Kadujet: instructions for using the medicine, structure, Contraindications

Active material: Amlodipine, Atorvastatin
When ATH: C10BX03
CCF: The antihypertensive and lipid-lowering drug with activity antianginalny
ICD-10 codes (testimony): I10
When CSF: 01.09.16.07
Manufacturer: GOEDECKE GmbH (Germany)

Pharmaceutical form, composition and packaging Caduet

Pills, Film-coated white, Oval, on one side is applied “Pfizer”, another – “CDT” and “051”.

Excipients: calcium carbonate, Croscarmellose sodium, microcrystalline cellulose, pre-gelatinized starch, polysorbate 80 (Tween 80), giproloza, colloidal silicon dioxide, magnesium stearate, film Opadraj shell II white 85F28751 (polyvinyl alcohol, Titanium dioxide, macrogol (PEG) 3000, talc).

10 PC. – blisters (3) – packs cardboard.

Pills, Film-coated blue, Oval, on one side is applied “Pfizer”, another – “CDT” and “101”.

Excipients: calcium carbonate, Croscarmellose sodium, microcrystalline cellulose, pre-gelatinized starch, polysorbate 80 (Tween 80), giproloza, colloidal silicon dioxide, magnesium stearate, film Opadraj shell II blue 85F10919 (polyvinyl alcohol, Titanium dioxide, macrogol (PEG) 3000, talc, lacquer aluminium indigokarmina).

10 PC. – blisters (3) – packs cardboard.

* international non-proprietary name, recommended by the WHO – amlodipine besylate.

Pharmacological action Caduet

Combined preparation, used to treat children with cardiovascular diseases (hypertension/strokes and Dyslipidemia).

Mechanism of action the drug is due to the action of its constituent components: amlodilin – dihydropyridine derivative, Calcium channel blockers slow, and atorvastatin – gipolipidemicescoe vehicle, HMG-CoA reductase. Amlodipine inhibits calcium current across the membrane in and cardiomiotita gladkomyshechne cells. Atorvastatin is selective and competitive ingibiruet g-KOA-reduktazu, which catalyzes the conversion of 3-Hydroxy-3-metilgljutarilkojenzima and in mevalonovuju acid – the predecessor of steroids, including cholesterol (Hs).

Clinical studies in patients with arterial hypertension and Dyslipidemia

The study RESPOND at 1600 patients with a combination of arterial hypertension and Dyslipidemia Kadujet compared with amlodipine and atorvastatin is appropriate alone alone or placebo. In addition to arterial hypertension and Dyslipidemia 15% patients suffered from diabetes mellitus, 22% smokers, and in 14% There were weighed down by the ancestral history of cardiovascular diseases. Through 8 weeks of combined drug therapy in all 8 doses resulted in statistically significant and augmentation depending on decrease in systolic and diastolic arterial pressure and low density lipoprotein cholesterol (LDL-C) compared to placebo. The effect on systolic BP and diastolic hell or CHS level of LDL cholesterol medication Kadujet is not significantly different from monotherapy amlodipine and atorvastatin is appropriate.

In a study of GEMINI 1220 patients with a combination of arterial hypertension and Dyslipidemia were receiving amlodipine/atorvastatin during 14 weeks. Included patients with uncontrolled arterial hypertension (receiving and not receiving antihypertensive; patients could continue receiving other gipotenziveh drugs, In addition to blocking slow calcium channels, during the 14-week dose titration period) and normal or elevated Cholesterol-LDL. All patients were raised hell or CHS level of LDL cholesterol, and in 62% – both indicators. Treatment with Kadujet has led to a decrease in systolic and diastolic HELL on average 17.1 and 9.6 mm Hg. Article. Consequently, the level of LDL-Cholesterol by an average of 32.7%. Control of HELL and the level of LDL-Cholesterol has been achieved at the 58% patients (criteria for control of HELL and XC-LDL was considered less 140/90 mm Hg. Article. less 160 mg/dl in patients with arterial hypertension and Dyslipidemia combination; less 140/90 mm Hg. Article. less 130 mg/dl in patients with the combination of hypertension and Dyslipidemia and another one cardiovascular risk factor, but without ISCHEMIC HEART DISEASE or diabetes; less 130/85 mm Hg. Article. less 100 mg/dl in patients with arterial hypertension and Dyslipidemia combination, as well as CHD, diabetes and other diseases, due to atherosclerosis). It has been shown, that decline ad and the level of LDL-Cholesterol has been achieved at the 65% patients, who were Kadujet in the initial phase of therapy for the treatment of hypertension and Dyslipidemia, and 55-64% patients, which was added amlodipine correction HELL (55% patients, receiving other hypolipidemic drugs in addition to atorvastatin, 58% patients, treated with atorvastatin to research, and 64% patients, hypolipidemic drugs who had not been).

Pharmacodynamics of amlodipine

Amlodipine blocks the flow of calcium ions through the membranes in gladkomyshechne cells of the myocardium and vascular.

The mechanism of action is attributable to amlodipine gipotenzivnogo direct relaxing effect on smooth muscle receptacles. The exact mechanism of action of amlodipine in angina not yet installed, but amlodipine reduces ischemia following two ways:

1. Amlodipine expands peripheral arteriola reduces round, and thus, ie. postnagruzku heart. Because the heart rate is not changed, reducing the burden on the heart leads to a decrease in consumption of energy and oxygen requirements.

2. The mechanism of action of amlodipine, probably, also includes the expansion of the main coronary arteries and coronary arterioles as unchanged, and in ischemic areas of the myocardium. Their dilation increases the oxygen supply to the myocardium in patients with vasospastic angina (stenocardia prinzmetala or variant angina) and prevents the development of coronary vazokonstrikcii, caused by smoking.

In patients with arterial hypertension reception of amlodipine in one daily dose provides a clinically significant decrease ad over 24 h in the supine position, and standing. Due to the slow start actions amlodipine is not causing severe arterial hypotension.

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

Amlodipine has no adverse effect on metabolism and plasma lipids and can be used in patients with bronchial asthma, diabetes and gout.

Use in patients with ischemic heart disease

Effects of amlodipine on cardiovascular morbidity and mortality, the progression of coronary atherosclerosis and atherosclerosis of the carotid arteries were examined in the study of PREVENT. In this study for 3 years observed patients with angiograficheski confirmed coronary atherosclerosis. Patients, treated with amlodipine, It was observed a significant reduction (on 31%) total frequency of cardiovascular mortality, myocardial infarction, stroke, transljuminal'noj percutaneous coronary angioplasty (PTCA), aorto-coronary bypass surgery, hospitalization about unstable angina and progression of chronic heart failure. Besides, It was observed, that progressive intimal thickening warned amlodipine-media carotid arteries.

The study examined the effectiveness of the CAMELOT of amlodipine in the prevention of adverse outcomes in patients with ischemic heart disease, roughly half of which, received amlodipine dose 5-10 mg, and the remaining patients – placebo in combination with standard therapy.. Duration of therapy was 2 year. Amlodipine therapy resulted in a reduction in cardiovascular mortality, nonfatal myocardial infarction, fatal and nonfatal stroke or tranzitornyh ischemic attack and other serious cardiovascular complications 31%, hospitalizations about strokes on 42%.

Pharmacodynamics of atorvastatin

Atorvastatin – selective competitive inhibitor of HMG-CoA reductase inhibitors, which HMG-CoA in mevalonovuju acid – the predecessor of steroids, including Xc. In patients with homozygous and heterozygous Familial Hypercholesterolemia, non-familial forms of hypercholesterolemia and Mixed Dyslipidemia atorvastatin reduces levels of total Cholesterol, XC-LDL and apolipoprotein in (APO-), as well as the very low density lipoprotein cholesterol (Hs-LPONP) and triglycerides (TG) and causes variable increase cholesterol-HDL Cholesterol.

Atorvastatin reduces Cholesterol levels and the Plasma lipoproteins from the oppression of HMG-CoA reductase and Cholesterol synthesis in the liver and increase the number of hepatic LDL receptors on the surface of cells, that leads to increased grip and catabolism of LDL.

Atorvastatin reduces the formation of LDL and HDL particle number. He calls and persistent increase in LDL receptor activity coupled with favorable changes in the quality of LDL particles. Atorvastatin reduces Cholesterol-LDL in patients with homozygous Familial Hypercholesterolemia, that is typically not amenable to therapy lipid means.

Atorvastatin and some of its metabolites are pharmacologically active in humans. Primary place of action of atorvastatin serves the liver, the synthesis of Cholesterol and LDL clearance. Degree of reducing the level of Cholesterol-LDL correlates with a dose of the drug, more, than with its system concentration. Dose picked on the basis of the response to treatment.

In a clinical study, which studied the effect dozozavisimost', Atorvastatin in doses 10-80 mg reduced the level of total Cholesterol (on 30-46%), LDL-C (on 41-61%), APO- (on 34-50%) and TG (on 14-33%). These results were similar in patients with heterozygous Familial Hypercholesterolemia, non-familial forms of hypercholesterolemia and mixed Hyperlipidemia, including patients with non-insulin-dependent diabetes mellitus. In patients with isolated hypertriglyceridemia atorvastatin reduces levels of total Cholesterol, LDL-C, Xc-VLDL, APO-, TG and HS-LPneVP and increases the level of HDL Cholesterol. In patients with disbetalipoproteinemiej atorvastatin reduced the level of intermediate density lipoprotein Cholesterol.

In patients with giperlipoproteinemiej IIa and IIb types by Conny Fredriksson, participating in 24 controlled studies, the median increase the level of HDL Cholesterol in the treatment of atorvastatin is appropriate (10-80 mg) made 5.1-8.7%. Changes in this ratio does not depend on the dose. In the analysis of these patients have also identified a dose-dependent decrease in coefficients of common Xc/XC-HDL and Cholesterol-LDL/HDL-Xc on 29-44% and 37-55%, respectively.

Efficacy of atorvastatin in the prevention of ischemic outcomes and overall mortality was studied in the MIRACL study. It included patients with acute coronary syndrome (unstable angina or myocardial infarction without zubza Q), who received standard therapy, including diet, in combination with atorvastatin is appropriate 80 mg/day or placebo for 16 weeks (median). Atorvastatin is appropriate treatment resulted in a pronounced reduction in the risk of ischemic outcomes and mortality in 16%. The risk of repeated hospitalization about Angina and myocardial ischemia has decreased by 26%. Effect of atorvastatin on the risk of ischemic outcomes and mortality did not depend on the initial level of LDL cholesterol and Cholesterol was comparable in patients with myocardial infarction without zubza Q and unstable angina, men and women, patients aged younger and older 65 years.

Prevention of cardiovascular disease risk

In the Anglo-Scandinavian study of cardiovascular outcomes, lipidsnizhajushhaja branch (ASCOT-LLA), effect of atorvastatin on fatal and non-fatal CORONARY HEART DISEASE outcomes (cardiovascular mortality, hospitalization about unstable angina) been evaluated in patients aged 40-80 years without myocardial infarction in history and with baseline total cholesterol more 6.5 mmol / l (251 mg / dL). All patients also attended, least, 3 cardiovascular risk factor: male sex, older than 55 years, smoking, diabetes, IBS 1st functional class in history, the correlation of the level of total cholesterol to HDL-Cholesterol level more 6, peripheral vascular disease, left ventricular hypertrophy, violations of cerebral circulation in history, specific changes on ECG, proteinuria and albuminuria. In a study of patients with arterial hypertension antihypertensive therapy apply concurrently with (target AD less 140/90 mm Hg. Article. for all patients in patients without diabetes mellitus and less 130/80 for patients with diabetes mellitus) was prescribed atorvastatin dose 10 mg/day or placebo.
Because, According to the interim analysis of the effect of therapy the drug significantly exceeded the effect of placebo, It was decided on early termination of research through 3.3 years instead of the anticipated 5 years. Atorvastatin significantly reduced the development of the following complications:

Significant reduction of total and cardiovascular mortality has not been pointed out, Although there was a positive trend.

The joint study of atorvastatin in diabetes (CARDS ) its effect on fatal and non-fatal cardiovascular disease outcomes evaluated in patients aged 40-75 years with diabetes mellitus type 2 without cardiovascular disease in history and with ENGINEERS no more 4.14 mmol / l (160 mg / dL) and TG no more 6.78 mmol / l (600 mg / dL). All the patients had at least one of the following risk factors: arterial hypertension, smoking, retinopathy, Micro- or makroal'buminurija. Patients received atorvastatin 10 mg/day or placebo for an average of 3.9 years. Because, According to the interim analysis of the effect of therapy the drug significantly exceeded the effect of placebo, It was decided early on when the investigation is complete 2 a year ahead of schedule.

Effect of atorvastatin on development of cardiovascular complications is given below:

Atherosclerosis

The study of reverse atherosclerosis with aggressive therapy lipidosnizhajushhej ( REVERSAL ) evaluated the effect of atorvastatin (80 mg) and Pravastatin on coronary atherosclerosis using intravascular ultrasonic angiography (VSUZI) in patients with coronary artery disease. VSUZI conducted at the beginning of the study and through 18 Months, at the end of the study. Atorvastatin group average reduction of the total atheroma (the primary criterion of research) Since the beginning of the study amounted to 0.4% (R = 0.98). In the Group of atorvastatin LDL-Cholesterol level decreased to an average of 2.04 ± 0.8 mmol/l (78.9± 30 mg/dl) compared to the initial level of 3.89 ± 0.7 mmol/l (150± 28 mg/dl), When the decline of the average level of total cholesterol in the 34.1%, TG – on 20%, APO- – on 39.1%. increase the level of HDL Cholesterol to 2.9%, as well as reducing the level of c-reactive protein on average 36.4%.

Pharmacokinetics Caduet

Absorption

After intake of the drug combination Kadujet registered two distinct peaks (C)_max plasma. C_max Atorvastatin was achieved through 1-2 no, C_max amlodipina – through 6-12 no. The speed and degree of suction (bioavailability) Amlodipine and atorvastatin in applying the drug Kadujet is not different from itself, while the pill amlodipine and atorvastatin: C_max amlodipine = 101%, AUC of amlodipine = 100%, C_max Atorvastatin = 94%, AUC atorvastatin = 105%.

After eating the bioavailability of amlodipine does not change (C_max = 105% and AUC = 101% compared to fasting). Although simultaneous eating caused a slowdown in the rate and degree of suction when using the drug atorvastatin Kadujet approximately 32% and 11% respectively (FROM_makh = 68% and AUC = 89%), However, similar changes bioavailability were identified using one atorvastatin. While eating does not influence the extent of reducing the level of Cholesterol-LDL.

Amlodipine is well absorbed after administration inwards at therapeutic doses, reaching C_max in the blood through 6-12 h after administration. Absolute bioavailability is estimated 64-80%. Eating does not affect the induction of amlodipine.

Atorvastatin is rapidly absorbed after administration inwards, C_max achieved through 1-2 no. The intake and concentrations of atorvastatin in plasma increases proportionally with the dose. Absolute bioavailability of atorvastatin is approximately 14%, and system bioavailability inhibiting activity against HMG-CoA reductase inhibitors – about 30%. Low system bioavailability due to presistemnym metabolism (suction) in the mucosa of the INTESTINE and/or metabolism when “first pass” through the liver. Food reduces the speed and degree of suction (on 25% and 9%, respectively, as evidenced by the results of (C)_max и AUC), However, the reduction of LDL-Cholesterol is similar to that of atorvastatin in the employment prandial. Despite, that after taking atorvastatin in the evening its concentration in plasma below (C_max and AUC by approximately 30%), than after taking the morning, lowering LDL cholesterol Cholesterol does not depend on the time of day, which take the drug.

Distribution

V_d amlodipine is approximately 21 l / kg. Studies in vitro have shown, that circulating amlodipine approximately 97.5% bound to plasma proteins. C_ss plasma levels achieved after 7-8 days of continuous use of the drug.

Average V_d Atorvastatin is approximately 381 l. Linking blood plasma proteins is not less 98%. Relevant content in erythrocytes/plasma is about 0.25, ie. Atorvastatin poorly crosses in red blood cells.

Metabolism

Amlodipine is metabolized in the liver with the formation of active metabolites.

Atorvastatin is largely metabolized with the formation of Ortho- and para-gidroksilirovannyh derivatives and various products beta oxidation. In vitro Ortho- and para-hydroxylated metabolites exert inhibitory effects on g-KOA-reduktazu, comparable to that of atorvastatin. About 70% reducing the activity of HMG-CoA reductase occurs due to the action of active circulating metabolites. Results of in vitro studies suggest, that CYP3A4 liver plays an important role in the metabolism of atorvastatin. This fact demonstrates increased concentrations of atorvastatin in human plasma while receiving erythromycin, that is an inhibitor of the izofermenta. In vitro studies have also shown, that atorvastatin is a weak inhibitor of CYP3A4. No clinically significant effect of atorvastatin on blood plasma concentration terfenadina, which is metabolized mainly CYP3A4, Therefore, it is unlikely, that atorvastatin has a significant impact on other CYP3A4 substrates farmakokinetiku.

Deduction

T_1/2 Amlodipine from blood plasma is about 35-50 no, that allows you to assign the drug 1 time / day. 10% unaltered amlodipine and 60% metabolites are excreted by the kidneys.

Atorvastatin and its metabolites are excreted mainly jelchew resulting in hepatic and/or vnepechenochnogo metabolism, Atorvastatin is not subject to pronounced kishechno-pechenocna recycling. T_1/2 is about 14 no, wherein T_1/2 inhibiting activity against g-KOA-reduktaza thanks to active metabolites is approximately 20-30 no. Intake in the urine detected less 2% dose.

Pharmacokinetics in special clinical situations

Atorvastatin concentration in plasma is greatly improved (FROM_makh about 16 time, AUC approximately 11 time) in patients with alcoholic cirrhosis of the liver (Class B classification Child-Pugh).

Amlodipine concentration in plasma does not depend on the degree of renal failure; amlodipine is not displayed by dialysis.

Kidney disease do not affect the concentrations of atorvastatin in plasma, in this regard, the dose adjustment in patients with renal impairment is not required.

Atorvastatin concentration in the blood plasma in women differs (C_max about 20% higher, (a) the AUC on 10% below) of such men, However, clinically significant differences influence on lipid metabolism in both men and women is not revealed.

Time, needed to achieve C_max amlodipine plasma, practically does not depend on age. Older people have a tendency to decrease in clearance of amlodipine, which leads to an increase in AUC and T_1/2 . In patients of different age groups with chronic heart failure, there has been an increase in AUC and T_1/2. Tolerability of amlodipine in the same doses in the elderly and young people are equally good.

Atorvastatin concentrations in blood plasma in people aged 65 years and over above (C_max about 40%, AUC approximately 30%), than in adult patients of young age; differences in safety assessment, performance or achievement of the objectives of the cholesterol-lowering therapy in the elderly compared with the general population not detected.

Indications for use Caduet

• hypertension with three or more risk factors for cardiovascular events (fatal nefatal'naja and ISCHEMIC HEART DISEASE, the need for revascularization, fatal and nonfatal myocardial infarction, stroke and transient ischemic attack), with normal or moderately elevated Cholesterol without clinically expressed HEART ISCHEMIC DISEASE.

The drug is applied in cases, When is combination therapy amlodipine and low doses of atorvastatin. The combination with other antigipertenzivei Kadujeta and/or antianginalnami means.

Caduet is used in cases, When the goal diet and other non-pharmacological therapies Dyslipidemia are little- or ineffective.

Dosing regimen Caduet

Drug taking into 1 tab. 1 times per day at any time, regardless of the meal.

Starting and supporting dose picked individually, taking into account the effectiveness and tolerability of both components in the treatment of hypertension and angina pectoris/Dyslipidemia. Kadujet you can assign patients, who are already taking one of the components of the drug in monotherapy.

Kadujet used in combination with drug-free treatments, including diet, physical exertion, decrease in body weight in obese patients, smoking cessation.

Start treatment should receive tablets 5/10 mg (Amlodipine/atorvastatin, respectively). In patients with arterial hypertension it is necessary to monitor ad every 2-4 week and, if necessary, We can also translate to the reception tablets 10/10 mg (Amlodipine/atorvastatin, respectively).

At CHD the recommended dose of amlodipine is 5-10 mg 1 time / day.

At primary hypercholesterolemia and combined (mixed) giperlipidemii Atorvastatin dose for most patients – 10 mg 1 time / day; therapeutic effect manifests itself within 2 weeks and usually reaches its peak during 4 weeks; in long-term care effect lasts.

In patients with impaired renal function dose adjustment is required.

In appointing the drug elderly patients dose adjustment is required.

Side effects of Caduet

In clinical studies, the safety of amlodipine and atorvastatin was studied in patients with a combination of arterial hypertension and dyslipidemia., any unexpected adverse effects when combined therapy is not registered.

Unwanted effects were consistent with previously identified in the treatment of amlodipine and atorvastatin is appropriate and/or. In general the portability of combination therapy was good. The majority of adverse effects were slightly or moderately expressed. In controlled clinical trials due to adverse effects or deviations of laboratory indicators of amlodipine and atorvastatin is appropriate treatment was terminated at 5.1% patients, and placebo – in 4.0%.

Amlodipine

Further under the frequency of adverse reactions is understood: frequent (> 1%), infrequent (< 1%), few (< 0.1%), very rare (< 0.01%).

Cardio-vascular system: often – peripheral edema (ankles and feet), heartbeat; infrequently – excessive reduction of blood pressure, orthostatic hypotension, vasculitis; rarely – development or exacerbation of congestive heart failure; rarely – heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, chest pain, migraine.

On the part of the musculoskeletal system: infrequently – arthralgia, muscle cramps, myalgia, backache, arthrosis; rarely – myasthenia.

From the central and peripheral nervous system: sensation of heat and tidal blood to the skin, fatigue, dizziness, headache, drowsiness; infrequently – malaise, fainting, increased perspiration, asthenia, gipestezii, paresthesia, perifericheskaya neuropathy, tremor, insomnia, mood lability, unusual dreams, nervousness, depression, alarm; rarely – convulsions, apathy, ažitaciâ; rarely – ataxia, amnesia.

From the digestive system: often – abdominal pain, nausea; infrequently – vomiting, changing bowel movement (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dry mouth, thirst; rarely – giperplaziya right, increased appetite; rarely – gastritis, pancreatitis, giperʙiliruʙinemija, jaundice (usually cholestatic), increase in liver transaminases, hepatitis.

From the hematopoietic system: rarely – trombotsitopenicheskaya purpura, leukopenia, thrombocytopenia.

Metabolic disorders: rarely – giperglikemiâ.

On the part of the respiratory system: infrequently – breathlessness, rhinitis; rarely – cough.

From the urinary system: infrequently– frequent urination, urodynia, nocturia, impotence; rarely – dizurija, polyuria.

On the part of the organ of vision: infrequently – visual impairment, diplopia, ccomodation, xerophthalmia, conjunctivitis, sore eyes.

For the skin: infrequently – alopecia; rarely – dermatitis; rarely – dermatoxerasia, violation of skin pigmentation.

Allergic reactions: infrequently – itching, rash; rarely – angioedema, erythema multiforme, hives.

Other: infrequently – tinnitus, gynecomastia, increase / decrease in body weight, dysgeusia, chills, nose bleed; rarely – parosmija, “cold” sweat.

Atorvastatin

Usually well tolerated. Adverse Reactions, usually, light and fleeting.

The most frequent adverse reactions (≥1%):

On the side CNS: insomnia, headache, asthenic syndrome.

From the digestive system: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.

On the part of the musculoskeletal system: myalgia.

Less frequent adverse reactions:

From the central and peripheral nervous system: malaise, dizziness, amnesia, paresthesia, perifericheskaya neuropathy, gipesteziya.

From the digestive system: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.

On the part of the musculoskeletal system: backache, muscle cramps, myositis, myopathy, artralgii, raʙdomioliz.

Allergic reactions: hives, itch, skin rash, anaphylaxis, bullous rash, erythema multiforme exudative, toxic epidermal necrolysis (Lyell's syndrome), malignant exudative erythema (Stevens-Johnson syndrome).

Metabolic disorders: gipoglikemiâ, giperglikemiâ, Increase serum CPK, weight gain.

From the hematopoietic system: thrombocytopenia.

Other: impotence, peripheral edema, chest pain, secondary renal failure, alopecia, noise in ears, fatigue.

Causal link with the admission of the drug is not for all of the above reactions.

Not all of these effects have established causal link with atorvastatin is appropriate therapy.

Contraindications for Caduet

• active liver disease or persistent elevation of liver enzymes for more than 3 times above normal unclear etiology;
• severe hypotension;
• pregnancy;
• lactation (breast-feeding);
• use in women of reproductive age, not using adequate contraception methods;
• childhood and adolescence up 18 years (efficacy and safety have not been established);
• hypersensitivity to amlodipine and other dihydropyridine derivatives, Atorvastatin or any of the preparation components.

FROM caution the drug should be used in patients, alcohol and/or liver disease (history).

Kadujet: Pregnancy and lactation

Kadujet contraindicated in pregnancy, tk. the product is atorvastatin.

Women of reproductive age at the time of treatment must use adequate contraception methods. The preparation may be nominated women of reproductive age only, If the probability of pregnancy is low, and patients informed about possible risks to the fetus.

Kadujet is contraindicated during breastfeeding, tk. It includes atorvastatin. Information about breeding of atorvastatin with breast milk no. Bearing in mind the possibility of adverse reactions in infants, women, receiving the drug, should stop breast-feeding.

Safety of amlodipine in pregnancy and lactation has not been established.

Special instructions for taking Caduet

Patients, treated with atorvastatin, There was myalgia. Diagnosis of myopathy (pain or weakness in muscles, combined with the increased activity of the KLF more than 10 times compared with FHG) assume in patients with common mialgijami, pain or weakness of muscles and/or expressed by increased activity of KFK. Patients should consult a doctor immediately when you see unexplained pain or weakness in the muscles, especially if they are accompanied by malaise or fever. Kadujet therapy should be discontinued in the case of explicit activity KLF or if there is a confirmed or suspected myopathy.

The risk of myopathy during treatment of other drugs of this class grows together with the use of Cyclosporine, derived fibroeva acid, Erythromycin, Nicotinic Acid or azole antifungals. Many of these drugs inhibit the metabolism of, mediated CYP3A4, and/or transport drugs. Known, that CYP3A4 – primary hepatic CYP, involved in the biotransformation of atorvastatin. Assigning atorvastatin in lipid lowering doses in combination with derivative fibroeva acid, Erythromycin, immunosuppressants, azole antifungal drugs or Nicotinic Acid, You should carefully weigh the expected benefits and risks of treatment and regularly monitor patients with the aim of identifying pain or weakness in the muscles, especially during the first months of treatment and dose of any drug enhancement period. In such situations, it is possible to recommend periodic determination of activity of KFK, Although such control does not allow you to prevent the development of severe myopathy.

Welcome Kadujeta can cause an increase in the activity of KFK. In the application of atorvastatin, like other drugs of this class, described rare cases of rhabdomyolysis with acute renal failure, caused by myoglobinuria. Kadujet therapy should temporarily suspend or Cancel when you see signs of possible myopathy or the existence of a risk factor for the development of renal failure on the background of rhabdomyolysis (eg, severe acute infection, hypotension, surgery, trauma, metabolic, metabolic and electrolyte disorders and uncontrolled convulsions). Amlodipine treatment in an adequate dose to control hypertension may be continued.

Effects on ability to drive vehicles and management mechanisms

Although the available data on amlodipine and atorvastatine suggests, that combined product should not impair the ability to drive and use technology, be careful when driving vehicles and management mechanisms (in view of the possible excessive loss AD, dizziness, fainting).

Overdose Caduet

Information about overdose no.

As amlodipine, and atorvastatin is actively associated with blood plasma proteins, Therefore, the significant increase in ground clearance combined the drug with hemodialysis is unlikely.

Symptoms an overdose of amlodipine: chrezmernaya perifericheskaya vasodilation, causing reflex tachycardia, and expressed and stable lowering ad, incl. with the development of shock and mortality.

Symptoms an overdose of atorvastatin is not described.

Treatment an overdose of amlodipine: reception activated carbon immediately or within 2 h after administration of amlodipine dose 10 mg leads to considerable delay drug intake. In some cases, can be an effective gastric lavage. Clinically significant hypotension, caused by overdose of amlodipine, requires active measures, to maintain the function of the cardiovascular system, including monitoring the performance of the heart and lungs, sublime position limbs and control and Bcc diureza. To restore vascular tone and hell may be a useful application of sossoudossouerveshchego drug, If no contraindications to his appointment, to eliminate the effects of calcium channel blockade – in / with the introduction of calcium gluconate.

Specific means for treatment an overdose of atorvastatin no. In the case of an overdose should be symptomatic and supportive care as needed.

Drug interaction Caduet

Displaying, that the pharmacokinetics of amlodipine 10 mg atorvastatin is appropriate combination therapy 10 mg in healthy volunteers not changing. Amlodipine does not influence (C)_max Atorvastatin, but caused an increase in AUC on 18%. Interaction Kadujet drug with other drugs not specifically studied, but studies of each component separately.

Amlodipine

It can be expected, Inhibitors of microsomal oxidation will increase the concentration of amlodipine in plasma, increasing the risk of side effects, and inducers of microsomal liver enzymes – reduce.

Together with the use of amlodipine with cimetidine pharmacokinetics of amlodipine does not change.

Simultaneous single dose 240 ml of grapefruit juice and 10 mg amlodipine inside is not accompanied by a significant change in the pharmacokinetics of amlodipine.

Unlike other blocking slow calcium channel blockers amlodipine clinically meaningful interaction was not detected when coupled with the use of NSAIDS, particularly indomethacin.

Perhaps increased antianginalnogo and gipotenzivnogo action blocking slow calcium channels when coupled with tiazidnami and “loop” Diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates, as well as increase their hypotensive effect when combined with alpha₁-adrenoblokatorami, neuroleptics.

Although the study of amlodipine inotropnogo usually does not effect negative watched, Nonetheless, some slow calcium channels blockers may increase the severity of adverse complications drugs action inotropnogo, causing QT prolongation (eg, amiodarone and quinidine).

When blocking slow calcium channels with the drug lithium may increase manifestations of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, noise in ears).

Amlodipine has no effect in vitro on the binding of plasma proteins digoxin, phenytoin, warfarin and indomethacin.

Aluminium/other magnesium-containing antacids when one-time admission did not have a significant impact on the farmakokinetiku amlodipine.

Single sil'denafila (dose 100 mg) in patients with essential hypertension has no effect on the pharmacokinetics of amlodipine.

With simultaneous use of amlodipine with digoxin in healthy volunteers serum levels and renal clearance of digoxin are not changed.

In single and repeated administration at a dose of 10 mg of amlodipine had no significant effect on the pharmacokinetics of ethanol.

Amlodipine has no effect on the changes of prothrombin time, caused by warfarin.

Amlodipine does not cause significant changes in the pharmacokinetics of cyclosporine.

Influence on the results of laboratory tests not known.

Atorvastatin

The risk of myopathy during treatment with other drugs of this class is increased, while the use of Cyclosporine, derived fibroeva acid, Erythromycin, antifungals, belonging to azolam, and Nicotinic Acid.

Simultaneous ingestion of slurry, containing magnesium and aluminium hydroxides, reduced concentrations of atorvastatin in plasma approximately 35%, However, the degree of reduction of LDL-Cholesterol while not changed.

Atorvastatin does not affect the farmakokinetiku Phenazone, Therefore, interaction with other drugs, those same izofermentami cytochrome P450, It is not expected.

While applying kolestipola atorvastatin concentration in plasma decreased by approximately 25%; However, lowering atorvastatin combination effects and kolestipola surpassed such each drug separately.

The readmission of Digoxin and atorvastatin dose 10 mg equilibrium concentration of Digoxin in plasma is not changed. However, when applied in combination with digoxin dose of atorvastatin is appropriate 80 mg/day concentration of Digoxin increased by about 20%. Patients, receiving digoxin combined with atorvastatin is appropriate, require appropriate monitoring.

Together with the use of atorvastatin and erythromycin (500 mg 4 times / day) or == (500 mg 2 times / day), that inhibit CYP3A4, There was an increase in concentrations of atorvastatin in plasma.

Together with the use of atorvastatin (10 mg 1 time / day) and azithromycin (500 mg 1 time / day) plasma atorvastatin concentrations did not change.

Together with the use of atorvastatin and clinically significant changes in the pharmacokinetics of terfenadine terfenadina not detected.

Together with the use of atorvastatin and oral contraceptive, contains norethisterone and ethinyl estradiol, There was a significant increase in AUC of ethinyl estradiol and norethisterone approximately 30% and 20%, respectively. This effect should be taken into account when choosing oral contraceptive for women, host atorvastatin.

Clinically meaningful interaction of atorvastatin with warfarin is not detected.

Clinically meaningful interaction of atorvastatin with cimetidine is not detected.

Together with the use of atorvastatin dose 80 mg and amlodipine dose 10 mg pharmacokinetics of atorvastatin in equilibrium has not changed.

The combined application of atorvastatin with protease inhibitors, known as CYP3A4 inhibitors, accompanied by increases in the concentrations of atorvastatin in plasma.

Atorvastatin is used in clinical trials in combination with antigipertenzivei means and estrogens, who appointed with replacement purpose; signs of clinically significant interactions have been noted; Research of interaction with specific drugs have been conducted.

Conditions for dispensing from Caduet pharmacies

The drug is released under the prescription.

Conditions and terms of storage Caduet

The drug should be stored out of reach of children at temperature from 15 ° to 30 ° C. Shelf life – 2 year.