Кадуэт

General characteristics. Structure:

International unlicensed or grouping name: амлодипин + аторвастатин.
Active agents: амлодипин (in the form of an amlodipin of a besilat) 5,0 (6,94) mg or 10,0 (13,87) mg, аторвастатин (in the form of an atorvastatin of calcium) 10,0 (10,85) mg; excipients: calcium carbonate, croscarmellose sodium, cellulose microcrystallic, starch prezhelatinizirovanny, polysorbate 80 (twin 80), hypro rod, silicon dioxide colloid, magnesium stearate, film cover of Opadray the II white 85F28751 (tablets of 5 mg +10 mg) (polyvinyl alcohol, titanium dioxide, macrogoal (PEG) 3000, talc), film cover of Opadray of the II blue 85F10919 (tablets of 10 mg +10 mg) (polyvinyl alcohol, titanium dioxide, macrogoal (PEG) 3000, talc, varnish aluminum indigo carmine).

Description. Tablets of 5 mg +10 mg: Oval tablets, film coated, white color. On one party "Pfizer", is applied on another - "CDT" and "051".

Tablets of 10 mg +10 mg: Oval tablets, film coated, blue color. On one party "Pfizer", is applied on another - "CDT" and "101".

Pharmacological properties:

Pharmacodynamics. KADUET is the combined drug intended for treatment of the combined cardiovascular diseases (arterial hypertensia / stenocardia and a dislipidemiya).

Action mechanism

Amlodipin/atorvastatin has two mechanisms of action: амлодипин is derivative dihydropyridine, the representative of blockers of "slow" calcium channels (BMKK), and аторвастатин – hypolipidemic means, HMG-CoA reductase inhibitor. Amlodipin inhibits calcium current through membranes in smooth muscle cells and cardiomyocytes. Atorvastatin selectively and competitively inhibits HMG-CoA reductase which catalyzes transformation of 3-hydroxy-3-metilglyutarilkoenzima A into mevalonovy acid – the predecessor of steroids, including cholesterol (Хс).

Clinical trials at patients with the arterial hypertension (AH) and a dislipidemiya

In the research RESPOND at 1600 patients with a combination of AG and a dislipidemiya of Kaduet compared to monotherapy amlodipiny and monotherapies atorvastatiny or placebo. In addition to AG and a dislipidemiya of 15% of patients 22% of smokers suffered from a diabetes mellitus, and 14% had a burdened hereditary anamnesis on cardiovascular diseases. In 8 weeks therapy by the combined drug in all 8 doses led to statistically significant and dozozavisimy decrease systolic (GARDEN) and the diastolic arterial pressure (DAP) and the level of cholesterol of lipoproteids of the low density (Hs-LPNP) in comparison with placebo. On influence on the GARDEN and DAD or the Hs-LPNP level drug KADUET significantly did not differ from monotherapy amlodipiny and atorvastatiny.

In the research GEMINI of 1220 patients with a combination of AG and a dislipidemiya received amlodipin/atorvastatin within 14 weeks. Patients from uncontrollable AG joined (the receiving and not receiving antihypertensives; patients could continue reception of other hypotensive drugs, in addition to BMKK, during the 14 weeks period of titration of a dose) and the normal or increased Hs-LPNP level. At all patients ABP or the Hs-LPNP level, and at 62% - both indicators were raised. Treatment by drug KADUET led to decrease the GARDEN and DAD on average on 17,1 and 9,6 mm of mercury. respectively and the Hs-LPNP level on average for 32,7%. Control of the ABP and the Hs-LPNP level managed to achieve from 58% of patients (criteria of control of the ABP and Hs-LPNP considered less than 140/90 mm of mercury. and patients have less than 160 mg/dl with a combination of AG and a dislipidemiya; less than 140/90 mm of mercury. and patients have less than 130 mg/dl with a combination of AG and a dislipidemiya and one more cardiovascular risk factor, but without ischemic heart disease or a diabetes mellitus; less than 130/85 mm of mercury. and patients have less than 100 mg/dl with a combination of AG and a dislipidemiya, and also the ischemic heart disease, a diabetes mellitus and other diseases caused by atherosclerosis). It was shown that decrease in the ABP and the Hs-LPNP level managed to achieve from 65% of patients who received KADUET at the initial stage of therapy for the purpose of treatment of AG and a dislipidemiya, and 55-64% of patients by which it was added амлодипин for the purpose of correction of the ABP (55% of the patients receiving other hypolipidemic means in addition to an atorvastatin, 58% of the patients receiving аторвастатин prior to a research, and 64% of patients who did not accept hypolipidemic drugs).

Pharmacodynamics of an amlodipin

Amlodipin represents BMKK and blocks receipt of calcium ions through membranes in smooth muscle cells of a myocardium and vessels.

The mechanism of hypotensive action of an amlodipin is caused by the direct weakening impact on unstriated muscles of vessels. The exact mechanism of action of an amlodipin at stenocardia is not finalized, but амлодипин reduces ischemia the next two ways:

1. Amlodipin expands peripheral arterioles and thus reduces the general peripheric resistance, i.e. a heart afterload. As heart rate does not change, reduction of load of heart leads to decrease in consumption of energy and oxygen requirement.

2. The mechanism of action of an amlodipin probably also includes expansion of the main coronary arteries and coronary arterioles both in not changed, and in ischemic zones of a myocardium. Their dilatation increases intake of oxygen in a myocardium at patients with vasospastic stenocardia (Printsmetal's stenocardia or alternative stenocardia) and prevents development of the coronary vasoconstriction caused by smoking.

At patients with AG the single daily dose of an amlodipin provides clinically significant decrease in the ABP for 24 hours as in a prone position, and standing. Thanks to the slow beginning of action амлодипин does not cause acute arterial hypotension.

At patients with stenocardia use of an amlodipin of 1 times a day increases time of performance of an exercise stress, prevents development of an attack of stenocardia and depression of a segment of ST (on 1 mm), reduces the frequency of attacks of stenocardia and the number of consumption of Tabulettaes Nitroglycerini.

Amlodipin does not exert adverse impact on a metabolism and lipids of a blood plasma and can be used at patients with bronchial asthma, a diabetes mellitus and gout.

Use for patients with the coronary heart disease (CHD)

Effects of an amlodipin on cardiovascular incidence and mortality, progressing of coronary atherosclerosis and the course of atherosclerosis of carotid arteries were studied in the research PREVENT. In this research within 3 years observed patients with angiographically the confirmed coronary atherosclerosis. At the patients receiving амлодипин considerable decrease (for 31%) the total frequency of cardiovascular mortality, by IT, a stroke, PTKA, aortocoronary shunting, hospitalization concerning unstable stenocardia and progressing of the chronic heart failure (CHF) was noted. Besides, it was noted that Amlodipin warned the progressing thickening erotic-medii of carotid arteries.

In the research CAMELOT efficiency of an amlodipin in prevention of failures at patients with ischemic heart diseases which about a half, received амлодипин in doses 5-10 mg, and other patients – placebo in a combination to standard therapy was studied. Duration of therapy made 2 years. Therapy amlodipiny was followed by decrease in cardiovascular mortality, not fatal IT, a fatal and not fatal stroke or TIA and other serious cardiovascular complications for 31%, hospitalization concerning stenocardia for 42%.

Pharmacodynamics of an atorvastatin

Atorvastatin is a selection competitive inhibitor of the HMG-CoA reductase turning GMG-KOA into mevalonovy acid – the predecessor of steroids, including Hs. At patients with a homozygous and heterozygous family hypercholesterolemia, single forms of a hypercholesterolemia and the mixed dislipidemiya аторвастатин reduces levels of general Hs, Hs-LPNP and apolipoprotein B (apo-V), and also cholesterol of lipoproteids of very low density (Hs-LPONP) and triglycerides (TG) and causes variable increase in level of Hs-LPVP cholesterol.

Atorvastatin reduces levels of Hs and lipoproteids in plasma due to oppression of HMG-CoA reductase and synthesis of Hs in a liver and increases in number of hepatic receptors of LPNP at surfaces of cells that leads to strengthening of capture and a catabolism of LPNP.

Atorvastatin reduces education LPNP and number of particles of LPNP. It causes the expressed and permanent increase in activity of LPNP of receptors in combination with favorable changes of quality of LPNP of particles. Atorvastatin reduces the Hs-LPNP level at patients with a homozygous family hypercholesterolemia which usually does not give in to therapy by hypolipidemic means.

Atorvastatin and some of his metabolites are pharmacological active at the person. As primary scene of action of an atorvastatin serves the liver where synthesis of Hs and clearance of LPNP are carried out. Extent of decrease in the Hs-LPNP level correlates with a drug dose more than with its system concentration. The dose is selected taking into account the response to treatment (see. "Route of administration and doses").

In clinical trial in which the effect dozozavisimost was studied аторвастатин in doses of 10-80 mg reduced the level of general Hs (by 30-46%), Hs-LPNP (for 41-61%), apo-V (for 34-50%) and TG (for 14-33%). Patients had similar these results with a heterozygous family hypercholesterolemia, single forms of a hypercholesterolemia and the mixed lipidemia, including patients with a non-insulin-dependent diabetes mellitus. At patients with the isolated gipertriglitseridemiya аторвастатин reduces levels of general Hs, Hs-LPNP, Hs-LONP, apo-V, TG and Hs-LPNEVP and increases the Hs-LPVP level. At patients with a disbetalipoproteinemiya аторвастатин reduced the level of Hs of lipoproteids of intermediate density.

Patients with a giperlipoproteinemiya have IIa and IIb of the types across Frederikson participating in 24 controlled researches, a median of increase in the Hs-LPVP level at treatment atorvastatiny (10-80 mg) made 5,1-8,7%. Changes of this indicator did not depend on a dose. In the analysis of these patients revealed also dozozavisimy decrease in coefficients general Hs/Hs-LPVP and Hs-LPNP/Hs-LPVP for 29-44% and 37-55%, respectively.

Efficiency of an atorvastatin in prevention of ischemic outcomes and the general mortality was studied in the research MIRACL. It included patients with an acute coronary syndrome (unstable stenocardia or IT without Q tooth) who received standard therapy, including a diet, in combination with atorvastatiny 80 mg/days or placebo within 16 weeks (median). Treatment atorvastatiny led to the expressed decrease in risk of ischemic outcomes and a lethality for 16%. The risk of repeated hospitalization concerning stenocardia and the confirmed ischemia of a myocardium decreased by 26%. Influence of an atorvastatin on risk of ischemic outcomes and a lethality did not depend on the initial Hs-LPNP level and was comparable at patients IT without tooth Q and unstable stenocardia, men and women, aged younger and 65 years are more senior than patients.

Prevention of risk of development of cardiovascular diseases

In Anglo-Cкандинавском a research of cardiovascular outcomes, a lipidsnizhayushchy branch (ASCOT-LLA), effect of an atorvastatin on fatal and not fatal outcomes of an ischemic heart disease (cardiovascular mortality, hospitalization concerning unstable stenocardia) it was estimated at patients at the age of 40-80 years without IT in the anamnesis and with the initial level of general cholesterol more than 6,5 mmol/l (251 mg/dl). All patients also had, at least, 3 cardiovascular risk factors: the male, age is more senior than 55 years, smoking, a diabetes mellitus, an ischemic heart disease of the 1st functional class in the anamnesis, a ratio of level of the general cholesterol to the Hs-LPVP level more than 6, a disease of peripheral vessels, a hypertrophy of a left ventricle, disturbance of cerebral circulation in the anamnesis, specific changes on an ECG, a proteinuria and an albuminuria. In a research to patients with AG along with the appointed hypotensive therapy (target the ABP less than 140/90 mm of mercury. for all patients at patients without diabetes mellitus and less than 130/80 for patients with a diabetes mellitus) it was appointed аторвастатин in a dose of 10 mg/days or placebo.

Because according to the intermediate analysis the effect of therapy of drug significantly exceeded effect of use of placebo, the decision on the early termination of a research in 3,3 years instead of estimated 5 years was made.

Atorvastatin significantly reduced development of the following complications:

Decrease in risk

Coronary complications

(An ischemic heart disease from the death and not fatal to THEM)
36%

General cardiovascular complications and procedures of revascularization
20%

General coronary complications
29%

Stroke (fatal and not fatal)
26%

Essential decrease in the general and cardiovascular mortality was not noted though the positive tendency was observed.

In the integrated research of an atorvastatin at a diabetes mellitus (CARDS) its influence on fatal and not fatal outcomes of cardiovascular diseases no more than 4,14 mmol/l (160 mg/dl) and TG estimated at patients at the age of 40-75 years with a diabetes mellitus of the 2nd type without cardiovascular diseases in the anamnesis and with LPNP no more than 6,78 mmol/l (600 mg/dl). All patients had at least one of the following risk factors: arterial hypertension, smoking, retinopathy, micro or macroalbuminuria. Patients received аторвастатин 10 mg/days or placebo within on average 3,9 years. Because according to the intermediate analysis the effect of therapy of drug significantly exceeded effect of use of placebo, the decision on early completion of a research for 2 years before the planned term was made.

The effect of an atorvastatin on development of cardiovascular complications is given below:

Relative decrease in risk

The main cardiovascular complications [fatal and not fatal acute to THEM, unstable stenocardia, shunting of a coronary artery, PTKA, revascularization, a stroke hidden by IT, death as a result of an ischemic heart disease aggravation]

37%

THEM (fatal and not fatal acute to THEM, hidden by IT)
42%

Stroke (fatal and not fatal)
48%


Atherosclerosis

In an atherosclerosis involution research at aggressive lipidsnizhayushchy therapy (REVERSAL) the effect of an atorvastatin (80 mg) and a pravastatina on coronary atherosclerosis by means of an intravascular ultrasonic angiography (VSUZI) at patients with an ischemic heart disease estimated. VSUZI was carried out at the beginning of the research and in 18 months, upon termination of a research. In group of an atorvastatin average reduction of total amount of an atheroma (primary criterion of a research) since the beginning of a research made 0,4%. (É = 0,98). In group of an atorvastatin the Hs-LPNP level decreased on average to 2,04±0,8 mmol/l (78,9±30 mg/dl) in comparison with the initial level of 3,89±0,7 mmol/l (150±28 mg/dl), at the same time decrease in the average level of the general cholesterol by 34,1%, TG - for 20%, apo-V - for 39,1% is noted, increase in the Hs-LPVP level by 2,9%, and also decrease in level of S-reactive protein on average by 36,4%.

Pharmacokinetics.
Absorption
after intake of the combined drug KADUET two clear peaks of the maximum concentration (Cmax) in plasma are registered. Concentration of an atorvastatin reached a maximum in 1-2 h, and an amlodipin – in 6-12 h. Speed and extent of absorption (bioavailability) of an amlodipin and an atorvastatin at use of drug KADUET did not differ from that at a concomitant use of tablets of an amlodipin and an atorvastatin: Cmax of an amlodipin = 101%; AUC of an amlodipin = 100%; Cmax of an atorvastatin = 94%; AUC (the area of distribution under a curve) an atorvastatina: 105%.

After meal bioavailability of an amlodipin does not change: Cmax = 105% and AUC = 101% in comparison with indicators on an empty stomach. Though a concomitant use of food caused reduction of speed and extents of absorption of an atorvastatin at drug KADUET use approximately for 32% and 11% according to (Cmax = 68% and AUC = 89%), however similar changes of bioavailability were revealed when using one atorvastatin. At the same time meal did not exert impact on extent of decrease in the Hs-LPNP level.

Amlodipin is well soaked up after intake in therapeutic doses, reaching Cmax in blood in 6-12 hours after reception. Absolute bioavailability by calculations makes 64-80%. The volume of distribution is equal to about 21 l/kg. The researches in vitro showed what circulating амлодипин approximately for 97,5% contacts proteins of plasma. Meal does not influence absorption of an amlodipin.

Atorvastatin is quickly soaked up after intake, concentration it in a blood plasma reaches a maximum in 1-2 hours. Extent of absorption and concentration of an atorvastatin in a blood plasma raise in proportion to a dose. Absolute bioavailability of an atorvastatin makes about 14%, and system bioavailability of the inhibiting activity concerning GMG-KOA-reduktazy - about 30%. Low system bioavailability is caused by presistemny metabolism (absorption) in a mucous membrane of digestive tract and/or metabolism at "the first passing" through a liver. Food reduces the speed and extent of absorption a little (by 25% and 9%, respectively, what results of definition of Cmax and AUC testify to), however decrease in Hs-LPNP is similar to that at reception of an atorvastatin on an empty stomach. In spite of the fact that after reception of an atorvastatin at evening its concentration in a blood plasma is lower (Cmax and AUC approximately for 30%), than after reception at morning, decrease in Hs-LPNP does not depend on time of day in which accept drug.

Distribution

The average volume of distribution of an atorvastatin makes about 381 l. Communication with proteins of a blood plasma not less than 98%. The relation of content in erythrocytes/plasma makes about 0,25, i.e. аторвастатин badly gets into erythrocytes.

Metabolism

The elimination half-life (T1/2) of an amlodipin makes about 35-50 h of a blood plasma that allows to appoint drug once a day. Equilibrium concentration in a blood plasma is reached in 7-8 days of constant administration of drug. It is metabolized in a liver with formation of inactive metabolites; 10% of not changed drug and 60% of metabolites are removed by kidneys.

Atorvastatin is substantially metabolized with education orto-and para-hydroxylated derivatives and various products of beta oxidation. In vitro orto-and para-hydroxylated metabolites have an inhibiting effect on GMG-KOA-reduktazu, comparable to that of an atorvastatin. About 70% of decrease of the activity of GMG-KOA-reduktazy happen due to action of the active circulating metabolites. Results of the researches in vitro give the grounds to assume that P450 3A4 cytochrome of a liver plays an important role in metabolism of an atorvastatin. In favor of this fact increase in concentration of an atorvastatin in a blood plasma of the person at a concomitant use of erythromycin which is inhibitor of this isoenzyme testifies. The researches in vitro also showed what аторвастатин is weak inhibitor of P450 3A4 cytochrome. Clinically significant influence of an atorvastatin on concentration in a blood plasma of a terfenadin who is metabolized mainly by P450 3A4 cytochrome therefore it is improbable that аторвастатин has significant effect on pharmacokinetics of other substrates of P450 3A4 cytochrome (see is noted. "Interaction with other medicines").

Removal

Atorvastatin and his metabolites are removed mainly with bile as a result of hepatic and/or extrahepatic metabolism, аторвастатин is not exposed to the expressed enterohepatic recirculation. T1/2 of drug makes about 14 h, at this T1/2 of the inhibiting activity concerning GMG-KOA-reduktazy thanks to existence of active metabolites makes about 20-30 h. After intake in urine less than 2% of a dose are found.

Special groups of patients
Abnormal liver function: concentration of an atorvastatin in a blood plasma considerably increases (Cmax approximately by 16 times, and AUC approximately by 11 times) at patients with alcoholic cirrhosis (on classification of Chayld-Pyyu In) (cm. section "Contraindications").

Renal failure: concentration of an amlodipin in plasma do not depend on degree of a renal failure; he is not brought at dialysis.

Diseases of kidneys do not influence concentration of an atorvastatin in a blood plasma, in this regard dose adjustment with a renal failure is not required from patients (see. "Route of administration and doses").

Floor: concentration of an atorvastatin in a blood plasma at women differs (Cmax about 20% higher, and AUC 10% lower) from that at men, however clinically significant distinctions of influence of drug on lipidic exchange at men and women are not revealed.

Elderly
Time necessary for achievement of the maximum concentration of an amlodipin in a blood plasma, practically does not depend on age. At people of advanced age the tendency to decrease in clearance of an amlodipin is noted that leads to increase in AUC and T1/2. At patients, various age groups with HSN increase in AUC and the period of T1/2 was observed. Portability of an amlodipin in the same doses at elderly and young people equally good.
Concentration of an atorvastatin in a blood plasma at aged people of 65 years are also more senior above (Cmax approximately for 40%, AUC approximately for 30%), than at adult patients of young age; distinctions at assessment in safety, efficiency or achievement of goals of hypolipidemic therapy at elderly people in comparison with the general population are not revealed.

Indications to use:

KADUET is shown to sick AG with 3 and more risk factors of development of cardiovascular events (a fatal and not fatal ischemic heart disease, need for revascularization, a fatal and not fatal myocardial infarction, a stroke and the tranzitorny ischemic attack), with the normal or moderately increased level of XC without clinically expressed ischemic heart disease.

KADUET is applied in cases when the combination therapy amlodipiny and low doses of an atorvastatin is recommended. KADUETA combination to other hypotensive and/or anti-anginal means is possible.

KADUET is applied in cases when the hypolipidemic diet and other not pharmacological methods of treatment of a dislipidemiya are a little - or inefficient.

Route of administration and doses:

Drug is accepted inside on one tablet of 1 times a day at any time, irrespective of meal. One tablet of drug KADUET contains 5 mg +10mg and 10 mg +10mg (an amlodipina and an atorvastatina, respectively). The initial and supporting doses are selected individually taking into account efficiency and portability of both components in treatment of AG/stenocardia and a dislipidemiya. Patients who already accept one of drug components in monotherapy can appoint KADUET.

KADUET use in combination with non-drug remedies, including a diet, exercise stresses, decrease in body weight at patients with obesity, refusal of smoking.

At an initiation of treatment from a dose of 5/10 mg at patients with AG it is necessary to control the ABP each 2-4 weeks and, if necessary, transfer into a dose of 10/10 mg is possible.

Ischemic heart disease (амлодипин): the recommended dose makes 5-10 mg once a day.

Primary hypercholesterolemia and the combined (mixed) lipidemia (аторвастатин): for most of patients - 10 mg once a day; therapeutic action is shown within 2 weeks and usually reaches a maximum within 4 weeks; at prolonged treatment the effect remains.

Use for patients with an abnormal liver function: see. "Contraindications" and "Special instructions".
Use for patients with a renal failure: dose adjustment is not required.
Use for elderly people: dose adjustment is not required.

Features of use:

Action on skeletal muscles

At the patients receiving аторвастатин the mialgiya was observed (see. "Side effect").

The diagnosis of a myopathy (pain or weakness in muscles in combination with increase in activity of a kreatinfosfokinaza (KFK) more than by 10 times in comparison with the upper bound of norm) should be assumed at patients with widespread mialgiya, morbidity or weakness of muscles and/or the expressed increase in activity of KFK. Patients have to see immediately a doctor at emergence of inexplicable pains or weakness in muscles, especially if they are followed by an indisposition or fever. Therapy by drug KADUET should be stopped in case of the expressed increase in activity of KFK or in the presence of the confirmed or estimated myopathy. The risk of a myopathy at treatment by other drugs of this class increases at simultaneous use of cyclosporine, derivatives of fibrinous acid, erythromycin, niacin or azolny antifungal drugs. Many of these drugs inhibit the metabolism mediated by P450 3A4 cytochrome and/or transport of medicines. It is known that P450 3A4 cytochrome – the main isoenzyme of a liver participating in biotransformation of an atorvastatin. Appointing аторвастатин in hypolipidemic doses in combination with derivatives of fibrinous acid, erythromycin, immunodepressants, azolny antifungal drugs or niacin, the doctor has to weigh carefully expected advantage and risk of treatment and to regularly observe patients for the purpose of detection of pains or weakness in muscles, especially within the first months of treatment and during increase in a dose of any drug. In similar situations it is possible to recommend periodic definition of activity of KFK though such control does not allow to prevent development of a heavy myopathy (see. "Interaction with other medicines"). KADUET can cause increase in activity of KFK (see. "Side effect"). At use of an atorvastatin, as well as other drugs of this class, exceptional cases of a rabdomioliz with the acute renal failure caused by a myoglobinuria are described. Therapy by drug KADUET should be stopped temporarily or to cancel completely at emergence of signs of a possible myopathy or existence of risk factor of development of a renal failure against the background of a rabdomioliz (for example, a heavy acute infection, arterial hypotension, an operative measure, an injury, metabolic, endocrine and electrolytic disturbances and uncontrollable spasms). Treatment amlodipiny in an adequate dose for the purpose of control of arterial hypertension can be continued.

Influence on ability to driving of the car and to control of mechanisms
Though the available data on the amlodipena and the atorvastatena demonstrate that the combined drug should not worsen ability of driving and use of the equipment, it is necessary to be careful during the driving of motor transport and control of mechanisms (considering possible development of excessive decrease in the ABP, dizziness, faint).

Side effects:

In clinical trials safety of an amlodipin and atorvastatin was studied at patients with a combination of AG and a dislipidemiya, at the same time any unexpected undesirable effects at a combination therapy are not registered. Undesirable effects corresponded revealed earlier at treatment amlodipiny and/or atorvastatiny (see below). In general portability of a combination therapy was good. The majority of undesirable effects were easily or moderately expressed. In controlled clinical trials because of undesirable effects or deviations of laboratory indicators treatment amlodipiny and atorvastatiny was stopped at 5,1% of patients, and placebo – at 4,0%.

Amlodipin.

Further as the frequency of side reactions it is understood: frequent (> 1%), infrequent (<1%), rare (<0,1%), very rare (<0,01%).

Cardiovascular system: peripheral hypostases (anklebones and feet), heartbeat, it is not frequent – excessive decrease in the ABP, orthostatic hypotension, a vasculitis; seldom – development or aggravation of heart failure; very seldom - disturbances of a heart rhythm (including bradycardia, ventricular tachycardia and atrial fibrillation), a myocardial infarction, thorax pains, migraine.

From a musculoskeletal system: not often - an arthralgia, myotonia, a mialgiya, a dorsodynia, arthrosis, it is rare - a myasthenia.

Central and peripheral nervous system: the feeling of heat and "inflows" of blood to face skin, increased fatigue, dizziness, a headache, drowsiness, is not frequent - an indisposition, a syncope, the increased sweating, an adynamy, hypesthesias, paresthesias, peripheral neuropathy, a tremor, sleeplessness, lability of mood, unusual dreams, nervousness, a depression, alarm; seldom – spasms, apathy, agitation; very seldom - an ataxy, amnesia.

Digestive tract: an abdominal cavity pain, nausea, it is not frequent - vomiting, changes of the mode of defecation (including a lock, a meteorism), dyspepsia, diarrhea, anorexia, dryness in a mouth, thirst, it is rare - a hyperplasia of gums, increase in appetite, is very rare – gastritis, pancreatitis, a hyperbilirubinemia, jaundice (usually cholestatic), increase in activity of "hepatic" transaminases, hepatitis.

System of a hemopoiesis: very seldom – a Werlhof's disease, a leukopenia, thrombocytopenia.

Metabolic disturbances: very seldom – a hyperglycemia.

System of breath: not often - short wind, rhinitis, it is very rare – cough.

Urinogenital system: not often - the speeded-up urination, an urodynia, a nocturia, impotence, is very rare - a dysuria, a polyuria.

Allergic reactions: not often - a skin itch, rash, it is very rare - a Quincke's disease, a multiformny erythema, a small tortoiseshell.

Others: not often - an alopecia, "ring" in ears, the gynecomastia, increase/decrease in body weight, a vision disorder, a diplopia, accommodation disturbance, a xerophthalmia, konjyuktivit, eye pain, a food faddism, a fever, nasal bleeding, is rare – dermatitis; very seldom - a parosmiya, a xerodermia, "cold" sweat, disturbance of a xanthopathy.

Atorvastatin.

It is usually well transferred. Side reactions, as a rule, easy and passing.

The most frequent side reactions (≥ 1%):

Nervous system: sleeplessness, headache, asthenic syndrome.

System of digestion: nausea, diarrhea, abdominal pain, dyspepsia, lock, meteorism.

From a musculoskeletal system: mialgiya.

Less frequent side reactions:

Nervous system: indisposition, dizziness, amnesia, paresthesias, peripheral neuropathy, hypesthesia.

System of digestion: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.

From a musculoskeletal system: dorsodynia, myotonia, miositis, myopathy, arthralgias, рабдомиолиз.

Allergic reactions: urticaria, itch, skin rash, anaphylaxis, violent rash, polymorphic exudative erythema, toxic epidermal necrolysis (Lyell's disease), malignant exudative erythema (Stephens-Johnson's syndrome).

Metabolic disturbances: hypoglycemia, hyperglycemia, increase in a serumal kreatinfosfokinaza.
System of a hemopoiesis: thrombocytopenia.

Others: impotence, peripheral hypostases, increase in body weight, stethalgia, secondary renal failure, alopecia, sonitus, exhaustion.

Relationship of cause and effect is established with administration of drug not for all listed above reactions.

Not all listed effects had the established causal relationship with therapy atorvastatiny.

Interaction with other medicines:

It is shown that the pharmacokinetics of an amlodipin of 10 mg at a combination therapy of atorvastatiny 10 mg at healthy volunteers does not change. Amlodipin did not exert impact on Cmax of an atorvastatin, but caused increase in AUC by 18%.

Interaction of drug KADUET with other medicines specially was not studied, but researches of each of components separately were conducted.

AMLODIPIN

It is possible to expect that inhibitors of a microsomal oxidation will increase concentration of an amlodipin in plasma, strengthening risk of side effects, and inductors of microsomal enzymes of a liver – to reduce.

Cimetidinum: at simultaneous use of an amlodipin with Cimetidinum the pharmacokinetics of an amlodipin does not change.

Grapefruit juice: the concomitant single dose of 240 ml of grapefruit juice and 10 mg of an amlodipin inside is not followed by essential change of pharmacokinetics of an amlodipin.

Unlike other BMKK of clinically significant interaction of an amlodipin (the III generation of BMKK) it was not revealed at combined use with non-steroidal anti-inflammatory drugs (NPVP), especially indometacin.

Strengthening of anti-anginal and hypotensive action of BMKK at combined use with thiazide and "loopback" diuretics, verapamil, APF inhibitors, beta adrenoblockers and nitrates, and also increase in their hypotensive action at combined use with alfa1-adrenoblockers, neuroleptics is possible.

Though when studying an amlodipin of a negative inotropic effect usually did not observe, nevertheless some BMKK can increase expressiveness of negative inotropic effect of the antiarrhytmic drugs causing lengthening of an interval of QT (for example, Amiodaronum and quinidine).

At combined use of BMKK with drugs of lithium strengthening of manifestation of their neurotoxicity (nausea, vomiting, diarrhea, an ataxy, a tremor, a sonitus) is possible.

Amlodipin does not influence in vitro extent of linkng with proteins of a blood plasma of digoxin, Phenytoinum, warfarin and indometacin.

Aluminum/magnesium the containing antacids: their single dose has no significant effect on pharmacokinetics of an amlodipin.

Sildenafil: the single dose of 100 mg of a sildenafil at patients with essential hypertensia does not exert impact on parameters of pharmacokinetics of an amlodipin.

Digoxin: at simultaneous use of an amlodipin with digoxin at healthy volunteers serumal levels and renal clearance of digoxin do not change.

Ethanol (alkogolsoderzhashchy drinks): at single and repeated use in a dose of 10 mg амлодипин has no significant effect on ethanol pharmacokinetics.

Warfarin: амлодипин does not influence the changes of a prothrombin time caused by warfarin.

Cyclosporine: амлодипин does not cause considerable changes of pharmacokinetics of cyclosporine.

Influence on results of laboratory tests: it is not known.

аторвастатин
The risk of a myopathy during treatment by other drugs of this class increases at simultaneous use of cyclosporine, derivatives of fibrinous acid, erythromycin, the antifungal drugs relating to azoles and niacin (see. "Special instructions" - "Action on skeletal muscles").

Antacids: the concomitant use in the suspension containing magnesium and aluminum hydroxides reduced concentration of an atorvastatin in a blood plasma approximately by 35%, however extent of reduction of maintenance of Hs-LPNP at the same time did not change.

Phenazone: аторвастатин does not influence phenazone pharmacokinetics therefore interaction with other drugs, the metabolized same isoenzymes of cytochrome, is not expected.

Kolestipol: at simultaneous use of a kolestipol concentration of an atorvastatin in a blood plasma decreased approximately by 25%; however the hypolipidemic effect of a combination of an atorvastatin and kolestipol surpassed that of each drug separately.

Digoxin: At repeated reception of digoxin and an atorvastatin in a dose of 10 mg equilibrium concentration of digoxin in a blood plasma did not change. However at use of digoxin in a combination with atorvastatiny in a dose of 80 mg/days concentration of digoxin increased approximately by 20%. The patients receiving digoxin in combination with atorvastatiny demand the corresponding observation.

Erythromycin / кларитромицин: at simultaneous use of an atorvastatin and erythromycin (500 mg four times a day) or a klaritromitsina (500 mg two times a day) which inhibit P450 3A4 cytochrome, increase in concentration of an atorvastatin in a blood plasma was observed (see. "Special instructions" - "Action on skeletal muscles").

Azithromycin: at simultaneous use of an atorvastatin (10 mg once a day) and azithromycin (500 mg once a day) concentration of an atorvastatin in plasma did not change.

Terfenadin: at simultaneous use of an atorvastatin and terfenadin of clinically significant changes of pharmacokinetics of a terfenadin it is not revealed.

Oral contraceptives: at simultaneous use of the atorvastatin and oral contraceptive containing Norethisteronum and ethinylestradiol substantial increase of AUC norethindrone and ethinylestradiol approximately for 30% and 20%, respectively was observed. This effect should be considered at the choice of an oral contraceptive for the woman accepting аторвастатин.

Warfarin: signs of clinically significant interaction of an atorvastatin with warfarin are not revealed.

Cimetidinum: signs of clinically significant interaction of an atorvastatin with Cimetidinum are not revealed.

Amlodipin: at simultaneous use of an atorvastatin of 80 mg and an amlodipina of 10 mg the pharmacokinetics of an atorvastatin in an equilibrium state did not change.

Inhibitors of proteases: simultaneous use of an atorvastatin with the inhibitors of proteases known as inhibitors of P450 3A4 cytochrome, was followed by increase in concentration of an atorvastatin in a blood plasma.

Other accompanying therapy: in clinical trials аторвастатин applied in combination with anti-hypertensive means and estrogen which appointed with the replaceable purpose; signs of clinically significant undesirable interaction are noted; interaction researches with specific drugs were not conducted.

Contraindications:

1. Hypersensitivity to an amlodipin and other derivatives of dihydropyridine, an atorvastatin or any component of drug.

2. The active disease of a liver or permanent increase in activity of "hepatic" enzymes is more than 3 times higher than norm of not clear etiology.

3. Pregnancy, the feeding period a breast, use for the women of reproductive age who are not using adequate methods of contraception.

4. At children aged up to 18 years (efficiency and safety are not established).

5. The expressed arterial hypotension.

With CARE to apply at the patients abusing alcohol and/or having a liver disease (in the anamnesis).

USE AT PREGNANCY AND THE FEEDING PERIOD THE BREAST
KADUET is contraindicated at pregnancy as it is a part of drug аторвастатин. Women of reproductive age during treatment have to use adequate methods of contraception. Women of reproductive age can appoint drug only if probability of pregnancy low, and patients are informed on possible risk for a fruit.

KADUET is contraindicated during feeding by a breast as it it is a part аторвастатин. There are no data on removal of an atorvastatin with breast milk. Considering a possibility of development of undesirable reactions in babies, the woman, receiving drug, have to stop feeding by a breast.

Safety of use of an amlodipin at pregnancy and during feeding by a breast is not established.

Overdose:

There are no data on overdose of drug.

Both амлодипин, and аторвастатин actively contact proteins of a blood plasma therefore essential increase in clearance of the combined drug at a hemodialysis is improbable.

Symptoms of overdose of an amlodipin:
- the excessive peripheral vazodilatation leading to reflex tachycardia.
- the expressed and permanent decrease in the ABP, including with development of shock and a lethal outcome.

Symptoms of overdose of an atorvastatin: are not described.

Treatment of overdose of an amlodipin:

- Use of absorbent carbon or during 2 h after reception of an amlodipin in a dose of 10 mg leads at once to a considerable delay of absorption of drug. In certain cases there can be effective a gastric lavage.

- Clinically significant arterial hypotension caused by overdose of an amlodipin demands holding the active actions directed to maintenance of function of cardiovascular system including control of indicators of cardiac performance and lungs, sublime position of extremities and control of volume of the circulating blood and a diuresis.

- For recovery of a tone of vessels and the ABP there can be useful a use of vasoconstrictive drug if there are no contraindications to its appointment, for elimination of effects of blockade of calcium channels - intravenous administration of a gluconate of calcium.

There are no specific means for treatment of overdose of an atorvastatin. In case of overdose it is necessary to carry out the symptomatic and supporting treatment as required.

Storage conditions:

At a temperature of 15-30 ºС. To store in the place, unavailable to children! A period of validity - 3 years. Not to use after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 5 mg + 10 mg and 10 mg + 10 mg. 7 or 10 tablets in the blister from polyamide / an aluminum foil / PVC. 1, 2, 4 or 8 blisters on 7 tablets or 1, 2, 3, 5, 6, 10 or 20 blisters on 10 tablets together with the application instruction place in a cardboard pack on which face for the purpose of control of the first opening the perforated line reminding an outline of half rings is put; side surfaces of a pack densely stick together when packaging drug.