Atorpa-E medicine 20/10 Apimed prevents cardiovascular disease and hypercholesterol (3 blisters x 10 tablets)

mā ATC: cioba05

Plasma cholesterol is made up of intestinal absorption and endogenous synthesis. Atorpa-E contains Ezetimibe and Atorvastatin, two components that reduce lipid with additional mechanism of action.

Atorpa-E reduces total cholesterol, LDL-Cholesterol (LDL-C), Apolipoprotein B (APO B), Triglycerides (TG) and Cholesterol Lipoprotein are low density (no HDL-C) and increase HDL-C through double inhibition of cholesterol absorption and synthesis.

ezetimibe

Ezetimibe inhibits cholesterol absorption from the intestine. Ezetimibe works when used orally and has mechanisms that are different from the cholesterol -reducing drugs of other groups (such as statins, bile acid secretion inhibitors [resin], fibric acid derivatives, and stanols of plant origin).

Ezetimibe localized at the brush edge of the small intestine and inhibit cholesterol absorption, resulting in reduced cholesterol transportation from the intestine into the liver; Statines reduce cholesterol synthesis in the liver and these two separate mechanisms complement each other to reduce cholesterol.

In a 2 -week clinical study on 18 patients with hypercholesterolemia, Ezetimibe inhibits the absorption of cholesterol in the intestine about 54% compared to Placebo.

A series of clinical studies have been conducted to determine the inhibition of selective cholesterol absorption of Ezetimibe.

Ezetimibe inhibits absorption [14C] - Cholesterol without affecting triglyceride absorption, fatty acids, bile acid, progesterone, ethinyl estradiol, or vitamins A and D in fat.

atorvastatin

Atorvastatin is a selective and HMG-CoA Reductase inhibitor, the speed limit enzyme plays a role in transforming 3-hydroxy-3-methylglutarianl-coenzyme A into Mevabonate, a precursor of sterols including cholesterol. Triglycerides and cholesterol in the liver are combined with very low density lipoprotein (VLDL) and are released into plasma to distribute to peripheral tissues.

Lipoprotein is low density (LDL) created from VLDL and is catabolized mainly through high -sized receptors for LDL (LDL receptor).

Atorvastatin reduces cholesterol and lipoprotein levels by inhibiting HMG-Coa Reductasc and then a cholesterol biosynthesis process in the liver and increases the number of LDL receptors in the liver on the cell surface, enhances the absorption and catabolism of LDL.

Atorvastatin reduces the formation of LDL and the number of LDL feces. Atorvastatin creates a complete and sustainable increase in the activity of the LDL receptor along with the beneficial change in quality of circulating LDL particles.

Atorvastatin is effective in reducing LDL-C in patients with hypertonic blood cholesterol-type blood cholesterol, patients who do not respond to lipid medications.

The drug also works for patients with hyperlested hypertension, heterozygous, hypercholesteroline hypercholesterol, and mixed hyperlipidemia, including diabetes without insulin.

Dynamic pharmacokinetics

absorption

ezetimibe

After drinking, Ezetimibe is absorbed quickly and strongly into a substance that has the effect of Phenolic Glucoronid (Ezetimibe - Glucoronid). Maximum maximum plasma concentration (CMAX) appears about 1 to 2 hours for Ezetimibe-Glucoronid and 4 to 12 hours for Ezetimibe.

Not determined to be absolutely used by Ezetimibe because this active ingredient does not soluble in the solvent for injection.

Use the same food (high -fat or non -fat meals) does not affect the oral bioavailability of Czetimibe when using Czetimibe 10 mg.

Atorvastatin

Atorvastatin is absorbed quickly after drinking. The peak concentration in plasma (CMAX) is achieved within 1 to 2 hours. The level of absorption increases corresponding to the dose of Atorvastatin.

After drinking, Atorvastatin film tablets are 95% to 99% compared to oral solution. The absolute bioavailability of Atorvastatin reaches approximately 12% and the system of systemic use of HMG-CoA Reductase inhibitors reach approximately 30%. Low -body bioavailability is due to clearance before absorbing the whole body in the gastrointestinal mucosa and/ or the initial metabolism in the liver.

distribution

ezetimibe

Ezetimibe and Ezetimibe - Glucoronid linked to plasma proteins, respectively 99.7% and 88 - 92%.

Atorvastatin

Average distribution volume of Atorvastatin reaches approximately 381 liters with> 98% Atorvastatin associated with plasma proteins.

transformation

ezetimibe

Ezetimibe is basically metabolized in the small intestine and the liver thanks to the conjugate with glucoronid (phase II reaction) and then excreted through bile.

have seen minimum oxidation metabolism (stage 1 reaction) in all species of research.

Ezetimibe and Ezetimibe - Glucoronid are the main metabolic components of the drug determined in plasma, accounting for about 10 to 20% and 80 to 90% of the total number of drugs in plasma.

Ezetimibe and Ezetimibe - Glucoronid are eliminated from plasma slowly with significant reuse in the gut. Half of the excretion of Czetimibe and Ezetimibe - Glucoronid about 22 hours.

Atorvastatin

Atorvastatin is converted by Cytochrom P450 3A4 into Ortho and ParahydroxyLatization derivatives and different beta-oxidation products. These products are also continued to be transformed through glucuronide.

In in vitro, the HMG-CAA Reductase inhibitors of the metabolites of ortho and parahydroxylate chemicals are equivalent to Atorvastatin. About 70% of HMG-CoA Reductase inhibitors are of active metabolites.

Elimination

ezetimibe

In humans, after taking "C-Ezetimibe (20 mg), the total czetimibe accounts for about 93% of the total active active active ingredient in plasma. It has been found to be 78% and 11% of the active active ingredient in the stool and urine obtained for 10 days.

Atorvastatin

Atorvastatin is excreted mainly through bile after the metabolism in the liver and/ or outside the liver. However, Atorvastatin does not significantly participate in the intestinal circulation. The average disposal time of Atorva 1 in plasma is approximately 14 hours. The waste time for HMG-CoA Reductase inhibitors is about 20 to 30 hours due to the participation of active metabolites.

Special subjects

Children

ezetimibe:

ezetimibe:

ezetimibe:

ezetimibe:

Atorvastatin:

ezetimibe:

atorvastatin:

Elderly: No dose adjustment in elderly patients.

Children: The safety and effectiveness of Atorpa-E in children has not been proven.

Hepatic failure: Be careful when using Atorpa-E in patients with liver failure. Atorpa-E contraindicent in patients with liver disease.

Kidney failure: There is no need to adjust the dose in patients with renal failure.

Note: The above dose is for reference only. Specific dosage depends on the condition and level of progression of the disease. For a suitable dose, you need to consult a doctor or medical specialist.

What to do when overdose?

ezetimibe

In clinical studies, Ezetimibe dose of 50 mg/ day for up to 14 days in 15 healthy subjects or a dose of 40 mg/ day for 56 days in 18 patients with primary blood cholesterol, in general, well -tolerated. Only a few reports on the case of overdose and large feces are not accompanied by adverse effects.

The adverse effects reported when using overdose are not serious. In animals, do not observe toxicity after taking the only dose of 5000 mg/ kg in mice and 3000 mg/ kg in dogs.

atorvastatin

Because Atorvastatin is strongly connected to plasma proteins, the hemorrhage is difficult to significantly increase the clearance of Atorvastatin.

What to do when you forget a dose? However, if near the next dose time, skip the forgotten dose. Do not take double the dose to compensate for the forgotten dose.

There is no special requirement on drug treatment after use.

Caution when using

muscle disease/muscle pilot

There have been reports on cases of muscle pattern when using Ezetimibe. Most patients with muscle pattern when used in combination with ezetimibe with a statin. However, there are very rare cases of muscle targets that are still reported when using alone ezetimibe or when ezetimibe combined with other drugs involved in the ability to increase the risk of muscle pattern.

Atorvastatin as well as other HMG-Coa Reductase inhibitors, in rare cases that can affect skeletal muscle and muscle pain, muscle inflammation and muscle disease can progress into muscle syndrome, a situation that can be life-threatening manifested by creatin phosphokinase levels (CPK) significantly increased (> 10 times the upper limit of the normal level) Myoglobinuria can lead to renal failure.

Before treatment

Atorpa-E needs to be used cautiously in patients with factors affecting muscle syndrome. CPK tests should be done before starting treatment in the following cases:

Creatin phosphokinase test (CPK)

Do not measure the concentration of creatin phosphokinase (CPK) after exertion exercise or when there is the presence of a certain cause that can increase the CPK concentration because this can make the result deviation
results. If the concentration of CK increases significantly before treatment (> 5 times the upper limit of normal level), a test should be done to redefine within 5-7 days.

during treatment

Ask the patient to notify immediately when muscle pain, muscle weakness or muscle spasticity especially when accompanied by fatigue or fever, or if the signs and symptoms still exist after stopping treatment with Atorpa-E.

If these symptoms occur while patients use Atorvastatin, CPK concentration should be measured.

If the CPK concentration increases significantly (> 5 times the upper limit of normal level) should stop treatment.

If muscle symptoms are serious and cause daily discomfort, even if the CPK concentration

If the symptoms are relieved and the CPK concentration returns to normal, it is advisable to consider using Atorpa-E or another statin at the lowest dose and closely monitoring.

It is necessary to stop using Atorvastatin if the CK concentration increases significantly in terms of clinical (> 10 times the upper limit of normal level), or if diagnosed or suspected of muscle pilot.

There have been very rare reports on muscle necrotic disease due to immunity (IMNM) during or after treatment with some statins. The clinically IMNM shows continuous muscle aches and increases serum creatinin. These manifestations continue to stop treating with statin.

Because Atorpa-E contains Atorvastatin, the risk of muscle and muscle elimination increases when Atorpa-E is simultaneously used with drugs that can increase the level of Atorvastatin in plasma such as strong inhibitors or CYP3A4 or shipping proteins (e.g. Colchicin, Ciclosporin, Telithromycin, Clarithromycin, Delavidin, StirPentol, StirPentol, StirPentol, StirPentol, StirPentol, StirPentol, StirPentol Ketoconazole, Voriconazole, Itraconazole, Posaconazole and HIV Protease inhibitors include Ritonavir, Lopinavir, Atazanavir, Indinavir, Darunavir ...).

The risk of muscle disease can also increase when coordinated with gemfibrozil and other fibrats, erythromycin, niacin, antiviral antiviral drugs, Boceprevir, Telaprevir, ElbasVL, Grazeprevir, or combined Tipranaviri Ritonavir.

In cases where it is necessary to simultaneously use these drugs with Atorvastatin, it is necessary to consider the benefits and risks of treatment. When patients are taking drugs that can increase the concentration of Atorvastatin in plasma, Atorvastatin should be used at a lower dose than the maximum dose.

In addition, when using strong CYP3A4 inhibitors, Atorvastatin is required at a lower starting dose and it is necessary to conduct appropriate clinical monitoring for these patients (see the interaction).

Do not use Atorpa-E simultaneously with fusidic acid. In patients needed to use fusidic acid, statin should be stopped during fusidic acid treatment.

There have been reports on cases of muscle pattern (some deaths) in patients who are using fusidic acid in combination with statin (see interaction).

Statin therapy can be reused after 7 days from the last dose of fusidic acid.

In special cases, if it is required for prolonged treatment with fusidic acid, for example, to treat severe infections, the simultaneous use of Atorpa-E with fusidic acid should be considered on the basis of specific cases under strict medical monitoring.

Liver enzymes:

In control clinical trials that combine Atorvastatin and Ezetimibe, the continuous transaminase increased (> 3 times limited to normal levels) (see unwanted effects).

Check the liver function before starting to use Atorpa-E and often afterwards. Liver function should be monitored in patients with signs or symptoms of liver damage. Patients with high transaminase levels should be monitored until the abnormalities have been resolved.

If the transaminase concentration is still higher than 3 and the upper limits of normal levels, the dose or stop use of Atorpa-E (see the unwanted effect).

Be cautious when using Atorpa-E for patients to drink a lot of alcohol and/ or a history of liver disease.

Hepatic failure:

Due to the unknown effect of increasing Ezetimibe concentration in patients with medium or severe liver failure, Atorpa-E should not be used for patients bouncing (see pharmacokinetics).

Fibrats:

Not studying safety and efficiency of using Ezetimibe combination with fibrats. Therefore, should not use Atorpa-E combined with fibrats.

ciclosporin:

Be careful when starting with Atorpa-E during treatment with ciclosporin.

Need to monitor ciclosporin levels in patients using Atorpa-E combined with ciclosporin.

anticoagulants:

Should follow the appropriate internationalization of internationalization (INR) when combining Atorpa-E with wafarin, anti-anticoagulant drug resistant to vitamin K or Fluindion.

Stroke prevention by actively reducing cholesterol levels (Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SparCl)):

According to an analysis of posting analysis of stroke groups in patients with no new coronary artery disease or transient infarction, the rate of hemorrhagic stroke in patients begins to treat atorvastatin 80 mg higher than the same fake. Increased risk has been especially noted in patients who have had a stroke or a disabled infarction before treatment.

For patients who have had a hemorrhagic stroke or an infarction, the balance between the risk and benefits of Atorvastatin 80 mg has not been determined and the potential risk of hemorrhage stroke should be carefully considered before starting treatment (see pharmacokinetics).

Interstitial lung disease:

Some special cases of interstitial lung disease have been recorded when using some statins, especially long -term treatment (see unwanted effect). The most common manifestation includes shortness of breath, dry cough and impaired health in general fatigue, weight loss and fever). If a patient is suspected of interstitial lung disease, statin should be stopped.

diabetes:

Some evidence suggests that statins increase blood sugar levels in some patients at high risk of diabetes, causing hyperglycemia, leading to treatment. However, this risk is not significant compared to reducing the cardiovascular risk of statin and therefore it is not the reason to stop treatment with statin.

Patients are at risk of hyperglycemia (blood sugar at 5.6 to 6.9 mmol, body mass index (BMI)> 30 kg/m, increase triglycerides, hypertension) should be monitored both clinical and biochemical according to national instructions.

excipients:

The drug contains lactose. Patients with rare genetic diseases are galactose, deficiency of lactase enzyme or malposive glucose-galactose should not be taken.

Using drugs for pregnant and lactating women

Pregnant women:

Atherosclerosis is a chronic process, and shyly treating conventional lipid medications during pregnancy has little impact on the risk of long -term associated with hypercolenic cholesterol.

Contraindicated to use Atorpa-E during pregnancy.

Simultaneous use of Ezetimibe and Atorvastatin in pregnant mice shows an abnormal increase in bone "reducing bone chemistry in sternum burning" related to high doses of Ezetimiber Atorvastatin. This is related to the fetal weight reduction. In pregnant rabbits, observed a small percentage of skeletal abnormalities.

Atorvastatin

ezetimibe:

Fibrats: Use in combination with Tenofibrat or Gemfibrozil, increasing the total concentration of Ezetimibe about 1.5 - 1.7 times but not clinical significance. Contraindications to Atorpa-E simultaneously with Gemfibrozil and other fibrats are not recommended.

Atorvastatin

CYP3A4 inhibitors:

Medium CYP3A4 inhibitors (such as erythromycin, diltiazem, verapamil and fluconazole) may increase the concentration of Atorvastatin in plasma. The increased risk of muscle disease has been recorded when using erythromycin simultaneously with the statins. Research on drug interaction assessment of the effect of Amiodaron or Verapamil to Atorvastatin has not been conducted.

Both Amiodaron and Verapamil are known to inhibit the activity of CYP3A4 and when used simultaneously with Atorpa-E can cause an increase in contact with Atorvastatin. Therefore, Atorvastatin should be considered at a lower doses and the clinical monitoring is suitable for patients to use Atorvastatin simultaneously with medium -level CYP3A4 inhibitors. Appropriate clinical monitoring after starting or after
adjust the CYP3A4 inhibitors.

Anti -cancer protein inhibitors and (BCRP):

Concomitance BCRP inhibitors (such as Elbasvir and Grazoprevir) may increase the level of lattvastatin in plasma and increase the risk of muscle disease. Therefore, it is necessary to consider adjusting the dose of Atorvastatin. Simultaneous use of Elbasvir with Grazoprevir with Atorvastatin increases the level of Atorvastatin in plasma 1.5 times (see Table 1). Therefore, the atorpa-E dose should not exceed 10/20 mg daily in patients who use drug products and contain elbasvir or grazeprevir.

Cytochrom P450 344:

Simultaneous use Atorvastatin with P450 3A4 (such as Efavirenz, Rifampicin, St. John's Wort) may reduce the concentration of Atorvastatin in plasma.

Due to the dual interaction mechanism of Rifampicin (Cytochrom P450 3A4 touch and OatP1B1 transport inhibitors in the liver), Rifampicin can significantly reduce the level of plasma Atorvastatin levels of rifampicin on Atorvastatin concentration in liver cells, but if it is not known, it cannot be prevented with a combination of treatment.

Transport protein inhibitors:

Transport protein inhibitors (eg ciclosporin) may increase the body's body contact level. The influence of the inhibition of the liver absorption substances on the Atorvastatin concentration in liver cells is not known. If these drugs cannot be avoided, they should reduce the dose and clinical monitoring to control the effectiveness of treatment.

gemfibrozil/ fibrats:

The use of solitary fibrats is sometimes related to mechanical events, including muscle pattern. The risk of these events can be increased by simultaneous use of fibrats and atorvastatin. If it is not possible to avoid these drugs, the lowest atorvastatin dose should be used to achieve the purpose of treatment and need to monitor the patient appropriately.

Ezetimibe: The use of solitary ezetimibe can cause muscle -related events, including muscle pattern. The risk of these events can be increased by simultaneous use of Ezetimibe and Atorvastatin. Clinical monitoring appropriately for these patients.

Colestipol: Atorvastatin concentration in plasma and lower active metabolites (approximately 25%) when concurrent Colestipol together with Atorvastatin. However, the lipid reduction effect is greater when
is simultaneously used atorvastatin and colestipol compared to when using one of these two drugs alone.

Fosidic acid: The risk of muscle disease, including muscle pattern increases when using fusidic acid and statin. Cases of muscle pattern (some deaths) have been told
when using fusidic and statin acid simultaneously. If the body is needed with fusidic acid, should stop treatment with Atorvastatin during fusidic acid treatment.

Colchicin: Although there has been no study on drug interaction between Atorvastatin and Colchicin, cases of muscle disease have been reported when Atorvastatin is simultaneously used with colchicin, so be careful when indicated atorvastatin general with colchicin.

boceprevir: Atorvastatin's exposure increases when combined with boceeprevir. If it is necessary to coordinate with Atorpa-E, it is necessary to start with Atorpa-E at the lowest possible dose and then increase the dose under close supervision until the desired clinical effect does not exceed the daily dose of 10 20 mg.

In patients who are being treated with Atorpa-E, the daily dose of Atorpa-E should not exceed 10/20 mg when used with BoCeprevir.

Atorvastatin in unknown liver cells. If these drugs cannot be avoided, they should reduce the dose and clinical monitoring to control the effectiveness of treatment.

gemfibrozil/ fibrats:

The use of solitary fibrats is sometimes related to mechanical events, including muscle pattern. The risk of these events can be increased by simultaneous use of fibrats and atorvastatin. If it is not possible to avoid these drugs, the lowest atorvastatin dose should be used to achieve the purpose of treatment and need to monitor the patient appropriately.

ezetimibe:

The use of solitary ezetimibe can cause muscle -related events, including muscle pattern. The risk of these events can be increased by simultaneous use of Ezetimibe and Atorvastatin. Clinical monitoring appropriately for these patients.

Colestipol:

Atorvastatin concentration in plasma and lower active metabolites (approximately 25%) when using Colestipol simultaneously with Atorvastatin. However, the lipid reduction effect is greater when using Atorvastatin and Colestipol compared to when using one of these two drugs alone.

Fosidic acid:

The risk of muscle disease, including muscle pattern increases when using fusidic and statin acid simultaneously.

The mechanism of this interaction is not known. Cases of muscle pattern (some deaths) have been told when using fusidic and statin acid simultaneously. If the body is needed with fusidic acid, should stop treatment with Atorvastatin during fusidic acid treatment.

colchicin:

Although studies have not been conducted on drug interaction between Atorvastatin and Colchicin, cases of muscle disease have been reported when Atorvastatin is used simultaneously with Colchicin, so be careful when indicating Atorvastatin with Colchicin.

boceprevir:

increases in contact with BoCeprevir. If it is necessary to coordinate with Atorpa-E, should start with Atorpa-E at the lowest possible doses and then increase the dose under close supervision until the desired clinical effect does not exceed the daily dose of 10 20 mg. In patients who are being treated with Atorpa-E, the daily dose of Atorpa-E should not exceed 10/20 mg when used with BoCeprevir.

The influence of Atorpa-E on the dynamics of other drugs

ezetimibe:

In preclinical studies, it has been shown that ezetimibe does not cause enzymes to metabolize Cytochrom P450. There is no clinical pharmacokinetic interaction between Ezetimibe and drugs metabolized by Cytochrom P450 1A2, 2D6, 2C8, 2C9, and 3A4, or N-acetyltransferase.

Anticoagulant. In a study on 12 healthy male volunteers, simultaneously used with Ezetimibe (10 mg once a day) does not significantly affect the bioavailability of warfarin and prothrombin time.

However, after the drug circulated on the market, there was a report on Inr increasing in patients using Ezetimibe simultaneously with Warfarin or Fluindion. Therefore, when using Atorpa-E simultaneously with warfarin or other anticoagulants, or fluindion, should monitor the appropriate INR index.

Atorvastatin

Digoxin: simultaneously use repeated dosgoxin and Atorvastatin 10 mg increases the equilibrium concentration of digoxin. Patients who are being treated with digoxin should be monitored regularly.

Oral contraceptive: simultaneous use of Atorvastatin and oral contraceptives increases the plasma concentrations of Norethisteron and Ethinyl Estradio.

warfarin:

In a clinical study in patients who are under long -term treatment with warfarin, simultaneously taking Atorvastatin 80 mg daily reduces prothrombin time to 1.7 seconds in the first 4 days, this value is normal for 15 days from the start of Atorvastatin.

Although there are very rare cases of clinical interactions are reported, prothrombin time should be determined before starting treatment with Atorpa-E in patients who are taking anticoagulant drugs, and we often often start treatment. Apply similarly to the cases of changing the dose or stopping atorpa-e treatment.

Atorvastatin treatment is not related to bleeding or changing prothrombin time in patients without anticoagulants.

Table 1: Effect of other drugs on the pharmacokinetics of Atorvastatin.