Caduet, 10 mg+10 mg 30 pcs

A combination drug that combines two drugs: dihydropyridine calcium antagonist amlodipine and HMG-CoA reductase inhibitor atorvastatin. In this combination, amlodipine inhibits the transmembrane flux of calcium ions in vascular and cardiac smooth muscle fibers; atorvastatin is a selective potent inhibitor of HMG-CoA reductase, the key enzyme converting HMG-CoA to mevalonate, a substance that is a precursor of styrenes, including CHF.

The mechanism of antihypertensive action: amlodipine affects the relaxation of vascular smooth muscle fibers. The mechanism of antianginal action of amlodipine is poorly understood, it is believed that the drug:
– dilates peripheral arterioles and due to this reduces RPS (afterload). As HR practically does not change, decrease of heart load leads to decrease of energy consumption and myocardial oxygen demand;
– promotes dilatation of large coronary arteries and coronary arterioles both in unchanged, and in ischemic areas of myocardium. Such dilatation increases oxygen supply to the myocardium in patients with vasospastic angina (Prinzmetal’s angina or variant angina) and prevents development of coronary vasoconstriction.

In patients with AH, a single dose of amlodipine provides clinically significant BP reduction for 24 hours in both supine and standing position. Due to slow onset of action amlodipine does not cause acute arterial hypotension. In patients with angina patients amlodipine increases exercise tolerance and decreases angina attacks frequency and necessity of nitroglycerin tablets use.

Amlodipine does not cause metabolic disorders or changes in plasma lipids, and therefore the drug can be indicated in patients with AD, diabetes, or gout. Results of hemodynamic studies and controlled clinical trials in patients with heart failure class II-III functional class (NYHA) showed that amlodipine does not cause worsening of their condition by such criteria as exercise tolerance, left ventricular ejection fraction and clinical symptoms.

In placebo-controlled studies, amlodipine has not been shown to increase the risk of mortality or the combined mortality rate in patients with heart failure class III-IV (NYHA) receiving digoxin, diuretics, and ACE inhibitors. Atorvastatin is a selective potent HMG-CoA reductase inhibitor that regulates the rate of conversion of HMG-CoA to mevalonate, a precursor of styrenes (including CH). In patients with homozygous and heterozygous hereditary and non-hereditary forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces total cholesterol, LDL-C and apolipoprotein B, LDL-C and TG concentrations and slightly increases HDL-C levels. It also decreases plasma levels of cholesterol and lipoproteins due to inhibition of HMG-CoA reductase and cholesterol synthesis in the liver and increased number of hepatic LDL receptors on the cell surface, which causes increased capture and catabolism of LDL.

Atorvastatin reduces LDL synthesis and decreases the number of LDL particles. It causes a pronounced and persistent increase in LDL receptor activity combined with positive changes in the quality of circulating LDL particles. Atorvastatin lowers LDL levels in patients with homozygous hereditary hypercholesterolemia in whom therapy with conventional hypolipidemic agents is often ineffective.

In humans, both atorvastatin and some of its metabolites have pharmacological activity. The primary site of action of atorvastatin is the liver, which plays a major role in HC synthesis and LDL clearance. Decrease in LDL-C correlates well with the dose of the drug and its concentration in the body. Individual dosing of the drug is based on therapeutic efficacy.

Atorvastatin (10-80 mg) reduced total CHD (30-46%), LDL-C (41-61%), apolipoprotein B (34-50%) and TG (14-33%) during a dose effect study. This result is persistent in patients with heterozygous hereditary and non-hereditary forms of hypercholesterolemia and mixed hyperlipidemia, including patients with insulin-dependent diabetes.

In patients with isolated hypertriglyceridemia atorvastatin decreases total cholesterol, LDL-C, LDL-C, apolipoprotein B, TG, LDL-C and increases HDL-C. In patients with dysbetalipoproteinemia, atorvastatin reduces LDL-C levels. In patients with hyperlipoproteinemia of Fredrickson type IIa and IIb the mean percentage increase of HDL-C was 5,1-8,7% regardless of dose when using 10-80 mg atorvastatin. In addition, there were significant dose-dependent reductions in the ratios of total CHD/CHD-LBP and CHD-LBP/CHD-LBP.

The effect of atorvastatin at a dose of 80 mg daily for 16 weeks on the occurrence of ischemia and overall mortality in patients with unstable angina or myocardial infarction without Q-wave was manifested by a significant reduction in the risk of myocardial ischemia and mortality, risk of rehospitalization for angina and confirmed myocardial ischemia. Atorvastatin reduced the risk of ischemia and mortality inversely proportional to LDL-C concentration, the risk of ischemia and mortality in patients with myocardial infarction without Q-wave and unstable angina equally in patients aged under 65 and older of both sexes.

Atorvastatin significantly reduced the incidence of fatal cardiovascular events and nonfatal myocardial infarction, the overall incidence of cardiovascular events, the incidence of fatal and nonfatal stroke, and reduced the need for myocardial revascularization. When using atorvastatin, overall mortality and mortality due to cardiovascular disease were slightly reduced. The effect of therapy did not depend on gender, age or initial LDL-C level. In boys and girls in postpubertal period (10-17 years) with heterozygous hereditary hypercholesterolemia or hypercholesterolemia atorvastatin in dose 10-20 mg once daily significantly reduced plasma levels of total CH, LDL-C, TG and apolipoprotein B. At the same time, no significant effect on growth and puberty in boys or on menstrual cycle duration in girls was found. The safety and efficacy of doses above 20 mg for the treatment of children have not been studied. The effect of long-term efficacy of atorvastatin therapy in children on the reduction of morbidity and mortality in adult patients has not been established.

Absorption. When oral administration of amlodipine/atorvastatin combination, two separate maxima of plasma concentration are observed. The first, within 1-2 h after administration, bound to atorvastatin; the second, within 6-12 h after administration, bound to amlodipine. The absorption rate (bioavailability) of amlodipine and atorvastatin in the amlodipine/atorvastatin combination is not different from the bioavailability of amlodipine and atorvastatin taken separately as tablets, as shown by the maximum plasma concentration (Cmax) of 101% (90% confidence interval (CI): 98; 104) and AUC 100% (90% CI: 97; 103) for amlodipine in the amlodipine/atorvastatin combination, and Cmax 94% (90% CI: 85; 104) and AUC 105% (90% CI: 99; 111) for atorvastatin in the amlodipine/atorvastatin combination.

The bioavailability of amlodipine in the amlodipine/atorvastatin combination was not impaired when the drug was used after meals, as confirmed by Cmax of 105% (90% CI: 99; 111) and AUC of 101% (90% CI: 97; 105) compared with those when the drug was taken on an empty stomach. Although food intake decreased atorvastatin absorption rate and volume by almost 32% and 11%, respectively, when using the combination drug, as confirmed by Cmax – 68% (90% CI: 60; 79) and AUC 89% (90% CI: 83; 95) compared to those when the drug was taken on an empty stomach. A similar decrease in plasma concentrations with atorvastatin after intake was noted with atorvastatin monotherapy, but it was not accompanied by a reduced effect on the decrease of LDL-C.

Studies conducted with amlodipine. After oral administration in therapeutic doses, amlodipine is well absorbed, reaching maximum concentration in blood after 6-12 hours. Absolute bioavailability reaches 64-80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of amlodipine is bound to plasma proteins. Food intake has no effect on the absorption of amlodipine.

Studies conducted with atorvastatin. Atorvastatin is rapidly absorbed after oral administration; its concentration in blood plasma reaches a maximum within 1-2 hours. Absorption and plasma concentration increase in proportion to the drug dose. Atorvastatin tablets have bioavailability of 95-99% compared to the solution. Absolute bioavailability of atorvastatin is approximately 12% and systemic availability of inhibitory activity relative to HMG-CoA reductase is about 30%. Low systemic bioavailability is associated with presystemic clearance in the gastrointestinal mucosa and/or biotransformation during first passage through the liver. Despite the fact that fraction and degree of drug absorption decreased when taking it with food by approximately 25 and 9%, respectively (according to Cmax and AUC), decrease of LDL-C levels did not depend on whether atorvastatin was taken with food or not. When atorvastatin is taken in the evening, its plasma concentration is lower (approximately 30% for Cmax and AUC) than when taken in the morning. However, the decrease in LDL-C levels does not depend on the time of taking the drug.

Distribution of atorvastatin. Mean volume of distribution of atorvastatin is approximately 381 liters. More than 98% of the drug is bound to plasma proteins. The erythrocyte/plasma ratio is approximately 0.25, which indicates poor penetration of the drug into erythrocytes.

Metabolism and excretion of amlodipine. The blood plasma elimination half-life is approximately 35-50 h, which allows the drug to be administered once daily. Stable equilibrium concentration in blood plasma is reached after 7-8 days of regular use of amlodipine. Amlodipine is extensively transformed in the liver to form inactive metabolites. It is excreted in the urine: 10% of the administered dose – unchanged, 60% – as metabolites.

Studies conducted with atorvastatin. Atorvastatin is metabolized into ortho- and parahydroxylated derivatives and various β-oxidized products. In vitro inhibition of HMG-CoA reductase due to ortho- and parahydroxylated metabolites is almost equal to the effect of atorvastatin. The inhibitory effect of the drug with respect to HMG-CoA reductase is approximately 70% realized due to the activity of circulating metabolites. The results of in vitro studies showed the importance of hepatic cytochrome P450 cA4 for metabolism of atorvastatin that may influence on increasing of concentration of atorvastatin in human blood plasma due to combined use with erythromycin, which is an inhibitor of this enzyme. In in vitro studies, it was also found that atorvastatin is a weak inhibitor of cytochrome P450 CA4. Concomitant use of atorvastatin and terfenadine, a compound that is mainly metabolized by cytochrome P450 WA4, had no significant effect of increasing the plasma concentration of terfenadine. It is unlikely that atorvastatin will significantly alter the pharmacokinetics of other cytochrome P450 WA4 substrates. In animals, orthohydroxyl metabolites undergo further glucuronidation. Atorvastatin and its metabolites are excreted mainly with bile due to hepatic and/or extrahepatic metabolism. However, the drug does not undergo significant intestinal hepatic recirculation. Mean elimination half-life of atorvastatin in humans is approximately 14 hours, but mean period of inhibitory activity regarding HMG-CoA reductase, due to circulating active metabolites, is 20-30 hours. Less than 2% of the dose of atorvastatin after oral administration is excreted in the urine.

Hepatic failure. Level of atorvastatin concentration in plasma is significantly increased (Сmax approximately 16 times, and AUC – 11 times) in patients with alcoholic cirrhosis (degree of severity according to Child-Pugh classification – B).
Renal insufficiency. Studies conducted with amlodipine. Changes in plasma concentrations of amlodipine did not correlate with the degree of renal failure. Amlodipine is not excreted by hemodialysis.
Studies conducted with atorvastatin. Renal disease did not affect the plasma concentration of atorvastatin or its effect on lipids. Therefore, a change in atorvastatin concentration for patients with impaired renal function is not required.

Performance. Plasma concentration level of atorvastatin in women differs from that in men (approximately 20% higher for Cmax and 10% lower for AUC). However, there is no clinically significant difference between the effect on lipids in men and women.

Patients of the elderly and senile age. Studies conducted with amlodipine. The time to reach equilibrium plasma concentrations of amlodipine is similar in elderly patients as well as in adults. Amlodipine clearance. In elderly patients and patients with congestive heart failure there is a tendency to decrease clearance of amlodipine, which leads to increased AUC and half-life of the drug. The same doses of amlodipine were well tolerated in both younger and elderly patients.

Studies conducted with atorvastatin. Concentration level of atorvastatin in plasma in healthy elderly patients (over 65 years old) is higher (approximately by 40% for maximal concentration and by 30% for AUC) than in young patients.
Patients of pediatric age. When amlodipine was administered at an average daily dose of 0.17 mg/kg in children with a median body weight of 45 kg, the drug clearance was 23.7 l/h in boys and 17.6 l/h in girls. These values were similar to those (24.8 l/h) in adults with a body weight of 70 kg. The average volume of distribution in patients with a body weight of -45 kg was 1130 l (25.11 l/kg). Hypotensive effect varied insignificantly during the day. When studying pharmacokinetic parameters in adults it was found that the use of amlodipine once a day is optimal.

Indications

The drug Caduet® is used for the following indications in adults over 18 years of age:

· Caduet® is indicated for patients with arterial hypertension with three or more risk factors for cardiovascular events (fatal and non-fatal coronary artery disease, the need for revascularization procedures, fatal and non-fatal myocardial infarction, stroke and transient ischemic attack), with normal or moderately elevated cholesterol concentrations without clinically significant coronary artery disease.

· Caduet® is used in cases where combination therapy with amlodipine and low doses of atorvastatin is recommended. It is possible to use the drug Kaduet® simultaneously with other antihypertensive and/or antianginal drugs.

· Caduet® is used in cases where a lipid-lowering diet and other non-pharmacological methods of treating dyslipidemia are ineffective or ineffective.

Pharmacological effect

Caduet® is a combination drug intended for the treatment of concomitant cardiovascular diseases (arterial hypertension/angina pectoris and dyslipidemia).

Mechanism of action

Amlodipine is a dihydropyridine derivative, a blocker of “slow” calcium channels (SCMC), and atorvastatin is a lipid-lowering agent, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA reductase inhibitor). Amlodipine/atorvastatin has two mechanisms of action: amlodipine inhibits calcium flux across membranes into smooth muscle cells and cardiomyocytes, and atorvastatin selectively and competitively inhibits HMG-CoA reductase, which catalyzes the conversion of HMG-CoA to mevalonic acid (a precursor to steroids, including cholesterol). In terms of its effect on systolic blood pressure (SBP), diastolic blood pressure (DBP) and low-density lipoprotein (LDL) concentrations, Caduet® does not differ significantly from monotherapy with amlodipine and atorvastatin.

Pharmacodynamics of amlodipine

Amlodipine blocks the entry of calcium ions through membranes into the smooth muscle cells of the myocardium and blood vessels. The mechanism of the hypotensive effect of amlodipine is due to a direct relaxing effect on vascular smooth muscle. The exact mechanism of action of amlodipine in angina pectoris has not been fully established, however, two ways to reduce myocardial ischemia under the influence of amlodipine are known:

1. amlodipine dilates peripheral arterioles and thus reduces total peripheral resistance (afterload). The heart rate does not change, which consequently leads to a decrease in the load on the heart, a decrease in energy consumption and oxygen demand;

2. The mechanism of action of amlodipine probably also includes dilation of the main coronary arteries and coronary arterioles in both unchanged and ischemic areas of the myocardium. Their dilation increases the supply of oxygen to the myocardium in patients with vasospastic angina (Prinzmetal’s angina or variant angina) and prevents the development of coronary vasoconstriction caused by smoking.

In patients with arterial hypertension, a single daily dose of amlodipine provides a clinically significant reduction in blood pressure (BP) over 24 hours in both the “lying” and “standing” positions. At physiological pH levels, amlodipine is presented as an ionized compound, which is characterized by gradual interaction with calcium channel receptors, and therefore a gradual onset of effect is noted. Due to its slow onset of action, amlodipine does not cause acute arterial hypotension.

In patients with angina pectoris, the use of amlodipine once a day increases the time of physical activity, prevents the development of an attack of angina and ST segment depression (by 1 mm), reduces the frequency of angina attacks, and reduces the amount of consumption of nitroglycerin tablets.

Amlodipine does not have an adverse effect on metabolism and plasma lipids and can be used in patients with bronchial asthma, diabetes mellitus and gout.

Amlodipine has been noted to prevent progressive intima-media thickening of the carotid arteries. Patients receiving amlodipine experienced a significant reduction in total mortality from cardiovascular events, myocardial infarction (MI), stroke, progression of chronic heart failure (CHF), and unstable angina. The frequency of percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting is also decreasing. The frequency of hospitalizations for unstable angina is reduced.

Pharmacodynamics of atorvastatin

Atorvastatin reduces the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase and cholesterol synthesis in the liver and increasing the number of “liver” LDL receptors on the cell surface, which leads to increased uptake and catabolism of LDL.

Atorvastatin and some of its metabolites are pharmacologically active in humans. The primary site of action of atorvastatin is the liver, where cholesterol synthesis and LDL clearance occur. The degree of reduction in LDL concentration correlates with the dose of the drug to a greater extent than with its systemic concentration. The dose is selected taking into account the response to treatment (see section “Method of administration and dosage”).

In patients with homozygous and heterozygous familial hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed dyslipidemia and hypercholesterolemia (including patients with type 2 diabetes mellitus), atorvastatin in doses of 10-80 mg reduces the concentrations of total cholesterol (C), LDL-C and apolipoprotein B (apo-B), as well as very low-density lipoproteins (VLDL-C) and triglycerides (TG) and causes a variable increase in the concentration of high-density lipoprotein (HDL-C).

Atorvastatin reduces the formation of LDL and the number of LDL particles. It causes a pronounced and persistent increase in LDL receptor activity combined with favorable changes in the quality of LDL particles. Atorvastatin reduces LDL-C concentrations in patients with homozygous familial hypercholesterolemia, which usually does not respond to lipid-lowering drugs.

In patients with isolated hypertriglyceridemia, atorvastatin reduces the concentrations of total cholesterol, LDL-C, VLDL-C, apo-B, TG and LDL-C and increases the concentration of HDL-C.

In patients with dysbetalipoproteinemia, atorvastatin reduces the concentration of intermediate-density lipoprotein cholesterol.

In patients with Fredriksen types IIa and IIb hyperlipoproteinemia, the median increase in HDL concentrations during treatment with atorvastatin (10-80 mg) is 5.1-8.7%. Changes in this indicator do not depend on the dose. An analysis of these patients also revealed a dose-dependent decrease in the ratios of total cholesterol/HDL-C and LDL-C/HDL-C by 29-44% and 37-55%, respectively.

Treatment with atorvastatin leads to a significant reduction in the risk of ischemic outcomes and mortality by 16%. The risk of readmission to hospital for angina and confirmed myocardial ischemia is reduced by 26%. The effect of atorvastatin on the risk of ischemic outcomes and mortality does not depend on the initial concentration of LDL-C and is comparable in patients with non-Q wave MI and unstable angina, men and women, patients aged younger and older than 65 years. Atorvastatin significantly reduces the development of the following complications: – Coronary complications (fatal coronary artery disease and non-fatal myocardial infarction) – 36% risk reduction – General cardiovascular complications and revascularization procedures – 20% risk reduction – General coronary complications – 29% risk reduction – Stroke (fatal and non-fatal) – 26% risk reduction

There is no significant reduction in overall and cardiovascular mortality, although a positive trend is observed.

In patients with type 2 diabetes mellitus and at least one of the following risk factors, atorvastatin affected the development of cardiovascular events as follows: – Major cardiovascular events [fatal and non-fatal acute MI, latent MI, death due to exacerbation of coronary artery disease, unstable angina, coronary artery bypass grafting, PTCA, revascularization, stroke] – 37% relative risk reduction – MI (fatal and non-fatal acute MI, latent MI) – relative risk reduction by 42% – Stroke (fatal and non-fatal) – relative risk reduction by 48%

In patients with atherosclerosis, while taking atorvastatin, there is a decrease in the total volume of atheroma, LDL-C, total cholesterol, triglycerides, apo-B, C-reactive protein, and an increase in HDL-C.

After oral administration of the combined drug Caduet®, two distinct peaks of maximum concentration (Cmax) were recorded in the blood plasma. The concentration of atorvastatin reached a maximum after 1-2 hours, and amlodipine – after 6-12 hours. The rate and degree of absorption (bioavailability) of amlodipine and atorvastatin when using the drug Caduet® did not differ from that when taking amlodipine and atorvastatin tablets simultaneously: Cmax of amlodipine = 101%; area under the concentration-time curve (AUC) of amlodipine = 100%; Atorvastatin Cmax = 94%; Atorvastatin AUC = 105%.

Although concomitant food intake caused a decrease in the rate and extent of absorption of atorvastatin when using Caduet® by approximately 32% and 11%, respectively (Cmax = 68% and AUC = 89%), similar changes in bioavailability were detected when using atorvastatin alone. However, food intake had no effect on the degree of reduction in LDL concentrations. Amlodipine Absorption

Amlodipine is well absorbed after oral administration in therapeutic doses, reaching Cmax in the blood 6-12 hours after administration. Absolute bioavailability is calculated to be 64-80%. In vitro studies have shown that circulating amlodipine is approximately 97.5% bound to plasma proteins. Food intake does not affect the absorption of amlodipine. The bioavailability of amlodipine did not change after food intake: Cmax = 105% and AUC = 101% compared with fasting values. Distribution

The volume of distribution is approximately 21 liters.

Metabolism and excretion

The half-life (T1/2) of amlodipine from blood plasma is about 35-50 hours, which allows the drug to be administered once a day. Equilibrium concentration in blood plasma is achieved after 7-8 days of continuous use of the drug. Metabolized in the liver to form inactive metabolites; 10% of the unchanged drug and 60% of metabolites are excreted by the kidneys. Atorvastatin Absorption

Atorvastatin is rapidly absorbed after oral administration, its concentration in the blood plasma reaches a maximum after 1-2 hours. The degree of absorption and the concentration of atorvastatin in the blood plasma increase in proportion to the dose. The absolute bioavailability of atorvastatin is about 14%, and the systemic bioavailability of HMG-CoA reductase inhibitory activity is about 30%. Low systemic bioavailability is due to first-pass metabolism (absorption) in the mucous membrane of the gastrointestinal tract and/or first-pass metabolism through the liver. Food slightly reduces the rate and extent of absorption (by 25% and 9%, respectively, as evidenced by the results of determining Cmax and AUC), but the reduction in LDL concentrations is similar to that when taking atorvastatin on an empty stomach. Despite the fact that after taking atorvastatin in the evening, its plasma concentration is lower (Cmax and AUC by approximately 30%) than after taking it in the morning, the decrease in LDL concentration does not depend on the time of day at which the drug is taken.

Distribution

The mean volume of distribution of atorvastatin is approximately 381 L. Communication with blood plasma proteins is not less than 98%. The content ratio in red blood cells/blood plasma is about 0.25, i.e. Atorvastatin penetrates red blood cells poorly.

Metabolism and excretion

Atorvastatin is extensively metabolized to form ortho- and para-hydroxylated derivatives and various beta-oxidation products. In vitro, ortho- and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase comparable to that of atorvastatin. Approximately 70% of the decrease in HMG-CoA reductase activity occurs due to the action of active circulating metabolites. Results from in vitro studies suggest that hepatic cytochrome P450 3A4 plays an important role in the metabolism of atorvastatin. This fact is supported by an increase in the concentration of atorvastatin in human plasma while taking erythromycin, which is an inhibitor of this isoenzyme. In vitro studies have also shown that atorvastatin is a weak inhibitor of cytochrome P450 3A4. There is no clinically significant effect of atorvastatin on the plasma concentration of terfenadine, which is metabolized mainly by cytochrome P450 3A4, so it is unlikely that atorvastatin has a significant effect on the pharmacokinetics of other cytochrome P450 3A4 substrates (see section “Interactions with other drugs”).

Atorvastatin and its metabolites are excreted mainly in bile as a result of hepatic and/or extrahepatic metabolism; atorvastatin does not undergo significant enterohepatic recirculation. T1/2 of atorvastatin is about 14 hours, while T1/2 of inhibitory activity against HMG-CoA reductase due to the presence of active metabolites is about 20-30 hours. After oral administration, less than 2% of the dose is excreted by the kidneys.

Atorvastatin is a substrate for the liver enzyme transporters OATP1B1 and OATP1B3. Metabolites of atorvastatin are substrates of OATP1B1. Atorvastatin has also been identified as a substrate of the efflux transporters MDR1 and breast cancer resistance protein, which may limit the intestinal absorption and biliary clearance of atorvastatin.

Special patient groups

Liver dysfunction: The plasma concentration of atorvastatin is significantly increased (Cmax approximately 16 times and AUC approximately 11 times) in patients with alcoholic cirrhosis of the liver (Child-Pugh class B) (see section “Contraindications”).

Impaired renal function: plasma concentrations of amlodipine do not depend on the degree of renal failure; it is not removed by dialysis.

Kidney disease does not affect the concentration of atorvastatin in the blood plasma; therefore, dose adjustment is not required in patients with impaired renal function (see section “Dosage and Administration”).

Gender: the plasma concentration of atorvastatin in women differs (Cmax is approximately 20% higher and AUC is 10% lower) from that in men, but no clinically significant differences in the effect of the drug on lipid metabolism have been identified in men and women.

Elderly

the time required to achieve the maximum concentration of amlodipine in the blood plasma is practically independent of age. In elderly patients, there was a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC and T1/2. In patients of various age groups with CHF, an increase in AUC and T1/2 period was observed. Tolerability of amlodipine in the same doses in elderly and young patients is equally good.

Plasma concentrations of atorvastatin in patients aged 65 years and older are higher (Cmax approximately 40%, AUC approximately 30%) than in younger adult patients; There were no differences in the safety, effectiveness, or achievement of lipid-lowering therapy goals in elderly patients compared with the general population.

Pediatric patients

Amlodipine studies

In one clinical study with long-term use of the drug, 73 pediatric patients (from 12 months to 17 years inclusive) with arterial hypertension received amlodipine at an average dose of 0.17 mg/kg per day. The clearance of amlodipine in the tested boys and girls with a median body weight of 45 kg was 23.7 and 17.6 l/h, respectively. These values ​​are in the range of the published estimate of 24.8 L/h for an adult weighing 70 kg. The mean estimated volume of distribution for patients weighing 45 kg was 1130 L (25.11 L/kg). The drug maintained a decrease in blood pressure throughout the entire 24-hour dosing interval, while fluctuations in drug concentrations from maximum to minimum had little effect on the hypotensive effect of the drug. When compared with previously observed pharmacokinetics in adults, the results obtained in this study indicate that once-daily dosing is acceptable.

Atorvastatin studies

In an open-label, 8-week study of Tanner Stage 1 (N = 15) and Tanner Stage 2 (N = 24) pediatric patients (ages 6 to 17 years) with heterozygous familial hypercholesterolemia and a baseline LDL-C level of 4 mmol/L, patients received a dose of 5 or 10 mg of atorvastatin chewable tablet or a dose of 10 or 20 mg of atorvastatin in the form of a film-coated tablet, respectively. Body weight was the only significant covariate in the population PK model of atorvastatin. The apparent oral clearance of atorvastatin in pediatric patients was similar to that in adult patients when allometrically scaled by body weight. There was a consistent reduction in LDL-C and TC levels across the exposure ranges of atorvastatin and o-hydroxyatorvastatin.

Special instructions

Amlodipine

Use in patients with heart failure

In patients with CHF (III-IV functional class according to the NYHA classification) of non-ischemic etiology, when using amlodipine, there is a risk of pulmonary edema.

When using HMG-CoA reductase inhibitors, including atorvastatin, there have been cases of increased glycosylated hemoglobin (HbA1) and fasting plasma glucose concentrations. However, the risk of hyperglycemia is lower than the reduction in the risk of vascular complications with statins.

It is necessary to maintain dental hygiene and follow-up with a dentist (to prevent pain, bleeding and gum hyperplasia).

Elderly patients

The time to reach peak plasma concentrations of amlodipine is similar in elderly and young patients. In elderly patients, amlodipine clearance tends to decrease, leading to an increase in AUC and an increase in half-life. The increased AUC and half-life values ​​in patients with congestive heart failure were consistent with the expected values ​​for the age groups of patients studied. Amlodipine in similar doses in elderly or younger patients is also equally well tolerated.

Liver dysfunction

In patients with impaired liver function, the half-life of amlodipine is increased. In patients with chronic alcoholic liver disease (Child-Pugh class B), atorvastatin plasma concentrations were significantly increased (approximately 16-fold for Cmax and 11-fold for AUC). Since Caduet® contains atorvastatin and amlodipine, its use is contraindicated in patients with active liver disease.

Atorvastatin

Action on skeletal muscles

Myalgia has been observed in patients receiving atorvastatin (see section “Side effects”). The diagnosis of myopathy (muscle pain or weakness in combination with an increase in CPK activity more than 10 times the upper limit of normal) should be considered in patients with widespread myalgia, muscle soreness or weakness, and/or a marked increase in CPK activity. Patients should seek immediate medical attention if they experience unexplained muscle pain, tension, or weakness, especially if accompanied by malaise or fever. Therapy with Caduet should be discontinued in the event of a marked increase in CPK activity or in the presence of confirmed or suspected myopathy. The risk of myopathy during treatment with other drugs of this class increases with the simultaneous use of drugs that increase the systemic concentration of atorvastatin (see section “Interaction with other drugs” and “Pharmacokinetics”). Many of these drugs inhibit cytochrome P450 3A4-mediated metabolism and/or drug transport. It is known that cytochrome P450 3A4 is the main liver isoenzyme involved in the biotransformation of atorvastatin. When prescribing atorvastatin in combination with fibric acid derivatives, erythromycin, immunosuppressants, azole derivative antifungals, HIV/HCV protease inhibitors, hepatitis C viral non-structural protein inhibitors (NS5A/NS5B), letermovir or nicotinic acid in lipid-lowering doses (more than 1 g/day), the doctor must carefully weigh the expected benefits and risks treatment and regularly monitor patients for muscle pain, tension, or weakness, especially during the first months of treatment and during dose increases of any drug. If combination therapy is necessary, the possibility of using lower initial and maintenance doses of the above drugs should be considered (see section “Dosage and Administration”). The simultaneous use of Kaduet® and fusidic acid is not recommended, therefore, during treatment with fusidic acid, temporary withdrawal of Kaduet® is recommended. In such situations, periodic determination of CPK activity can be recommended, although such monitoring does not prevent the development of severe myopathy (see section “Interaction with other drugs”). Caduet® may cause an increase in CPK activity (see section “Side effects”).

There have been very rare reports of the development of immune-mediated necrotizing myopathy (IONM) during or after treatment with certain statins (see section “Side effects”). IONM is clinically characterized by persistent proximal muscle weakness and elevated serum creatine kinase levels that persist despite discontinuation of statin treatment, the presence of antibodies to HMG CoA reductase, and improvement with immunosuppressive medications.

When using atorvastatin, like other drugs of this class, rare cases of rhabdomyolysis with acute renal failure caused by myoglobinuria have been described. A risk factor for the development of rhabdomyolysis may be pre-existing renal impairment. Such patients should be provided with more careful monitoring of the musculoskeletal system. Therapy with Caduet should be temporarily discontinued or completely discontinued if signs of possible myopathy appear or if there is a risk factor for the development of renal failure due to rhabdomyolysis (for example, severe acute infection, hypotension, surgery, trauma, metabolic, endocrine and fluid-electrolyte disturbances, and uncontrolled seizures). Treatment with amlodipine at an adequate dose to control arterial hypertension can be continued.

Effect on the liver

As with the use of other lipid-lowering drugs of this class, after treatment with atorvastatin, a moderate (more than 3 times compared to the upper limit of normal) increase in the activity of liver transaminases aspartate aminotransferase (AST) and alanine aminotransferase (ALT) was noted. A persistent increase in serum activity of hepatic transaminases (more than 3 times the upper limit of normal) was observed in 0.7% of patients receiving atorvastatin. The incidence of such changes when using atorvastatin at doses of 10 mg, 20 mg, 40 mg and 80 mg was 0.2%, 0.2%, 0.6% and 2.3%, respectively. Increased activity of liver transaminases was usually not accompanied by jaundice or other clinical manifestations. With a reduction in the dose of atorvastatin, temporary or complete withdrawal, the activity of “liver” transaminases returned to the original level. Most patients continued to take atorvastatin at a reduced dose without any clinical consequences.

Before starting therapy, 6 weeks and 12 weeks after starting use of the drug Kaduet®, or after increasing its dose, liver function tests should be monitored. Liver function should also be monitored when clinical signs of liver damage appear. If the activity of “liver” transaminases increases, their activity should be monitored until it returns to normal. If an increase in AST or ALT activity by more than 3 times compared to the upper limit of normal persists, it is recommended to reduce the dose of atorvastatin or discontinue the drug Caduet® (see section “Side effects”).

Atorvastatin should be used with caution in patients who consume significant amounts of alcohol and/or have a history of liver disease. Active liver disease or persistently increased activity of hepatic transaminases of unknown origin are a contraindication to the use of the drug Caduet® (see section “Contraindications”).

Stroke Prevention by Aggressively Lowering Cholesterol Levels (SPARCL)

In a retrospective analysis of stroke subtypes in patients without coronary artery disease (CAD) who had a recent stroke or transient ischemic attack (TIA), a higher incidence of hemorrhagic stroke was observed in patients started on atorvastatin 80 mg compared with placebo. The increased risk was particularly true for patients with a history of hemorrhagic stroke or lacunar infarction at study entry. For patients with a history of hemorrhagic stroke or lacunar infarction, the benefit-risk ratio of atorvastatin 80 mg remains unclear, and the potential risk of hemorrhagic stroke should be carefully weighed before initiating treatment (see Pharmacodynamics section). However, patients receiving atorvastatin 80 mg therapy had fewer strokes of any type (265 atorvastatin/311 placebo) and fewer cases of coronary heart disease (123 atorvastatin/204 placebo).

Hyperglycemia
Some evidence suggests that statins as a class increase blood glucose levels and, in some patients at high risk for diabetes mellitus, may cause hyperglycemia to a degree that requires formal treatment of diabetes mellitus. This risk is, however, outweighed by the reduction in vascular risk with statins and should therefore not be a reason to discontinue statin therapy. In patients at risk (fasting glucose 5.6 to 6.9 mmol/L, BMI > 30 kg/m2, elevated triglycerides, hypertension), both clinical and biochemical parameters should be monitored according to national guidelines.

Active ingredient

Amlodipine, Atorvastatin

Composition

1 tablet contains:

Active ingredients: amlodipine (as amlodipine besilate) 5.0 (6.94) mg or 10.0 (13.87) mg, atorvastatin (as atorvastatin calcium) 10.0 (10.85) mg or 10.0 (10.85) mg.

Excipients: calcium carbonate 33.15 mg and 33.15 mg, croscarmellose sodium 6.0 mg and 6.0 mg, microcrystalline cellulose 24.26 mg and 17.33 mg, pregelatinized starch 15.0 mg and 15.0 mg, polysorbate 80 0.40 mg and 0.40 mg, hyprolose 2.0 mg and 2.0 mg, colloidal silicon dioxide 0.65 mg and 0.65 mg, magnesium stearate 0.75 mg and 0.75 mg, film coating Opadry II white 85F28751 3.0 mg (tablets 5 mg + 10 mg) (polyvinyl alcohol 1.2 mg, titanium dioxide 0.75 mg, macrogol (PEG) 3000 0.606 mg, talc 0.444 mg), film coating Opadry II blue 85F10919 3.0 mg (tablets 10 mg + 10 mg) (polyvinyl alcohol 1.2 mg, titanium dioxide 0.645 mg, macrogol (PEG) 3000 0.606 mg, aluminum varnish on based on indigo carmine 0.105 mg, talc 0.444 mg).

Pregnancy

Atorvastatin

Caduet® is contraindicated during pregnancy, since the drug contains atorvastatin. Women of reproductive age should use adequate contraception during treatment. The drug can be prescribed to women of reproductive age only if the likelihood of pregnancy is low and patients are informed of the possible risk to the fetus.

Caduet® is contraindicated during breastfeeding, as it contains atorvastatin. There is no information on the excretion of atorvastatin into breast milk. Given the possibility of adverse reactions in infants, women receiving the drug should stop breastfeeding.

Amlodipine

In animal studies, amlodipine had no effect on reproduction, but was reproductively toxic when administered at very high doses (50 times the maximum recommended human dose). The use of amlodipine during pregnancy or breastfeeding is not recommended.

Experience with the drug shows that amlodipine is excreted into women’s breast milk. The mean amlodipine concentration in the milk/plasma ratio was 0.85 among 31 lactating women with pregnancy-related hypertension receiving amlodipine at an initial dosage of 5 mg per day. The dosage of the drug was adjusted if necessary (depending on the average daily dose and weight: 6 mg and 98.7 mcg/kg, respectively). The estimated daily dose of amlodipine received by an infant through breast milk is 4.17 mcg/kg.

Contraindications

· Hypersensitivity to amlodipine and other dihydropyridine derivatives, atorvastatin or to any of the excipients;

· Active liver disease or persistent increase in the activity of “liver” enzymes more than 3 times higher than normal of unknown etiology;

· Pregnancy, breastfeeding, use in women of reproductive age who do not use adequate methods of contraception;

· In children under 18 years of age (efficacy and safety have not been established);

· Severe arterial hypotension (SBP less than 90 mmHg);

· Severe or clinically significant aortic stenosis;

· Hemodynamically unstable heart failure after acute myocardial infarction (amlodipine).

Side Effects

Overall, the combination therapy was well tolerated. No unexpected undesirable effects were reported during combination therapy. Adverse effects were consistent with those previously identified during treatment with amlodipine and/or atorvastatin (see below). Most adverse effects were mild or moderate. Due to adverse effects or laboratory abnormalities, treatment with amlodipine and atorvastatin was discontinued in 5.1% of patients, and placebo in 4.0%.
The following adverse events, listed by MedDRA system organ class and frequency category, are listed separately for amlodipine and atorvastatin. Very common (³ 1/10), common (³ 1/100 to < 1/10), uncommon (³ 1/1000 to < 1/100), rare (³ 1/10,000 to < 1/1000), very rare (< 1/10,000) and frequency unknown (cannot be estimated from available data).
Infectious and parasitic diseases
Often (Atorvastatin) – Nasopharyngitis
Blood and lymphatic system disorders
Very rare (Amlodipine) – Leukopenia, Thrombocytopenia
Rarely (Atorvastatin) – Thrombocytopenia
Immune system disorders
Very rare (Amlodipine) – Hypersensitivity
Often (Atorvastatin) – Hypersensitivity
Very rare (Atorvastatin) – Anaphylaxis
Metabolic and nutritional disorders
Uncommon (Atorvastatin) – Hypoglycemia, Weight gain, Anorexia
Often (Atorvastatin) – Hyperglycemia*
Very rare (Amlodipine) – Hyperglycemia*
Uncommon (Amlodipine) – Weight gain, Weight loss
Mental disorders
Uncommon (Amlodipine) – Insomnia, Mood changes (including agitation), Depression
Rarely (Amlodipine) – Confusion
Uncommon (Atorvastatin) – Insomnia, Nightmares
Unknown(Atorvastatin) – Depression
Nervous system disorders
Common (Amlodipine) – Drowsiness, Dizziness, Headache (especially at the beginning of treatment)
Uncommon (Amlodipine) – Tremor, Hypoesthesia, paresthesia, Syncope, Dysgeusia
Very rare (Amlodipine) – Hypertonicity, Peripheral neuropathy
Unknown(Amlodipine) – Extrapyramidal syndrome
Uncommon (Atorvastatin) – Dizziness, Hypoesthesia, paresthesia, Amnesia, Dysgeusia
Common (Atorvastatin) – Headache (especially at the beginning of treatment)
Rarely (Atorvastatin) – Peripheral neuropathy
Visual disorders
Common (Amlodipine) – Visual impairment (including diplopia)
Rarely (Atorvastatin) – Visual impairment (including diplopia)
Uncommon (Atorvastatin) – Blurred vision
Hearing and labyrinth disorders
Uncommon (Amlodipine) – Tinnitus
Uncommon (Atorvastatin) – Tinnitus
Very rare (Atorvastatin) – Hearing loss
Cardiac disorders
Often (Amlodipine) – Palpitations
Uncommon (Amlodipine) – Arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)
Rarely (Amlodipine) – Angina
Very rare (Amlodipine) – Myocardial infarction
Vascular disorders
Often (Amlodipine) – Hyperemia
Uncommon (Amlodipine) – Hypotension
Very rare (Amlodipine) – Vasculitis
Disorders of the respiratory system, chest and mediastinal organs
Often (Amlodipine) – Shortness of breath
Uncommon (Amlodipine) – Rhinitis, Cough
Common (Atorvastatin) – Pain in the pharynx and larynx, Nosebleeds
Unknown (Atorvastatin) – Interstitial lung disease, especially with long-term therapy
Disorders of the gastrointestinal tract
Very rare (Amlodipine) – Hypertrophic gingivitis, Gastritis, Pancreatitis
Common (Amlodipine) – Nausea, Upper and lower abdominal pain, Dyspepsia, Changes in stool frequency (including diarrhea and constipation)
Uncommon (Amlodipine) – Dry mouth, Dysgeusia
Often (Atorvastatin) – Nausea, Diarrhea, constipation, flatulence
Uncommon (Atorvastatin) – Pain in the upper and lower abdomen, Vomiting, Pancreatitis, Belching
Disorders of the liver and biliary tract
Very rare (Amlodipine) – Hepatitis, Jaundice
Uncommon (Atorvastatin) – Hepatitis
Rarely (Atorvastatin) – Cholestasis
Very rare (Atorvastatin) – Liver failure
Disorders of the skin and subcutaneous tissues
Very rare (Amlodipine) – Bullous dermatitis, including erythema multiforme, Quincke’s edema, Erythema multiforme, Angioedema, Exfoliative dermatitis, Photosensitivity, Stevens-Johnson syndrome
Uncommon (Amlodipine) – Alopecia, Purpura, Skin discoloration, Itching, Skin rash, Hyperhidrosis, Exanthema, Urticaria
Rarely (Atorvastatin) – Bullous dermatitis, including erythema multiforme, Angioedema, Stevens-Johnson syndrome, Toxic epidermal necrolysis
Uncommon (Atorvastatin) – Alopecia, Pruritus, Skin rash, Urticaria
Musculoskeletal and connective tissue disorders
Common (Amlodipine) – Joint swelling (including ankle swelling), muscle cramps, muscle spasms
Uncommon (Amlodipine) – Arthralgia, myalgia, Back pain
Common (Atorvastatin) – Joint swelling (including ankle swelling), Muscle cramps, muscle spasms, Arthralgia, myalgia, Back pain, Pain in limb
Uncommon (Atorvastatin) – Neck pain, Muscle fatigue,
Rarely (Atorvastatin) – Myositis, Rhabdomyolysis, myopathy, Tendinopathy, in rare cases, tendon rupture
Unknown (Atorvastatin) – Immune-mediated necrotizing myopathy
Renal and urinary tract disorders
Uncommon (Amlodipine) – Urinary disturbance, nocturia, frequent urination
Disorders of the genital organs and breast
Uncommon (Amlodipine) – Impotence, Gynecomastia
Uncommon (Atorvastatin) – Impotence
Very rare (Atorvastatin) – Gynecomastia
General disorders and disorders at the injection site
Very common (Amlodipine) – Edema
Often (Amlodipine) – Increased fatigue, Asthenia
Uncommon (Amlodipine) – Chest pain, Pain, Malaise
Uncommon (Atorvastatin) – Edema, Peripheral edema, Fatigue, Asthenia, Chest pain, Pain, Malaise, Pyrexia
Influence on the results of laboratory and instrumental studies
Very rare (Amlodipine) – Increased levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase (mainly indicative of cholestasis)
Common (Atorvastatin) – Increased levels of liver enzymes, alanine aminotransferase and aspartate aminotransferase (mainly indicative of cholestasis), Increased levels of creatine kinase in the blood
Uncommon (Atorvastatin) – Presence of leukocytes in urine
* Diabetes mellitus has been reported with some statins: the incidence will depend on the presence or absence of risk factors (fasting blood glucose ≥ 5.6 mmol/L, BMI > 30 kg/m2, elevated triglycerides,
history of arterial hypertension).

Interaction

It has been shown that the pharmacokinetics of amlodipine 10 mg in combination therapy with atorvastatin 80 mg in healthy volunteers does not change. Amlodipine had no effect on the Cmax of atorvastatin, but caused an increase in AUC by 18%.

The interaction of Kaduet® with other drugs has not been specifically studied. Below is information on each component separately.

Amlodipine

Amlodipine can be safely used concomitantly with antibiotics and oral hypoglycemic agents.

Inhibitors of the CYP3A4 isoenzyme: with simultaneous use of diltiazem at a dose of 180 mg and amlodipine at a dose of 5 mg in elderly patients (from 69 to 87 years) with arterial hypertension, there is an increase in systemic exposure of amlodipine by 57%. Concomitant use of amlodipine and erythromycin in healthy volunteers (18 to 43 years of age) does not lead to significant changes in amlodipine exposure (increase in area under the concentration-time curve (AUC) by 22%). Although the clinical significance of these effects is unclear, they may be more pronounced in older patients.

Potent inhibitors of the CYP3A4 isoenzyme (for example, ketoconazole, itraconazole, ritonavir) may increase the plasma concentration of amlodipine to a greater extent than diltiazem. Amlodipine and inhibitors of the CYP3A4 isoenzyme should be used with caution.

Clarithromycin: Clarithromycin is an inhibitor of the CYP3A4 isoenzyme. There is an increased risk of hypotension in patients receiving clarithromycin concomitantly with amlodipine. When amlodipine is used concomitantly with clarithromycin, it is recommended to carefully monitor the patient’s condition.

Inducers of the CYP3A4 isoenzyme: there is no data on the effect of inducers of the CYP3A4 isoenzyme on the pharmacokinetics of amlodipine. The simultaneous use of inducers of the CYP3A4 isoenzyme (for example, rifampicin, St. John’s wort) and amlodipine may lead to a decrease in the concentration of amlodipine in the blood plasma. Amlodipine and inducers of the CYP3A4 isoenzyme should be used with caution.

Cimetidine: with simultaneous use of amlodipine with cimetidine, the pharmacokinetics of amlodipine does not change.

Grapefruit juice: simultaneous single administration of 240 ml of grapefruit juice and 10 mg of amlodipine orally is not accompanied by a significant change in the pharmacokinetics of amlodipine, however, the possibility of genetic polymorphism of the CYP3A4 isoenzyme should be taken into account. In this regard, the simultaneous use of Caduet® and grapefruit or grapefruit juice is not recommended, due to the possible increase in the bioavailability of amlodipine in some patients, which may lead to an increase in the antihypertensive effect of amlodipine.

Unlike other BMCCs, no clinically significant interaction of amlodipine was found when used together with nonsteroidal anti-inflammatory drugs (NSAIDs), especially indomethacin.

It is possible to enhance the antianginal and antihypertensive effect of BMCC when used together with thiazide and loop diuretics, verapamil, angiotensin-converting enzyme (ACE) inhibitors, beta-blockers and nitrates, as well as enhance their antihypertensive effect when used together with alpha1-blockers, antipsychotics. Although a negative inotropic effect has not generally been observed in amlodipine studies, some CBMCs may enhance the negative inotropic effects of antiarrhythmic drugs that prolong the QT interval (eg, amiodarone and quinidine). When BMCC is used together with lithium preparations, it is possible to increase the neurotoxicity of lithium (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus). Amlodipine does not affect the degree of plasma protein binding of digoxin, phenytoin, warfarin and indomethacin in vitro.

Aluminum/magnesium-containing antacids: their single dose does not have a significant effect on the pharmacokinetics of amlodipine.

Sildenafil: a single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine. When used concomitantly, each drug independently reduces blood pressure.

Digoxin: When amlodipine is administered concomitantly with digoxin in healthy volunteers, the serum concentration and renal clearance of digoxin do not change.

Ethanol (alcohol-containing drinks): with single and repeated use in a dose of 10 mg, amlodipine does not have a significant effect on the pharmacokinetics of ethanol.

Warfarin: Amlodipine does not affect changes in prothrombin time caused by warfarin.

Cyclosporine: Interaction studies between amlodipine and cyclosporine have only been conducted in renal transplant patients. These studies showed that amlodipine may either have no effect on the minimum plasma concentration of cyclosporine or increase it by up to 40%. The possibility of monitoring plasma concentrations of cyclosporine in patients after kidney transplantation when using this combination of drugs should be considered.

Tacrolimus: There is a risk of increased tacrolimus blood concentrations when used concomitantly with amlodipine. To avoid the development of tacrolimus toxicity when using amlodipine in patients receiving treatment with tacrolimus, monitoring its concentration in the blood and dose adjustment if necessary.

Mammalian target of rapamycin (mTOR inhibitors): mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. When used together with mTOR inhibitors, amlodipine may increase their effect.

Dantrolene: In animal studies, cases of fatal atrial fibrillation and cardiovascular failure due to the development of hyperkalemia were observed with the simultaneous use of verapamil and dantrolene intravenously. Due to the risk of hyperkalemia, it is recommended to avoid the use of CBCIs such as amlodipine in patients with suspected or confirmed malignant hyperthermia, or during treatment for this condition.

Simvastatin: repeated simultaneous use of amlodipine at a dose of 10 mg and simvastatin 80 mg leads to an increase in simvastatin concentrations by 77% compared with simvastatin monotherapy. The dose of simvastatin should be limited to 20 mg per day.

Effect on laboratory test results: unknown.

Atorvastatin

Since atorvastatin is metabolized by the CYP3A4 isoenzyme, co-administration of atorvastatin with inhibitors of the CYP3A4 isoenzyme may lead to increased plasma concentrations of atorvastatin. The degree of interaction and potentiation effect is determined by the variability of the effect on the CYP3A4 isoenzyme.

Transport protein inhibitors: Atorvastatin is a substrate of liver enzyme transporters (see section “Pharmacokinetics”).

The combined use of atorvastatin at a dose of 10 mg and cyclosporine at a dose of 5.2 mg/kg/day leads to an increase in the concentration of atorvastatin in the blood plasma (AUC ratio: 8.7) (see section “Pharmacokinetics”). Cyclosporine is an inhibitor of organic anion transporting polypeptide 1B1 (OATP1B1), OATP1B3, multidrug resistance-associated protein 1 (MDR1) and breast cancer resistance protein, as well as CYP3A4, and therefore increases the exposure of atorvastatin. The daily dose of atorvastatin should not exceed 10 mg (see section “Dosage and Administration”).

Glecaprevir and pibrentasvir are inhibitors of OATP1B1, OATP1B3, MDR1 and breast cancer resistance protein and therefore increase the exposure of atorvastatin. The daily dose of atorvastatin should not exceed 10 mg (see section “Dosage and Administration”).

Co-administration of atorvastatin 20 mg and letermovir 480 mg daily resulted in increased atorvastatin exposure (AUC ratio: 3.29) (see Pharmacokinetics section). Letermovir is an inhibitor of the transporters P-gp, BCRP, MRP2, OAT2 and the hepatic transporter OATP1B1/1B3, thus increasing the level of exposure to atorvastatin. The daily dose of atorvastatin should not exceed 20 mg (see section “Dosage and Administration”).

The magnitude of indirect drug interactions of CYP3A and OATP1B1/1B3 on co-administration of drugs may differ when letermovir is co-administered with cyclosporine. It is not recommended to use atorvastatin in patients receiving letermovir therapy in combination with cyclosporine.

Elbasvir and grazoprevir are inhibitors of OATP1B1, OATP1B3, MDR1 and breast cancer resistance protein and therefore increase the exposure of atorvastatin. Should be used with caution and at the lowest dose required (see section “Dosage and Administration”).

The risk of myopathy during treatment with other drugs of this class increases with the simultaneous use of cyclosporine, fibric acid derivatives, erythromycin, antifungal drugs of azole derivatives, and nicotinic acid in lipid-lowering doses (more than 1 g / day) (see section “Special instructions” – “Effect on skeletal muscles”).

Gemfibrozil/fibric acid derivatives: The use of fibrates as monotherapy is sometimes accompanied by phenomena from the muscular system, including rhabdomyolysis. The risk of these effects may be increased with simultaneous use of fibric acid derivatives and atorvastatin. If concomitant use of these drugs cannot be avoided, use the lowest dose of atorvastatin sufficient to achieve therapeutic goals and patients should be monitored accordingly (see section 4.4).

Ezetimibe: the use of ezetimibe as monotherapy is accompanied by phenomena from the muscular system, including rhabdomyolysis. Therefore, the risk of these events may be increased when ezetimibe and atorvastatin are used concomitantly. Appropriate clinical monitoring of such patients is recommended.

Antacids: simultaneous oral administration of a suspension containing magnesium and aluminum hydroxides reduced the concentration of atorvastatin in the blood plasma by approximately 35%, but the degree of reduction in the concentration of LDL-C did not change.

Phenazone: Atorvastatin does not affect the pharmacokinetics of phenazone, so interaction with other drugs metabolized by the same cytochrome isoenzymes is not expected.

Itraconazole: Concomitant use of atorvastatin at doses of 20 mg to 40 mg and itraconazole at a dose of 200 mg resulted in an increase in the AUC value of atorvastatin.

Grapefruit juice: Since grapefruit juice contains one or more components that inhibit the CYP3A4 isoenzyme, excessive consumption (more than 1.2 L per day) may cause an increase in plasma concentrations of atorvastatin.

Inhibitors of the CYP3A4 isoenzyme: the use of potent CYP3A4 inhibitors has been shown to lead to a marked increase in atorvastatin concentrations. Concomitant use of strong CYP3A4 inhibitors (for example, cyclosporine, telithromycin, clarithromycin, delavirdine, stiripentol, ketoconazole, voriconazole, itraconazole, posaconazole, certain antiviral drugs for the treatment of HCV (for example, elbasvir/grazoprevir) and HIV protease inhibitors, including ritonavir, lopinavir, atazanavir, indinavir, darunavir, etc.) should be avoided whenever possible. In cases in which concomitant use of these drugs with atorvastatin cannot be avoided, the use of lower initial and maximum doses of atorvastatin should be considered, and appropriate clinical monitoring of the patient’s condition is recommended.

Moderate inhibitors of CYP3A4: (eg, erythromycin, diltiazem, verapamil and fluconazole) may increase plasma concentrations of atorvastatin. An increased risk of myopathy was observed when erythromycin was used in combination with statins. There are no drug interaction studies evaluating the effect of amiodarone or verapamil on atorvastatin. Both amiodarone and verapamil are known inhibitors of CYP3A4 activity, and their concomitant use with atorvastatin may result in increased atorvastatin exposure. Therefore, a lower maximum dose of atorvastatin should be considered, and appropriate clinical monitoring of the patient’s condition is recommended when coadministered with moderate CYP3A4 inhibitors. After initiation of use or dose adjustment of an inhibitor, appropriate clinical monitoring of the patient’s condition is recommended.

Inducers of the CYP3A4 isoenzyme: combined use of atorvastatin with inducers of the CYP3A4 isoenzyme (for example, efavirenz or rifampicin) may lead to a decrease in the concentration of atorvastatin in the blood plasma. Due to the dual mechanism of interaction with rifampicin (an inducer of the CYP3A4 isoenzyme and an inhibitor of the hepatocyte transport protein OATP1B1), simultaneous use of atorvastatin and rifampicin is recommended, since delayed administration of atorvastatin after taking rifampicin leads to a significant decrease in the concentration of atorvastatin in the blood plasma.

Colestipol: with simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma decreased by approximately 25%; however, the lipid-lowering effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.

Digoxin: with repeated administration of digoxin and atorvastatin at a dose of 10 mg, the equilibrium concentrations of digoxin in the blood plasma did not change. However, when digoxin was used in combination with atorvastatin at a dose of 80 mg/day, digoxin concentrations increased by approximately 20%. Patients receiving digoxin in combination with atorvastatin require appropriate monitoring.

Erythromycin/clarithromycin: with simultaneous use of atorvastatin and erythromycin (500 mg four times daily) or clarithromycin (500 mg twice daily), which inhibit the CYP3A4 isoenzyme, an increase in the concentration of atorvastatin in the blood plasma was observed (see sections “Special instructions” – “Effect on skeletal muscle” and “Pharmacokinetics”).

Azithromycin: with simultaneous use of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily), the concentration of atorvastatin in the blood plasma did not change.

Terfenadine: with simultaneous use of atorvastatin and terfenadine, no clinically significant changes in the pharmacokinetics of terfenadine were detected.

Oral contraceptives: When atorvastatin was coadministered with an oral contraceptive containing norethindrone and ethinyl estradiol, significant increases in the AUC of norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively, were observed. This effect should be taken into account when choosing an oral contraceptive for a woman taking atorvastatin.

Warfarin: There were no signs of clinically significant interaction between atorvastatin and warfarin.

Diltiazem: Concomitant use of atorvastatin at a dose of 40 mg with diltiazem at a dose of 240 mg leads to an increase in the concentration of atorvastatin in the blood plasma.

Cimetidine: A study was conducted on the interaction of atorvastatin with cimetidine, which did not reveal clinically significant interactions (see section “Pharmacokinetics”).

Amlodipine: with simultaneous use of atorvastatin 80 mg and amlodipine 10 mg, the pharmacokinetics of atorvastatin at steady state did not change.

Protease inhibitors: simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of the CYP3A4 isoenzyme, was accompanied by an increase in the concentration of atorvastatin in the blood plasma. In addition, an increase in the concentration of atorvastatin was observed when used simultaneously with HIV protease inhibitors (combinations of lopinavir and ritonavir, saquinavir and ritonavir, darunavir and ritonavir, fosamprenavir, fosamprenavir with ritonavir and nelfinavir), hepatitis C protease inhibitors (boceprevir), clarithromycin and itraconazole. Caution should be exercised when using these drugs together and the lowest effective dose of atorvastatin should be used.

Fusidic acid: Although interaction studies between atorvastatin and fusidic acid have not been conducted, there is an increased risk of rhabdomyolysis in patients taking concomitant statins, including atorvastatin and fusidic acid. The mechanism of this interaction is unknown. In patients for whom the use of fusidic acid is considered necessary, treatment with statins should be discontinued for the entire period of use of fusidic acid. Statin therapy can be resumed 7 days after the last dose of fusidic acid.

In exceptional cases where long-term systemic therapy with fusidic acid is necessary, for example for the treatment of severe infections, the need for co-administration of atorvastatin and fusidic acid should be considered on a case-by-case basis and under close medical supervision. The patient should seek immediate medical attention if symptoms of muscle weakness, tenderness, or pain occur.

Colchicine: Although studies have not been conducted with the simultaneous use of colchicine and atorvastatin, there are reports of the development of myopathy with the use of this combination. Caution should be exercised when atorvastatin and colchicine are used concomitantly.

Other concomitant therapy: In clinical studies, atorvastatin was used in combination with antihypertensive agents and estrogens, which were used as replacement therapy; there were no signs of clinically significant adverse interactions; No interaction studies with specific drugs have been conducted.

Overdose

There is no information about an overdose of the drug. Both amlodipine and atorvastatin actively bind to plasma proteins, so a significant increase in the clearance of the combination drug during hemodialysis is unlikely.

Symptoms of amlodipine overdose:

– excessive peripheral vasodilation, leading to reflex tachycardia;

– pronounced and persistent decrease in blood pressure, including with the development of shock and death.

Symptoms of atorvastatin overdose: not described.

Treatment of amlodipine overdose:

– taking activated carbon immediately or within 2 hours after taking amlodipine at a dose of 10 mg leads to a significant delay in drug absorption. In some cases, gastric lavage may be effective.

– a pronounced decrease in blood pressure caused by an overdose of amlodipine requires active measures aimed at maintaining the function of the cardiovascular system, including monitoring the performance of the heart and lungs, elevated position of the limbs, control of circulating blood volume and diuresis.

– to restore blood pressure and vascular tone, the use of a vasoconstrictor drug may be useful if there are no contraindications to its use.

– to eliminate the consequences of blockade of calcium channels – intravenous administration of calcium gluconate. There are no specific treatments for atorvastatin overdose. In case of overdose, symptomatic and supportive treatment should be provided as needed.

Storage conditions

At a temperature not exceeding 25°C

Shelf life

3 years
Do not use after the expiration date indicated on the package.

Manufacturer

USA