.8 mg, microcrystalline cellulose – 120 mg, hypromellose 2910 6 cps – 16 mg, croscarmellose sodium – 24 mg, citric acid monohydrate – 2 mg, butylated hydroxyanisole – 0.16 mg, propyl gallate – 0.04 mg, magnesium stearate – 12 mg.

10 pcs. – blisters (1) – cardboard packs.
10 pcs. – blisters (2) – cardboard packs.
10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (10) – cardboard packs.
14 pcs. – blisters (1) – cardboard packs.
14 pcs. – blisters (2) – cardboard packs.
14 pcs. – blisters (3) – cardboard packs.
14 pcs. – blisters (5) – cardboard packs.
14 pcs. – blisters (10) – cardboard packs.

Clinical-Pharmacological Group

Hypolipidemic agent

Pharmacotherapeutic Group

Combined hypolipidemic agent (HMG-CoA reductase inhibitor + cholesterol absorption inhibitor)

Pharmacological Action

Combined hypolipidemic agent, which reduces the absorption of cholesterol and related plant sterols in the intestine, and also suppresses endogenous cholesterol synthesis.

Simvastatin

After oral administration as an inactive lactone, Simvastatin undergoes hydrolysis to form the corresponding β-hydroxy acid derivative, which has high inhibitory activity against HMG-CoA reductase. This enzyme triggers the initial and most significant stage of cholesterol biosynthesis – the conversion of HMG-CoA to mevalonate.

Simvastatin reduces both elevated and normal LDL levels. LDL is formed from VLDL and is broken down primarily via the high-affinity LDL receptor. The reduction in LDL after simvastatin administration leads to a decrease in VLDL content and activation of LDL receptors, which results in reduced formation and enhanced catabolism of LDL. During simvastatin therapy, Apo-B levels also decrease. In addition, Simvastatin moderately increases HDL levels and reduces plasma TG. As a result of these changes, total cholesterol and LDL levels decrease.

Ezetimibe

The mechanism of action of ezetimibe differs from other classes of hypolipidemic agents (e.g., statins, bile acid sequestrants, fibrates).

Ezetimibe, upon entering the small intestine, slows down the absorption of cholesterol, leading to a reduction in the delivery of cholesterol from the intestine to the liver.

After 2 weeks of use, Ezetimibe reduces intestinal cholesterol absorption by 54% compared to placebo.

A number of preclinical studies of ezetimibe confirm its selectivity in reducing cholesterol absorption. Ezetimibe slows the absorption of ¹⁴C-cholesterol and has no effect on the absorption of TG, fatty acids, bile acids, progesterone, ethinyl estradiol, or fat-soluble vitamins A and D.

Pharmacokinetics

Simvastatin

The bioavailability of the β-hydroxy acid after oral administration of simvastatin is less than 5% of the dose. In addition to the β-hydroxy acid, 4 other active metabolites are detected in plasma.

Food intake does not affect the plasma concentrations of active and total simvastatin metabolites.

Simvastatin and the β-hydroxy acid are 95% bound to plasma proteins.

Pharmacokinetic studies have shown that Simvastatin does not accumulate in tissues after repeated doses. The maximum level of metabolites in plasma is observed 1.3-2.4 hours after administration.

It is an inactive lactone that is rapidly hydrolyzed in vivo to the corresponding β-hydroxy acid, a potent inhibitor of HMG-CoA reductase. Hydrolysis occurs mainly in the liver; the rate of hydrolysis in plasma is very low. Simvastatin is well absorbed and almost completely metabolized during the “first pass” through the liver. The uptake of simvastatin by the liver is determined by the rate of hepatic blood flow. The main metabolism occurs in the liver, and the drug’s metabolites are excreted in the bile. Therefore, the amount of active substance in the systemic circulation is very insignificant.

Within 96 hours after oral administration of radioactive simvastatin, 13% of the radioactive products were excreted by the kidneys, and 60% through the intestine. After intravenous administration of the β-hydroxy acid metabolite, only 0.3% was excreted by the kidneys as metabolites.

Ezetimibe

After oral administration, it is rapidly absorbed and intensively conjugated into a pharmacologically active phenolic glucuronide (Ezetimibe-glucuronide).

C_max of ezetimibe in plasma after oral administration is reached in 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined because it is insoluble in any of the aqueous solvents used for injections.

Food intake (low or high fat) does not affect the bioavailability of ezetimibe when taken orally, particularly in the form of 10 mg tablets.

Ezetimibe and Ezetimibe-glucuronide are 99.7% and 88-92% bound to plasma proteins, respectively.

The primary metabolism of ezetimibe occurs in the small intestine and liver by conjugation with glucuronide (phase II reaction), followed by excretion in the bile. Minimal oxidative metabolism (phase I reaction) was observed at all stages of ezetimibe transformation. Ezetimibe and Ezetimibe-glucuronide are slowly eliminated from plasma during enterohepatic recirculation. T_1/2 is approximately 22 hours.

After oral administration of 20 mg of ¹⁴C-labeled ezetimibe, 93% of total ezetimibe from the total level of radioactive products was found in plasma. Approximately 73% and 11% of the administered radioactive products are excreted through the intestine and kidneys, respectively, within 10 days. After 48 hours, no radioactive products were detected in plasma.

Indications

Primary hypercholesterolemia: heterozygous (familial and non-familial) hypercholesterolemia or mixed hyperlipidemia (as an adjunct to diet to reduce total cholesterol, LDL, apolipoprotein B, TG, non-high-density lipoproteins, and to increase HDL); homozygous familial hypercholesterolemia: to reduce elevated total cholesterol and LDL levels (both as an additional treatment to other hypolipidemic therapy, e.g., LDL apheresis, and in its absence).

ICD codes

Dosage Regimen

Take orally once daily in the evening, with or without food.

Swallow the tablet whole; do not crush or chew.

The recommended starting dose is one Inegy^® 20 mg/10 mg tablet daily.

For patients requiring a more pronounced LDL-cholesterol reduction, use a 40 mg/10 mg or 80 mg/10 mg tablet.

Do not exceed the maximum daily dose of 80 mg/10 mg (one 80 mg/10 mg tablet).

For patients with severe renal impairment (CrCl <30 mL/min), initiate therapy at 10 mg/10 mg daily with caution.

Prior to initiation, place patients on a standard cholesterol-lowering diet.

Continue the dietary regimen during treatment.

Perform liver function tests before treatment initiation and thereafter as clinically indicated.

Assess fasting lipid profile after 2 to 4 weeks of therapy and adjust dosage accordingly.

For patients already stabilized on individual components (simvastatin and ezetimibe), switch to the combined tablet at the same doses.

When used with gemfibrozil, the dose of simvastatin must not exceed 10 mg daily.

Avoid concomitant use with cyclosporine or danazol.

Adverse Reactions

From the digestive system flatulence, abdominal pain, constipation, diarrhea, dyspepsia, vomiting, cholelithiasis, cholecystitis, jaundice, hepatitis; nausea; pancreatitis; in some cases – liver failure.

From the hematopoietic system: thrombocytopenia, anemia.

From the musculoskeletal system: arthralgia, muscle weakness, muscle cramps, neck pain, limb pain.

From the nervous system: dizziness, headache.

Allergic reactions: skin rash and urticaria.

Laboratory data: increased activity of “liver” transaminases (ALT and/or AST), increased CPK activity, increased blood bilirubin concentration, increased gamma-glutamyltransferase activity, increased INR, proteinuria.

Other: increased fatigue, asthenia, malaise, peripheral edema.

Contraindications

Active liver disease or persistent increase in liver transaminase activity of unclear etiology; moderate and severe hepatic insufficiency (7 or more points on the Child-Pugh scale); pregnancy; lactation period (breastfeeding); age under 18 years; concomitant treatment with strong inhibitors of the CYP3A4 isoenzyme (itraconazole, ketoconazole, voriconazole, HIV protease inhibitors and preparations containing cobicistat); concomitant treatment with gemfibrozil, cyclosporine or danazol.

With caution

In severe renal failure (CrCl <30 ml/min), alcohol abuse, history of liver disease, painful sensations in the muscles or changes in skeletal muscle tone of unclear etiology, gallbladder diseases.

Use in Pregnancy and Lactation

Contraindicated during pregnancy and lactation (breastfeeding).

Use in Hepatic Impairment

Contraindicated in active liver disease or persistent increase in liver transaminase activity of unclear etiology; moderate and severe hepatic insufficiency (7 or more points on the Child-Pugh scale).

Use in Renal Impairment

Use with caution in severe renal failure (CrCl < 30 ml/min).

Pediatric Use

Use is contraindicated under the age of 18 years.

Geriatric Use

No dose adjustment is required for elderly patients.

Special Precautions

If it is necessary to prescribe to patients with severe renal failure (CrCl < 30 ml/min) at a dose of more than 10/10 mg/day, it should be used with caution.

Use with caution in patients who consume large amounts of alcohol, and/or have a history of liver disease. Acute liver disease or an unexplained persistent high level of liver enzyme activity are contraindications to taking this combination.

A few days before major surgical interventions and in the early postoperative period, administration is recommended to be temporarily discontinued.

Simvastatin, like other HMG-CoA reductase inhibitors, can cause myopathy, manifested by muscle pain, weakness, fatigue, as well as an increase in CPK levels of more than 10 times the ULN. Sometimes myopathy takes the form of rhabdomyolysis and may be accompanied by myoglobinuria, acute renal failure, and in rare cases with a fatal outcome. The risk of myopathy is increased by increasing the plasma inhibitory activity against HMG-CoA reductase.

All patients receiving therapy with this combination, as well as patients who need to increase the dose, should be warned about the possibility of myopathy and informed about the need to immediately consult a doctor if any unexplained muscle pain, muscle tenderness and muscle weakness occur.

Most cases of rhabdomyolysis during treatment with simvastatin were associated with a burdened history, including renal failure, predominantly of diabetic origin. Patients with a burdened history require careful monitoring during treatment.

At the start of administration or dose increase, periodic monitoring of CPK levels may be required; however, this measure does not guarantee the prevention of myopathy development.

Drug Interactions

When used in combination with potent CYP3A4 inhibitors, for example, with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, the risk of developing myopathy/rhabdomyolysis increases.

With simultaneous use of this combination and fenofibrate or gemfibrozil, the plasma concentration of ezetimibe increases by 1.5 and 1.7 times, respectively; however, such an increase is not clinically significant.

With simultaneous use with cyclosporine, danazol or nicotinic acid (more than 1 g/day), with amiodarone or verapamil, fusidic acid the risk of developing myopathy/rhabdomyolysis increases.

In patients receiving diltiazem and this combination at a dose of 10/80 mg, the risk of developing myopathy increases slightly. Clinical studies have shown that the risk of myopathy is the same in patients taking Simvastatin at a dose of 40 mg, with or without concomitant diltiazem therapy.

With combined use with cholestyramine, the mean AUC of total ezetimibe (ezetimibe and ezetimibe glucuronide) decreased by approximately 55%. With combined use with cholestyramine, the incremental reduction in LDL may become less pronounced.

With simultaneous administration with antacids, the absorption level of ezetimibe is slightly reduced, while its bioavailability does not change.

Grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme and can increase the plasma level of substances metabolized by this isoenzyme. The effect of consuming small amounts of juice (250 ml per day) is minimal (the HMG-CoA reductase inhibitory activity in plasma increases by 13%, as shown by the AUC value) and has no clinical significance. However, consuming large amounts of juice (more than 1 liter per day) while taking simvastatin significantly increases the level of HMG-CoA reductase inhibitory activity in plasma. Therefore, consumption of large amounts of grapefruit juice and simultaneous administration of the drug should be avoided.

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.