Atozet medicine 10mg/10mg MSD treats dyslipidemia, preventing cardiovascular diseases (3 blisters x 10 tablets)

Pharmacokology

ATC code: C10BA05

Atozet (Ezetimibe/Atorvastatin) is a drug that reduces blood lipids, selectively inhibits the intestinal absorption of cholesterol and related plant sterols and inhibits endogenous cholesterol synthesis.

Atozet

Plasma cholesterol is derived from intestinal absorption and endogenous synthesis. Atozet contains Ezetimibe and Atorvastatin, two compounds that reduce blood lipids with additional mechanisms. Atozet reduces the increasing concentration of total cholesterol (Total-C), LDL-C, APO B, TG and Non-HDL-C, and increases HDL-C through double inhibitors on cholesterol's absorption and synthesis.

ezetimibe

Ezetimibe memories of cholesterol absorption in the intestine. Ezetimibe has oral activity and has a mechanism of action different from other groups of cholesterol -reducing compounds (for example, statin, bile acid separating drugs [resin], derivatives of fibric acid and plant stanol). The target molecule of Ezetimibe is the shipping of sterol, niemann-pick C1-Like 1 (NPC1L1), responsible for the absorption of cholesterol and phytosterol in the intestine.

Ezetimibe positions at the edge of the brush of the small intestine and inhibits the absorption of cholesterol, leading to a decrease in cholesterol transport from the intestine to the liver; Statin reduces cholesterol synthesis in the liver and these different mechanisms bring a decrease in cholesterol.

In a 2 -week clinical study in 18 patients with hypercholesterol blood, Ezetimibe inhibits the absorption of cholesterol in the intestine of 54%, compared to placebo.

A series of clinical studies have been conducted to determine the selection of ezetimibe in inhibiting cholesterol absorption. Ezetimibe inhibits the collection [14C] -cholesterol without affecting the absorption of triglycerides, fatty acids, bile acid, progesterone, ethinyl estradiol or vitamins A and D in fat.

Atorvastatin

Atorvastatin is a selective and competitive inhibitor of HMG-Coa Reductase, this is a speed limit enzyme, responsible for the conversion of 3-hydroxy-3-methyl-glutaryl-coenzyme A into Meovalate, a precursor of sterol, including cholesterol. Triglycerides and cholesterol in the liver are combined into very low density lipoprotein (VLDL) and are released into plasma to distribute to peripheral tissues.

Lipoprotein is low density (LDL) formed from VLDL and is mainly catabolized through a highly affinity receptor with LDL (LDL receptor).

Atorvastatin reduces serum cholesterol and lipoprotein levels by inhibiting HMG-COA Reductase, which reduces cholesterol biosynthesis in the liver and increases the amount of LDL receptors on the surface of liver cells to enhance the absorption and catabolism of LDL.

Atorvastatin reduces LDL production and reduces the number of LDL particles. Atorvastatin increases and prolongs the activity of LDL receptors along with the beneficial change in the quality of LDL particles during the circulation. Atorvastatin is effective in reducing LDL-C in patients with hypertension hyperlested cholesterol, which is a group of patients who often do not respond to drugs that reduce blood lipids.

Atorvastatin has been shown to reduce the concentration of total cholesterol (Total -C) (30% - 46%), LDL -C (41% - 61%), ApoLipoprotein B (34% - 50%) and Triglycerid (14% - 33%) while creating an increase in HDL -C and Apolipoprotein A1 in a study in a research on a research on the dose of doses. These results are uniform in patients with hyperlemical hypertension hyperlested hypertension, blood cholesterol -hyperplasia forms and mixed blood lipid hyperplasia, including insulin -induced diabetes patients.

Dynamic pharmacokinetics

Atozet has been shown to be biological equivalent for simultaneous use of the corresponding doses of Ezetimibe and Atorvastatin tablets.

absorption

Atozet

The effects of a high -fat meal on Ezetimibe and Atorvastatin's pharmacokinetics when used in the form of Atozet tablets are equivalent to the effects that have been reported to the tablets of each separate substance.

ezetimibe

After oral use, Ezetimibe is quickly absorbed and strongly combined into a phenolic glucuronide with pharmacological activity (ezetimibe-glucuronide). Maximum concentration (cmax) in plasma averages occur within 1-2 hours for ezetimibe-glucuronide and 4-12 hours for ezetimibe. Ezetimibe's absolute use of absolute bioavailability because this chat is almost insoluble in the appropriate water environment for injection.

Simultaneously used with food (high -fat meals or non -fat meals) has no effect on ezetimibe oral bioavailability when used in the form of Ezetimibe 10mg tablets.

Atorvastatin

Atorvastatin is quickly absorbed after oral use; The maximum concentration in the Tuong (CMAX) occurs within 1-2 hours. The level of absorption increases proportional to Atorvastatin dose. After oral use, Atorvastatin film tablets have 95% to 99% of oral solution. The absolute bioavailability of Atorvastatin is about 12% and the whole body of the HMG-CA Reductase inhibitor activity is about 30%. Low -body bioavailability is thought to be due to the clearance of the whole body in the gastrointestinal mucosa and/or the metabolism through the liver for the first time.

distribution

ezetimibe

Ezetimibe connects 99.7% and Ezetimibe -Glucuronide binds 88 - 92% with plasma proteins.

Atorvastatin

The average distribution of Atorvastatin is about 381 liters. Atorvastatin cohesion> 98% with plasma protein.

transformation

ezetimibe

Ezetimibe is metabolized mainly in the small intestine and the liver through the glucuronide complex (stage II reaction) with the next secret excretion. The minimum oxidation metabolism (phase I reaction) has been observed in all species assessed. Ezetimibe and Ezetimibe -Glucuronide are the main metabolic compounds of the drug detected in plasma, Ezetimibe accounts for 10-20% and Ezetimibe -Glucuronide accounts for about 80 - 90% of the total amount of drugs in plasma. Both Ezetimibe and Ezetimibe-Glucuronide are gradually eliminated from plasma with significant evidence of intestinal circulation. The half-life of Ezetimibe and Ezetimibe-Glucuronide is about 22 hours.

Atorvastatin

Atorvastatin is converted by cytochrom P450 3A4 into hydroxy-chemical derivatives at Ortho and Para positions and different beta-oxidation products. In addition to other roads, these products are further transformed through glucuronide. In vitro the HMG-CoA Reductase inhibitors by hydroxy metabolites in Ortho and Para positions are equivalent to Atorvastatin. About 70% of inhibition activity for HMG-COA Reductase during circulation is thought to be due to active metabolites.

Elimination

ezetimibe

After using 14C-Ezetimibe (20mg) oral for humans, total ezetimibe accounts for about 93% of the total dose marked with radioactive in plasma. About 78% and 11% of the used radioactive dose were found in order in the feces and in the corresponding urine, within 10 days. After 48 hours, there is no level of radioactive markers detected in plasma.

Atorvastatin

Atorvastatin is excreted mainly through bile after metabolism through the liver and/or outside the liver. However, the drug does not seem to undergo a significant process of re -circulating the liver. The average selling time of Atorvastatin in people is about 14 hours. The half -life of inhibitory activity for HMG -CoA Reductase is about 20 - 30 hours due to the contribution of active metabolites.

Special patient groups

kidney failure

ezetimibe

After a single dose of Ezetimibe 10mg in patients with severe kidney disease (n = 8; Creatinin clearance (CRCI) average ≤ 30ml/min/1.73 m2), the area under the curve (AUC) of the average ezetlmibe increases about 1.5 times compared to healthy objects (n = 9).

A patient in this study (after kidney transplant and many drugs, including cyclosporin), has a total concentration of ezetimibe than 12 times higher.

Atorvastatin

Kidney disease does not affect plasma concentrations or atorvastatin's lipid effects and active metabolites.

liver failure

ezetimibe

After a single dose of Ezetimlbe 10 mg, the area of ​​the average curve (AUC) of the total ezetimibe total increased by about 1.7 times in patients with mild liver failure (Child Pugh 5 or 6) compared to healthy objects. In a multi -dose study, 14 days (10 mg/day) in average liver failure patients (the score of Child Pugh 7 - September), the average AUC of the total ezetimibe increased about 4 times on the first day and the 14th day compared to healthy subjects. There is no need to adjust the dose for patients with mild liver failure. Due to the unknown effect of ezetimibe concentration in patients with medium to severe liver failure (Child Pugh> 9), it is not recommended to use ezetimibe for these patients.

Atorvastatin

Atorvastatin concentration and its active metabolites in plasma increased significantly (about 16 times to CMAX and about 11 in AUC) in patients with chronic liver disease due to alcohol.

Children

ezetimibe

The absorption and metabolism of Ezetimibe is similar between children and teenagers (10 - 18 years old) and adults. Based on total ezetimibe concentration, there is no difference in pharmacokinetics between teenagers and adults. There is no pharmacokinetic data in groups of children

Atorvastatin

There is no pharmacokinetic data in groups of children.

Elderly

ezetimibe

The plasma concentration of the whole ezetimibe in the elderly (> 65 years) is about 2 times higher than the young (18 - 45 years old). The reduction of LDL-C and safety records between elderly and young subjects are treated with Ezetimibe.

Atorvastatin

Atorvastatin concentration and its active metabolites in plasma in healthy elderly people are higher in young people while the effect on lipid is equivalent to the effect of younger patients.

race

Based on the synthetic analysis of pharmacokinetic studies with Ezetimibe, there is no difference in pharmacokinetics between black and white people.

Gender

ezetimibe

The concentration of the total plasma ezetimibe in women is slightly higher (

Atorvastatin

Atorvastatin concentration and its active metabolites in women are different from men (women: about 20% higher in cmax and about 10% lower in AUC). These differences have no clinical significance, resulting in no clinical significance about lipids in men and women.

Hemataloagia

Atorvastatin

While studies have been conducted in patients with end -stage renal disease, hemolysis is not expected to significantly increase the clearance of Atorvastatin because the drug is strongly connected to plasma proteins.

None of the patients treated with Atozet have CK concentration ≥ 10 times the upper limit of the normal level.

After -sales experience and experience from other clinical trials

The following additional adverse reactions have been reported when using after -sales Atozet or in clinical studies or after -sales use with Ezetimibe or Atorvastatin:

Reports are usually not serious and admire when stopping statin, with time leading to a change in symptoms (1 day to many years) and reducing symptoms (on average 3 weeks).

Precautions when using

muscle disease/muscle disease

The rare cases of muscle pattern with secondary acute renal failure due to myoglobin the urine have been reported to Atorvastatin and with other drugs in this group. History of renal failure may be a risk factor for the generation of muscle pattern. These patients need to be more closely monitored for the effects on the muscle.

Atorvastatin, like other statins, sometimes cause muscle diseases, is defined as muscle pain or muscle weakness combined with increased creatin phosphokinase (CPK)> 10 times the upper limit of normal levels (ULN). It is recommended to consider muscle disease in any patient with spreading muscle pain, sensitivity of muscle pain or muscle weakness and/or increasing CPK significantly. It is necessary to advise patients to immediately report on muscle pain, muscle pain or muscle weakness, especially if accompanied by discomfort or crib or if the signs and muscle symptoms are still damaged after stopping at an acet. Atozet treatment should be discontinued if the CPK concentration increases significantly or muscle disease is diagnosed or suspected.

Caution should be careful in patients at risk of muscle pattern. Creatine Kinase (CK) levels should be measured before the beginning of treatment in the following cases: renal function, non -controlled thyroid defect, personal history or family with genetic disorders, a history of muscle poisoning due to statin or fibrat, alcohol abuse, elderly (> 65 years old) or women.

In these cases, it is necessary to consider the risk of treatment and possible and recommended benefits. If CK concentration increases significantly compared to the beginning (> 5 times the upper limit of normal levels) should not start treatment.

The risk of muscle disease during statin treatment is increased due to simultaneous use with cyclosporin, derivatives of acid
fibric, erythromycin, clarithromycin, hepatitis C Telaprevir, Elbasvir, Grazoprevir, combining
protease inhibitors of HIV -Including HIV, including HIVIVIRA Lopinavir plus Ritonavir, Tipranavir plus
with Ritonavir, Darunavir plus ritonavir, fosamprenavir, and fosamprenavir plus ritonavir, niacin, or
antifungal group Azol. Doctors consider Atozet combination therapy and derivative of fibric acid, erythromycin,
Clarithromycin, Elbasvir, Grazoprevir, combined with ritonavir, fosamprenavir, or fosam. Saquinavir plus itonavir, iopinavir plus ritonavir, darunavir with ritonavir, Azol or niacin dose reduces lipids should consider carefully between benefits and risks and should monitor patients carefully about any signs or symptoms of muscle pain, pain or muscle pain, especially in the first months of treatment and in the stage of increasing the dose of each dose of each dose medicine. Atozet dose should be considered and maintained lower when used simultaneously with the above drugs.

Use drugs for women during pregnancy and lactation

Women are likely to be pregnant

Women who are likely to be pregnant should use appropriate contraception during treatment.

Pregnant women

Atherosclerosis is a chronic process and the stopping of the drug that reduces lipid during pregnancy has a little impact on the long -term treatment results of primary hypercholesterolem.

contraindicated use of Atozet in pregnant women. Atozet should only be used for women of reproductive age when the patient is very difficult to conceive and has been notified of the possible dangers. If the patient is pregnant while taking this medication, the treatment must be stopped and notify the patient about the dangers that may occur for the fetus.

ezetimibe

There is no clinical data on cases of pregnant women using drugs.

When Ezetimibe is used with Atorvastatin, it does not observe the teratogenic effect in studies on the development of embryo in pregnant rats, in pregnant rabbits, observed a low percentage of skeletal deformities.

Atorvastatin

There is no adequate and well -controlled research on the use of Atorvastatin during pregnancy. There have been rare reports of birth defects after being exposed to the uterus. In an assessment of about 100 cases of pregnancy is monitored in the time in women who use other statins, the rate of birth defects, spontaneous miscarriage and fetus/death/death at birth does not exceed the expected rate in the general population. However, this study can only rule out an increase in the risk of birth defects 3-4 than the foundation ratio. In 89% of these cases, drug treatment begins before pregnancy and stops in the first 3 months of pregnancy when pregnancy has been determined.

breastfeeding mother

Rat studies have shown that Ezetimibe and Atorvastatin are excreted in mouse milk. It is unclear whether ezetimibe or Atorvastatin will excrete in breast milk, so women who are breastfeeding are not used atozet.

The effect of the drug on the ability to drive and operate machinery

There has been no research on impact on the ability to drive and operate machinery. However, some adverse effects have been reported to Atozet that can affect the ability to drive or operate machinery of some patients. The response of each patient changing to Atozet may change. [See the unrelenting reaction!]

Drug interactions

do not observe the clinical pharmacokinetic interaction when Ezetimibe is simultaneously used with Atorvastatin.

Interaction with CYP3A4

In preclinical studies, it has shown that ezetimibe does not induce the enzymes metabolic enzymes Cytochrom P450. It is not observed that the clinical pharmacokinetic interactions between Ezetimibe and drugs have been metabolized by Cytochrom P4501A2,2D6,2C8,2C9 and 3A4 or N-acetyltransferase.

Atorvastatin is metabolized by cytochrom P450 3A4. Simultaneous use of Atorvastatin with Cytochrom P450 3A4 inhibitors can lead to increased Atorvastatin levels in plasma. The degree of interaction and potential depends on the change of effect on Cytochrom P450 3A4.

Cytochrom P3A4 inhibitors increase the risk of muscle disease by reducing the elimination of Atozet's Atorvastatin ingredients.

Clarithromycin: The area under the curve (AUC) of Atorvastatin increases significantly when using the 80mg Atorvastatin period with clarithromycin (500mg, 2 times/day) compared to the unique Atorvastatin. Therefore, in patients using Clarithromycin, caution should be cautious when the Atozet dose exceeds 10/20mg.

Combining protease inhibitors: AUC of Atorvastatin increases significantly when using Atorvastatin simultaneously with some combined forms of HIV's protease inhibitors as well as Telaprevir is a protease inhibitor of hepatitis C virus compared to the unique Atorvastatin. Therefore, in patients who are taking Tipranavir plus ritonavir are protease inhibitors of HIV or Telaprevir are protease inhibitors of the hepatitis C virus, should avoid using Atozet simultaneously, in patients taking Lopinavir plus ritonavir are protease inhibitors of HIV, need to be cautious when prescribing the Atozet applications and should use the lowest -to -do doses of patients with the patients of the drug inhibitors inhibitors inhibitors inhibitors inhibitors The protease of HIV Saquinavir plus Ritonavir, Darunavir plus ritonavir, fosamprenavir, or fosamprenavir plus ritonavir, or boceprevir is a protease inhibitor of hepatitis C virus, Atozet dose should not exceed 10/20mg and need to be cautious when using [see warning and caution, muscle disease Cyclosporin, Clarithromycin, iTraconazole or some protease inhibitors] in patients taking Nelfinavir are HIV Protease inhibitors, Atozet dose should not exceed 10/40mg and recommend closely clinical monitoring. Itraconazole: The area under the curve (AUC) of Atorvastatin increases significantly when using Atorvastatin 40mg and iTraconazole 200mg simultaneously. Therefore, in patients who are taking Itraconazole, caution should be careful when Atozet dose exceeds 10/20mg.

Grapefruit juice: contains one or more CYP 3A4 inhibitors and can increase the concentration of Atorvastatin in plasma, especially when drinking too much grapefruit juice (> 1.2 liters/day).

Cyclosporin: In a study in 8 patients after kidney transplantation, Creatinine clearance> 50ml/minute with a stable dose of cyclosporin, a single dose of 10mg Ezetimibe has led to an average increase of ezetimibe of all 3.4 times (about 2,3,7.9 times) compared to a healthy control group from another study (N = 17). In another study, a patient with severe kidney failure (clearly 13.2ml of creatinine/minute/1.73m2), which is using many drugs, including cyclosporin, has shown a total concentration of ezetimibe 12 times higher than simultaneous control groups. In a two -stage cross -study study in 12 healthy subjects, using ezetimibe 20mg/day for 8 days with a single dose of Cyclosporin 100mg on Saturday, which led to the average AUC increase of Cyclosporin 15% (from 10% reduction to an increase of 51%) compared to a single dose of Cyclosporin 100mg single -use Atorvastatin and the transformations of AtorVastatin are the mechanicals OATP1B1. Oatp1b1 inhibitors (eg cyclosporin) may increase the bioavailability of Atorvastatin. Atorvastatin's AUC increases significantly when using Atorvastatin, 10mg and Cyclosporin 5.2mg/kg/day compared to the unique Atorvastatin use. Atozet period should be avoided with cyclosporin.