Inegy® [Simvastatin, Ezetimibe]

Brand Merck Sharp & Dohme

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Available since: 2019-09-19

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Clinical Pharmacology

Combined lipid-lowering drug that reduces the absorption of cholesterol and related plant sterols in the intestine, and also suppresses endogenous cholesterol synthesis.

The drug contains ezetimibe and simvastatin, two lipid-lowering components that complement each other with their mechanism of action.

Cholesterol enters the blood plasma as a result of intestinal absorption and endogenous synthesis. Inegy lowers elevated levels of total Xc, LDL, apolipoproteins B (Apo B), TG, and low density lipoproteins (non-HDL), and increases levels by double inhibition: absorption and cholesterol synthesis.

Ezetimibe

The mechanism of action of ezetimibe differs from other classes of lipid-lowering agents (for example, statins, bile acid sequestrants, fibrates).

Ezetimibe, when it enters the small intestine, slows down cholesterol absorption, which leads to a decrease in cholesterol from the intestine to the liver.

After 2 weeks of use, ezetimibe reduces cholesterol absorption in the intestines by 54% compared with placebo.

A series of preclinical studies of ezetimibe confirms its selectivity in reducing cholesterol absorption. Ezetimibe slows absorption 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.

Simvastatin

After ingestion in the form of an inactive lactone, simvastatin undergoes hydrolysis to form the corresponding P-hydroxy acid derivative, which has a high inhibitory activity against HMG-CoA reductase. This enzyme starts the initial and most significant stage of cholesterol biosynthesis - the conversion of HMG-CoA into mevalonate.

Simvastatin reduces both elevated and normal levels of LDL. LDLs are formed from VLDL and are cleaved predominantly by using a high affinity LDL receptor. A decrease in LDL after administration of simvastatin leads to a decrease in the content of VLDL and activation of LDL receptors, which leads to a decrease in the formation and enhancement of the catabolism of LDL. With simvastatin therapy, the level of ApoB also decreases. In addition, simvastatin moderately increases HDL levels and lowers plasma TG. As a result of these changes, the level of total cholesterol and LDL are reduced.

Pharmacokinetics

Suction

Ezetimibe

After ingestion, ezetimibe is rapidly absorbed and intensively conjugates into pharmacologically active phenolic glucuronide (ezetimib glucuronide).

C_max ezetemiba in blood plasma after taking the drug orally is achieved after 4-12 hours. The absolute bioavailability of ezetimibe cannot be determined, since it is insoluble in any of the aqueous solvents used for injections.

Eating (low or high fat) does not affect the bioavailability of ezetimibe when taken orally, in particular in the form of 10 mg pills.

Simvastatin

The bioavailability of β-hydroxy-acid after taking simvastatin orally is less than 5% of the dose. In addition to the P-hydroxy acid, 4 more active metabolites are detected in the blood plasma.

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

Distribution

Ezetimibe

Ezetimibe and ezetimib glucuronide bind to plasma proteins by 99.7% and 88-92%, respectively.

Simvastatin

Simvastatin and R-hydroxy acid bind to plasma proteins by 95%.

Pharmacokinetic studies have shown that simvastatin does not accumulate in the tissues after receiving repeated doses. The maximum level of metabolites in the blood plasma is observed 1.3-2.4 hours after taking the drug.

Metabolism

Ezetimibe

The primary metabolism of ezetimiba occurs in the small intestine and liver by conjugation with glucuronide (phase II reaction), followed by excretion with bile. Minimal oxidative metabolism (Iphase reaction) was observed at all stages of transformation of ezetimibe.Ezetimibe and ezetimibe-glucuronide, the main derivatives of the drug, make up 10-20% and 80-90% of the total content of the drug in blood plasma, respectively. Ezetimibe and ezetimib glucuronide are slowly excreted from the blood plasma during the enterohepatic recirculation process.

T_1/2 for ezetimibe and ezetimib glucuronide is approximately 22 hours.

Simvastatin

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

Removal

Ezetimibe

After ingestion of 20 mg of ezetimibe, labeled ¹⁴C, 93% of the total ezetimibe in the total level of radioactive products was detected in the blood plasma. Approximately 73% and 11% of respectively taken up radioactive products are excreted through the intestines and kidneys for 10 days. After 48 hours, no radioactive products were detected in the blood plasma.

Simvastatin

Within 96 hours after ingestion of radioactive simvastatin, 13% of the radioactive products were excreted by the kidneys, and 60% through the intestines. After iv administration of the P-hydroxy acid metabolite, only 0.3% was excreted by the kidneys as metabolites.

Pharmacokinetics in special clinical situations

Children

The pharmacokinetic data, absorption and metabolism of ezetimibe are the same in children / adolescents (10-18 years old) and adults. There is no data on the pharmacokinetics of the drug in children under 10 years of age. The clinical use of the drug in pediatric practice (in children and adolescents 9–17 years old) is limited to data on patients with homozygous familial hypercholesterolemia (HOSG) or homozygous sitosterolemia (hyper-apo-beta lipoproteinemia).

Elderly patients

In elderly patients (over 65 years), the concentration of total ezetimibe in the blood plasma is approximately 2 times higher than in younger patients (18-45 years). The level of LDL reduction and safety profiles in elderly and younger patients taking ezetimibe are about the same.

Patients with liver failure

After a single dose of ezetimibe 10 mg, the average AUC for total ezetimibe was 1.7 higher in patients with mild hepatic insufficiency (5-6 points on the Child-Pugh scale) than in patients with preserved liver function. In a 14-day study of ezetimibe at a dose of 10 mg / day with the participation of patients with moderate hepatic insufficiency (7–9 points on the Child-Pugh scale), the average AUC for total ezetimibe increased 4 times on the 1st and 14th day compared with patients with preserved liver function.

For patients with mild liver failure, dose adjustment is not required. Since the effects of increased concentration of total ezetimibe are unknown, ezetimibe is not recommended for patients with moderate and severe (more than 9 points on the Child-Pugh scale) liver failure.

Patients with renal failure

Ezetimibe. After a single dose of 10 mg of ezetimibe, the average AUC in patients with severe renal insufficiency (average CC less than 30 ml / min / 1.73 m²) increased 1.5 times compared with healthy patients.

Simvastatin. In a study of patients with severe renal failure (CC less than 30 ml / min), after administration of HMG-CoA reductase inhibitors, the total concentration of simvastatin metabolites was 2 times higher than in healthy volunteers.

Floor

The total concentration of ezetimibe is slightly higher (20%) in women than in men. The level of LDL reduction and safety profiles are about the same for men and women taking ezetimibe.

Indications

Primary hypercholesterolemia: heterozygous (familial and non-familial) hypercholesterolemia or mixed hyperlipidemia (as a supplement to a diet to reduce total cholesterol, LDL, apolipoprotein B, TG, low density lipoprotein, to increase HDL).

Homozygous familial hypercholesterolemia: to reduce elevated levels of total cholesterol and LDL (both as an additional treatment to other lipid-lowering therapy, for example, LDL-apheresis, and in its absence).

Composition

1 tablet contains:

Active substances: ezetimibe 10 mg, simvastatin 20 mg;

Excipients: lactose monohydrate, microcrystalline cellulose, hypromellose 2910 6 cps, croscarmellose sodium, citric acid monohydrate, butyl hydroxyanisol, propyl gallate, magnesium stearate.

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Dosage and Administration

Before initiating therapy with Inegy, patients should switch to a cholesterol-lowering diet and follow it throughout the entire course of treatment.

The drug is administered orally 1 time / day, in the evening, regardless of the meal.

The dose depends on the initial level of LDL, the purpose of treatment and the therapeutic effect and can vary from 10/10 mg (10 mg of ezetimibe + 10 mg of simvastatin) to 10/80 mg (10 mg of ezetimibe + 80 mg of simvastatin) per day. An initial dose of 10/20 mg (10 mg of ezetimibe + 20 mg of simvastatin) per day is usually recommended.

In order to gradually reduce the level of LDL, a dose of the drug of 10/10 mg can be recommended (10 mg of ezetimibe + 10 mg of simvastatin). For a significant reduction in LDL (more than 55%), patients may be recommended an initial dose of 10/40 mg (10 mg of ezetimibe + 40 mg of simvastatin) per day.

2 weeks after the start of treatment, as well as throughout the course of treatment, lipid levels should be monitored, and if necessary, adjust the dose of the drug.

Primary hypercholesterolemia (heterozygous familial and non-familial hypercholesterolemia, mixed dyslipidemia)

It is recommended to take Inegy daily in a dose of 10/40 mg (10 mg of ezetimibe + 40 mg of simvastatin) or 10/80 mg (10 mg of ezetimibe + 80 mg of simvastatin) in the evening.

Therapy should always be carried out against the backdrop of a cholesterol-lowering diet.

To further reduce levels of TG and non-HDL and increase HDL in patients with mixed dyslipidemia, treatment with Inegy can be supplemented with fenofibrate.

Homozygous familial hypercholesterolemia

Inegy is recommended to be taken in a dose of 10/40 mg or 10/80 mg 1 time / day in the evening. The drug should be used in combination with another lipid-lowering therapy (for example, LDL-apheresis). In the absence of the possibility of additional treatment, Inegy can be prescribed as monotherapy.

Elderly patients dose adjustment is not required.

Patients with mild hepatic impairment (5-6 points on the scale of Child-Pugh) dose adjustment is not required. It is not recommended to prescribe the drug. patients with moderate (7–9 points on the Child-Pugh scale) or severe (more than 9 points on the Child-Pugh scale) liver failure.

Patients with mild to moderate renal insufficiency dose adjustment is not required. With severe renal failure (QC <30 ml="" min="" the="" drug="" at="" a="" dose="" of="" more="" than="" 10="" mg="" day="" should="" be="" used="" with="" caution="" p="">

Use in combination with other drugs.

Inegy should be taken at least 2 hours before or 4 hours after taking bile acids.

For patients receiving nicotinic acid in a dose of more than 1 g / day, cyclosporine or danazol, the maximum dose of Inegy is 10/10 mg / day.

For patients receiving amiodarone or verapamil, the maximum dose of Inegy is 10/20 mg / day.

Adverse reactions

The safety of the drug Inegy has been studied in clinical studies involving more than 3,800 patients and during post-marketing surveillance in different countries. In general, Inegy is well tolerated by patients.

Side effects while taking Inegy are comparable to side effects previously reported when taking ezetimibe and / or simvastatin.

According to placebo-controlled studies and in the period of post-marketing monitoring of patients with Inegy, the following characteristic side effects were noted with a frequency of> 1/100 and <1/10, both related to the drug intake and without a well-established link:

From the digestive system: flatulence, abdominal pain, constipation, diarrhea, dyspepsia, vomiting, cholelithiasis, cholecystitis, jaundice, hepatitis; rarely (> 1/10 000, <1/1000) - nausea; very rarely (<1/1 000) - pancreatitis; in some cases - liver failure. According to controlled combined clinical studies, a clinically significant increase in serum transaminases (ALT and / or ACT 3 times or more) was observed in 1.7% of patients who received Inegy (these changes were asymptomatic, did not lead to cholestasis and passed on their own when discontinuing or continuation of treatment).

From the hemopoietic system: thrombocytopenia, anemia.

From the musculoskeletal system: myalgia, arthralgia; very rarely - myopathy / rhabdomyolysis.

From the side of the central nervous system: dizziness, headache.

Allergic reactions: rarely (> 1/10 000, <1/1000) - skin rash and urticaria; very rarely (<1/10 000) - anaphylactic reactions and angioedema.

Other: fatigue, asthenia. In 0.2% of patients who received Inegy, there was a clinically significant increase in CPK (10 times or more VGN).

Contraindications

Carefully: the drug should be used for severe renal failure (CC <30 ml="" min="" alcohol="" abuse="" a="" history="" of="" liver="" diseases="" muscle="" soreness="" or="" changes="" in="" skeletal="" tone="" unknown="" etiology="" gall="" bladder="" while="" inegy="" is="" administered="" with="" fibrates="" p="">

Drug interactions

When using Inegy, especially in high doses, in combination with powerful CYP3A4 inhibitors, for example, with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, nefazodone, the risk of myopathy / rhabdomyolysis increases. If you need therapy with itraconazole, ketoconazal, erythromycin, clarithromycin or telithromycin, Inegy should be discontinued. Strong inhibitors of the isoenzyme CYP3A4 increase the risk of myopathy, because prevent the removal of simvastatin. Concurrent use of the drug with other drugs containing strong CYP3A4 inhibitors should be avoided, unless the expected benefits of the combination therapy exceed the potential risk.

With the simultaneous use of Inegy and fenofibrate or gemfibrozil, the concentration of ezetimibe in plasma increases by 1.5 and 1.7 times, respectively; however, this increase is not clinically significant. The safety and efficacy of Inegy in combination with fibrates (with the exception of fenofibrate) are not well understood. In the study, which was attended by 184 patients who took Inegy at a dose of 10/20 mg / day and fenofibrate at a dose of 160 mg for 12 weeks, no adverse reactions were observed from the gallbladder. It is assumed that fibrates can increase the secretion of cholesterol in bile, which in turn can lead to cholelithiasis.

With the simultaneous use of the drug Inegy, especially in high doses, with cyclosporine, danazol or nicotinic acid (more than 1 g / day) increases the risk of myopathy / rhabdomyolysis. Inegy in combination with nicotinic acid (more than 1 g / day) should be administered with caution, since nicotinic acid as a monotherapy can cause myopathy. For patients taking cyclosporine or danazol at a dose of more than 1 g / day, the dose of Inegy should not exceed 10/10 mg / day. The potential benefit and potential risk should be assessed when Inegy is prescribed to patients receiving cyclosporine or danazol. When prescribing Inegy in combination with cyclosporine, constant monitoring of the concentration of cyclosporine in the blood is necessary.

With simultaneous use with Inegy, especially in high doses, with amiodarone or verapamil increases the risk of myopathy / rhabdomyolysis. There is evidence of the development of myopathy in 6% of patients who participated in relevant clinical studies and received simvastatin at a dose of 80 mg and amiodarone. For patients taking amiodarone or verapamil, the dose of Inegy should not exceed 10/20 mg / day. The combined use of Inegy in doses exceeding 10/20 mg / day with amiodarone or verapamil should be avoided, unless the benefits of combined therapy exceed the potential risk of myopathy.

In patients receiving fusidic acid at the same time as Inegy, the risk of myopathy may increase, so clinical monitoring is necessary for such patients.

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

Preclinical studies have shown that ezetimibe does not induce the CYP3A4 isoenzyme. There was no clinically significant pharmacokinetic interaction between ezetimibe and other drugs that are metabolism substrates involving isoenzymes of the cytochrome P450 system 1A2, 2D6, 2C8, 2C9, and 3A4 or N-acetyltransferase. Simvastatin is metabolized by a CYP3A4 isoenzyme, but does not possess CYP3A4 inhibitory activity, therefore its effect on the plasma concentration of other drugs metabolized by CYP3A4 is unlikely.

When combined with Kolestiramine, the average AUC of total ezetimibe (ezetimibe and ezetimibe glucuronide) decreased by approximately 55%. With the combined use of Inegy and Kolestiramine, the increasing decrease in LDL can be less pronounced.

In 2 clinical studies (one in healthy volunteers, the other in patients with hypercholesterolemia) simvastatin at a dose of 20-40 mg / day moderately potentiated the effect of coumarin anticoagulants, extending the prothrombin time when the initial value of MHO (the ratio of patient's prothrombin time to prothrombin time blood plasma) of 1.7 in healthy volunteers increased to 1.8, and in patients with hypercholesterolemia, the initial value of 2.6 increased to 3.4. Patients taking coumarin anticoagulants are carefully monitored for blood coagulation parameters (prothrombin time) before the first ingestion of Inegy. Subsequent measurements should be regular to achieve stable indicators of MHO, then measurements are carried out at the usual intervals recommended for monitoring in the treatment with coumarin anticoagulants. With the abolition of the drug and changing the dose Inegy spend an extraordinary determination of the parameters of blood clotting. In patients not taking anticoagulants, simvastatin therapy did not cause bleeding or changes in blood clotting parameters.

At the same time taking Inegy and antacids, the level of absorption of ezetimibe is slightly reduced, while its bioavailability does not change.

Grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, and may increase the level of substances metabolized by this isoenzyme in the blood plasma. The effect of drinking juice in small amounts (250 ml per day) is minimal (the activity inhibiting HMG-CoA reductase increases in plasma by 13%, as shown by the AUC value) and has no clinical significance. However, drinking large amounts of juice (more than 1 l per day) while taking simvastatin significantly increases the level of activity in the blood plasma that inhibits HMG-CoA reductase. Therefore, you should avoid eating large amounts of grapefruit juice and at the same time taking the drug.

Pregnancy and Lactation

The drug is contraindicated during pregnancy and lactation (breastfeeding).

Special instructions

If it is necessary to administer Inegy to patients with severe renal insufficiency (CC <30 ml="" min="" the="" drug="" at="" a="" dose="" of="" more="" than="" 10="" mg="" day="" should="" be="" used="" with="" caution="" p="">

Inegy should be used with caution in patients taking large amounts of alcohol and / or having a history of liver disease. Acute liver diseases or an inexplicably sustained high level of liver enzyme activity are contraindications to taking the drug. Inegy is not recommended for patients with moderate or severe liver failure. Patients with a history of history require careful observation during treatment with Inegy.A few days before the large surgical interventions and in the early postoperative period, it is recommended to stop taking the drug temporarily.

Simvastatin, like other HMG-CoA reductase inhibitors, can cause myopathy, manifested by muscle pain, weakness, fatigue, and an increase in the level of CPK more than 10 times relative to VGN. 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 due to an increase in the blood plasma inhibitory activity against HMG-CoA reductase. The decision to administer drug therapy to Inegy in combination with other drugs should be taken individually, taking into account the possible risk of myopathy.

Most cases of rhabdomyolysis during treatment with simvastatin were combined with an aggravated history, including renal failure, predominantly diabetic.

Patients with a history of history require careful observation during treatment with Inegy.

The risk of myopathy / rhabdomyolysis depends on the dose of simvastatin. In clinical studies, when the patient’s condition was carefully monitored, myopathy / rhabdomyolysis was observed: when taking simvastatin at a dose of 20 mg in approximately 0.03% of cases, at a dose of 40 mg in 0.08%, at a dose of 80 mg in 4% of cases.

At the beginning of the reception or with an increase in the dose of the drug Inegy patients should be warned about the risk of myopathy and the need to immediately inform the doctor about the occurrence of unexplained muscle pain, weakness or indisposition. In case of diagnosis or suspicion of myopathy, therapy with Inegy should be immediately discontinued. The presence of these symptoms and / or increase in the level of CPK more than 10 times higher than VGN, means the development of myopathy. In most cases, when discontinuing the administration of simvastatin, the symptoms of myopathy and elevated levels of CPK disappeared.

At the beginning of taking or increasing the dose of Inegy, periodic monitoring of CPK levels may be required, however, this measure does not guarantee the prevention of myopathy.

Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention

No studies have been conducted to evaluate the effect of the drug on the ability to drive and to other potentially dangerous activities. However, there is no reason to assume that Inegy can somehow influence these processes.

Overdosage

A few cases of simvastatin overdose have been reported with no clinically significant consequences for patients; the maximum dose taken was 3.6 g.

In clinical studies, 15 healthy patients who took ezetimibe at a dose of 50 mg / day for 14 days, and 18 patients with primary hypercholesterolemia who took ezetimibe at a dose of 40 mg / day for 56 days, showed good tolerability of therapy. Several cases of overdose have been reported in which undesirable effects were either not observed or were not serious.

Treatment: There are no antidotes for ezetimibu and simvastatin. In the event of an overdose of the drug Inegy, it is recommended to carry out symptomatic and supportive treatment.