Caduet® (Caduet® )

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAmlodipine + AtorvastatinAmlodipine + Atorvastatin
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    • Dosage form: & nbspfilm coated tablets
    Composition:

    1 tablet contains:

    active substances: Amlodipine (as amlodipine besylate) 5.0 (6.94) mg or 10.0 (13.87) mg, atorvastatin (in the form of 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, giprolase 2.0 mg and 2.0 mg, silicon dioxide colloid 0.65 mg and 0.65 mg, magnesium stearate 0.75 mg and 0.75 mg, film membrane Opadry II white 85F28751 3.0 mg (5 mg tablets + 10 mg) (polyvinyl alcohol 1.2 mg, titanium dioxide 0.75 mg, macrogol (PEG) 3000 0.606 mg, talc 0.444 mg), film membrane Opadry II blue 85F10919 3.0 mg (tablets of 10 mg + 10 mg) (polyvinyl alcohol 1.2 mg, titanium dioxide 0.645 mg, macrogol (PEG) 3000 0.606 mg, aluminum based on indigo carmine 0.105 mg, talc 0.444 mg).

    Description:

    Tablets 5 mg + 10 mg: oval tablets, coated with a film shell, white. On one side there is “Pfizer”, another - “CDT” and "051".

    Tablets 10 mg + 10 mg: oval tablets, film-coated, blue colors.On one side there is “Pfizer”, another - “CDT” and "101".

    Pharmacotherapeutic group:hypotensive + hypolipidemic agent.
    ATX: & nbsp

    C.10.A.A.05   Atorvastatin

    C.08.C.A.01   Amlodipine

    Pharmacodynamics:

    KADUET® is a combined preparation intended for the treatment of combined cardiovascular diseases (arterial hypertension / angina and dyslipidemia).

    Mechanism of action

    Amlodipine is a dihydropyridine derivative, a blocker of "slow" calcium channels (BCCC), and atorvastatin - a lipid-lowering agent, an inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A (inhibitor of HMG-CoA reductase). Amlodipine / atorvastatin has two mechanisms of action: amlodipine inhibits calcium flow through 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 of steroids, including cholesterol). The effect of systolic blood pressure (SBP), diastolic blood pressure (DBP) and concentration of low-density lipoprotein (LDL), the preparation KADUET® does not significantly differ from monotherapy with amlodipine and atorvastatin.

    Pharmacodynamics of amlodipine

    Amlodipine blocks the flow of calcium ions through the membranes into the smooth muscle cells of the myocardium and vessels. The mechanism of hypotensive action of amlodipine is due to a direct relaxing effect on the smooth muscles of the vessels. The exact mechanism of action of amlodipine in angina is not definitively established, however, two ways of reducing myocardial ischemia under the influence of amlodipine are known:

    - amlodipine expands peripheral arterioles and thus reduces the overall peripheral resistance (afterload). The heart rate does not change at the same time, which, consequently, leads to a decrease in the load on the heart, a reduction in energy consumption and oxygen demand;

    - The mechanism of action of amlodipine probably also includes expansion of the main coronary arteries and coronary arterioles both in unchanged and ischemic zones of the myocardium. Their dilatation increases the flow of oxygen into the myocardium in patients with vasospastic angina (Prinzmetal angina or variant angina) and prevents the development of coronary vasoconstriction caused by smoking.

    In patients with hypertension, a single daily dose of amlodipine provides a clinically significant decrease in blood pressure (BP) for 24 hours in both the "lying" and "standing" positions. At a physiological pH level amlodipine is presented in the form of an ionized compound, which is characterized by a gradual interaction with the calcium channel receptors, in connection with which a gradual onset of the effect is noted. Due to the slow start of action amlodipine does not cause acute arterial hypotension.

    In patients with angina, the use of amlodipine once a day increases the time required for exercise, prevents the development of an attack of angina and segment depression ST (by 1 mm), reduces the incidence of angina attacks, reduces the consumption of nitroglycerin tablets.

    Amlodipine does not adversely affect the metabolism and lipids of blood plasma and can be used in patients with bronchial asthma, diabetes and gout.

    It was noted that amlodipine prevents the progressive thickening of the intima-media of the carotid arteries. In patients receiving amlodipine, there is a significant decrease in the total mortality from cardiovascular events, myocardial infarction (MI), stroke, progression of chronic heart failure (CHF), unstable angina. The frequency of percutaneous transluminal coronary angioplasty (PTCA) and aorto-coronary shunting is also reduced. The frequency of hospitalizations for unstable angina decreases. Pharmacodynamics of atorvastatin

    Atorvastatin lowers the concentration of cholesterol and lipoproteins in the blood plasma by inhibiting HMG-CoA reductase and the synthesis of cholesterol in the liver and increasing the number of "liver" LDL receptors on the cell surface, which leads to increased capture 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 the synthesis of cholesterol and the clearance of LDL. The degree of decrease in the concentration of LDL is correlated 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 the section "Dosing and Administration"),

    In patients with homozygous and heterozygous familial hypercholesterolemia, non-family 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 (Xc), Xc-LDL and apolipoprotein B (apo-B), and very low density lipoproteins (X-VLDL) and triglycerides (TG) and causes a variable increase in the concentration of high-density lipoproteins (Xc-HDL).

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

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

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

    In patients with hyperlipoproteinemia IIa and IIb types according to Fredriksen, the median of increasing the concentration of HDL in the treatment with atorvastatin (10-80 mg) is 5.1-8.7%. Changes in this indicator do not depend on the dose. In the analysis of these patients, a dose-dependent decrease in total cholesterol / X-HDL and Xc-LDL / XPS-HDL ratios was also found to be 29-44% and 37-55%, respectively.

    Treatment with atorvastatin results in a marked reduction in the risk of ischemic outcomes and mortality by 16%. The risk of re-hospitalization 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 Xc-LDL and is comparable in patients with MI without a tooth Q and unstable angina, men and women, patients under the age of 65 years and younger. Atorvastatin significantly reduces the development of the following complications:

    Risk reduction

    Coronary complications

    (CHD with fatal outcome and non-fatal MI)

    36%

    General cardiovascular complications and revascularization procedures

    20%

    Common coronary complications

    29%

    Stroke (fatal and nonfatal) 26%

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

    In patients with type 2 diabetes, and at least one of the following risk factors atorvastatin influenced the development of cardiovascular complications as follows:

    Relative risk reduction

    Major cardiovascular complications [fatal and nonfatal acute myocardial infarction, latent myocardial infarction, death as a result of exacerbation of IHD, unstable angina, coronary artery bypass, PTCA, revascularization, stroke]

    37%

    MI (fatal and nonfatal acute MI, latent MI)

    42%

    Stroke (fatal and nonfatal)

    48%

    In patients with atherosclerosis, the total volume of atheroma, Xc-LDL, total cholesterol, triglycerides, apo-B, and C-reactive protein decreased in the presence of atorvastatin and there was an increase in HDL-C.

    Pharmacokinetics:

    Suction

    After ingestion of the combined preparation KADUET, two distinct peaks of maximum concentration (CmOh) in the blood plasma. The concentration of atorvastatin reached a maximum in 1-2 hours, and amlodipine - after 6-12 hours.The rate and degree of absorption (bioavailability) of amlodipine and atorvastatin with the use of the preparation KADUET® did not differ from that with simultaneous administration of tablets of amlodipine and atorvastatin: CmOh amlodipine = 101%; area under the curve "concentration-time" (AUC) amlodipine = 100%; FROMmOh atorvastatin = 94%; AUC atorvastatin = 105%.

    Although simultaneous ingestion of food caused a decrease in the rate and degree of absorption of atorvastatin with the use of the preparation KADUET® by approximately 32% and 11%, respectively (CmOh = 68% and AUC = 89%), but similar changes in bioavailability were detected when one atorvastatin was used. At the same time, eating did not affect the degree of decrease in LDL concentration.

    Amlodipine well absorbed after oral administration at therapeutic doses, reaching Cmah in the blood 6-12 hours after admission. Absolute bioavailability according to calculations is 64-80%. Research in vitro showed that circulating amlodipine approximately 97.5% is associated with plasma proteins. Food intake does not affect the absorption of amlodipine. Bioavailability of amlodipine did not change after eating: Cmax = 105% and AUC = 101% compared with fasting rates.

    Atorvastatin quickly absorbed after ingestion, its concentration in the blood plasma reaches a maximum after 1-2 hours. The degree of absorption and 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 inhibitory activity against HMG-CoA reductase is about 30%. Low systemic bioavailability is due to presystemic metabolism (absorption) in the mucous membrane of the gastrointestinal tract and / or metabolism during the "primary passage" through the liver. Food slightly reduces the rate and degree of absorption (by 25% and 9%, respectively, as evidenced by the results of the determination of CmOh and AUC), however, a decrease in the concentration of LDL is similar to that of fasting atorvastatin. Despite the fact that after taking atorvastatin in the evening its concentration in the blood plasma is lower (CmOh and AUC approximately 30%) than after taking in the morning, a decrease in the concentration of LDL does not depend on the time of day in which the drug is taken.

    Distribution

    Amlodipine: the volume of distribution is approximately 21 liters.

    Atorvastatin: the average volume of atorvastatin distribution is about 381 liters. The connection with plasma proteins is not less than 98%. The ratio of content to erythrocytes / blood plasma is about 0.25, i.e. atorvastatin poorly penetrates into red blood cells.

    Metabolism and excretion

    Amlodipine: the half-life (T1 / 2) of amlodipine from the blood plasma is about 35-50 hours, which allows you to prescribe the drug once a day. Equilibrium concentration in the blood plasma is achieved after 7-8 days of constant intake of the drug. Metabolised in the liver with the formation of inactive metabolites; 10% unchanged drug and 60% of metabolites are excreted by the kidneys.

    Atorvastatin is largely metabolized with the formation of 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% decrease in activity HMG-CoA reductase occurs due to the action of active circulating metabolites. Research results in vitro suggest that cytochrome P450 of SA4 liver plays an important role in the metabolism of atorvastatin. In favor of this fact is an increase in the concentration of atorvastatin in human blood plasma with simultaneous administration of erythromycin, which is an inhibitor of this isoenzyme. Research in vitro They also showed that atorvastatin is a weak inhibitor of cytochrome P450 3A4. There was no clinically significant effect of atorvastatin on the concentration in the blood plasma 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 substrates of cytochrome P450 ZA4 (see section "Interaction with other drugs"), Atorvastatin and its metabolites are excreted mainly with bile as a result of hepatic and / or extrahepatic metabolism, atorvastatin not subject to severe intestinal hepatic recirculation. T1/2 atorvastatin is about 14 hours, while T1/2 inhibitory activity against HMG-CoA reductase due to the presence of active metabolites is about 20-30 hours. After ingestion, less than 2% of the dose is excreted by the kidneys.

    Special patient groups

    Impaired liver function: the concentration of atorvastatin in blood plasma is significantly increased (CmOh about 16 times, a AUC approximately 11 times) in patients with alcoholic cirrhosis of the liver (class B according to Child-Pugh classification).section "Contraindications").

    Impaired renal function: Amlodipine concentrations in the blood plasma do not depend on the degree of renal failure; it is not excreted by dialysis.

    Kidney disease does not affect the concentration of atorvastatin in the blood plasma; therefore, dose adjustments in patients with renal dysfunction are not required (see section "Method of administration and dose").

    Floor: the concentration of atorvastatin in blood plasma in women is different (Cmax is about 20% higher, a AUC 10% lower) than that of men, but clinically significant differences in the effect of the drug on lipid metabolism in men and women have not been identified.

    Elderly

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

    Concentrations of atorvastatin in blood plasma in patients aged 65 years and older are higher (Cmah about 40%, AUC approximately 30%) than in adult patients of a young age; differences in assessing the safety, efficacy, or achievement of the goals of lipid-lowering therapy in elderly patients in comparison with the general population have not been revealed.

    Indications:

    CADUET® is indicated for patients with arterial hypertension with three or more risk factors for cardiovascular events (fatal and non-fatal IHD, need for revascularization procedures, fatal and nonfatal MI, stroke and transient ischemic attack) with normal or moderately elevated cholesterol concentration without clinically expressed ischemic heart disease.

    KADUET® is used in cases when combined therapy with amlodipine and low doses of atorvastatin is recommended. It is possible to use KADUET® simultaneously with other antihypertensive and / or antianginal agents.

    KADUET® is used in cases when the hypolipidemic diet and other non-pharmacological methods of treating dyslipidemia turn out to be little or ineffective.

    Contraindications:

    hypersensitivity to amlodipine and other derivatives of dihydropyridine, atorvastatin or any component of the drug;

    active liver disease or persistent increase in activity of "liver" enzymes more than 3 times higher than the norm of unclear etiology;

    pregnancy, the period of breastfeeding, the use of women of reproductive age who do not use adequate methods of contraception;

    in children under the age of 18 (efficacy and safety not established);

    severe arterial hypotension (SBP less than 90 mm Hg);

    severe or clinically significant aortic stenosis;

    uAnemodynamically unstable heart failure after acute myocardial infarction (according to amlodipine).

    Carefully:

    Hepatic failure or liver disease in history, CHF is not an ischemic etiology III-IV class by classification NYHA, unstable angina, aortic stenosis, acute myocardial infarction (and within 1 month after it), age over 70 years, impaired renal function, hypothyroidism.

    As with the appointment of other BCCC, caution should be exercised when receiving amlodipine in patients with sinus node weakness syndrome, mitral stenosis, hypertrophic obstructive cardiomyopathy, arterial hypotension.

    Also the preparation KADUET® should be used with caution in patients who abuse alcohol.

    Pregnancy and lactation:

    KADUET® contraindicated in pregnancy, as the composition of the drug is atorvastatin. Women of reproductive age during treatment should use adequate methods of contraception. The drug can be prescribed to women of reproductive age only if the probability of pregnancy is low, and the patients are informed of the possible risk to the fetus.

    KADUET® contraindicated in the period of breastfeeding, since it includes atorvastatin. There is no information on the induction of atorvastatin with breast milk. Given the possibility of developing adverse reactions in infants, women receiving the drug should stop breastfeeding.

    In animal studies amlodipine had no effect on reproductive function, but had reproductive toxicity when administered at very high doses (50 times the maximum recommended dose for a person). It is not recommended to use amlodipine during pregnancy or during breastfeeding.

    Dosing and Administration:

    The drug is taken orally one tablet once a day at any time, regardless of the time of ingestion.

    One tablet of the preparation KADUET® contains 5 mg + 10 mg or 10 mg + 10 mg (amlodipine and atorvastatin, respectively).

    The initial and maintenance doses are selected individually taking into account the efficacy and tolerability of both components in the treatment of arterial hypertension / angina and dyslipidemia.

    CADUET® can be administered to patients who are already taking one of the components drug in monotherapy.

    KADUET® is used in combination with non-medicated treatments, including diet, exercise, weight loss in obese patients, and quitting.

    When starting treatment with a dose of 5 + 10 mg in patients with hypertension, it is necessary to control blood pressure and lipid concentration in the blood plasma every 2-4 weeks and, if necessary, transfer to a dose of 10 + 10 mg.

    IHD (amlodipine): the recommended dose is 5-10 mg once a day.

    Primary hypercholesterolemia and combined (mixed) dyslipidemia (atorvastatin): for the majority of patients - 10 mg once a day; therapeutic actionmanifested within 2 weeks and usually reaches a maximum within 4 weeks; with prolonged treatment the effect is preserved.

    Use in patients with impaired liver function: see sections "Contraindications" and "Special instructions".

    PPatients with impaired renal function: correction of the dose is not required. Application in elderly patients: correction of the dose is not required.

    The maximum daily dose of atorvastatin is 80 mg, amlodipine - 10 mg.

    Use in combination with other medicines

    If a simultaneous use with cyclosporine, telaprevir, boceprevir, tipranavir / ritonavir is required, the dose of atorvastatin should not exceed 10 mg / day, with clarithromycin not more than 20 mg / day.

    Caution should be exercised and the lowest effective dose of atorvastatin should be used when combined with HIV protease inhibitors, hepatitis C inhibitors, clarithromycin and itraconazole.

    Side effects:

    Overall, the tolerability of combination therapy was good. There were no unexpected undesirable effects in combination therapy.Undesirable effects were consistent with those previously identified with amlodipine and / or atorvastatin (see below). Most of the undesirable effects were easily or moderately expressed. Because of adverse effects or laboratory abnormalities, treatment with amlodipine and atorvastatin was discontinued in 5.1% of patients, and placebo at 4.0%.

    Amlodipine

    Further under the frequency of adverse reactions is understood: very often -> 10%; often from> 1% to <10%; infrequently - from> 0.1% to <1%; rarely - from 0.01% to <0.1%, very rarely - <0.01%).

    Disturbances from the heart: often -peripheral edema (ankle and foot), palpitations, orthostatic hypotension; infrequent reduction of arterial pressure; rarely, development or exacerbation of heart failure; very rarely - heart rhythm disturbances (including bradycardia, ventricular tachycardia and atrial fibrillation), MI, chest pain, migraine.

    Violations from the vessels: often - a feeling of heat ("hot flashes" of blood); infrequent - marked decrease in blood pressure, vasculitis. Disorders from the musculoskeletal system and connective tissue: infrequently - arthralgia, muscle cramps, myalgia, back pain, arthrosis; rarely - myasthenia gravis.

    Disturbances from the nervous system: often - dizziness, headache, drowsiness; infrequent - syncope, hypoesthesia, paresthesia, hypertension, peripheral neuropathy, tremor, unusual dreams, nervousness, depression, anxiety, taste change, extrapyramidal disorder; rarely - cramps, apathy, agitation; very rarely - ataxia, amnesia.

    Disorders of the psyche: infrequent insomnia, frequent mood swings. Disorders from the side of the organ of vision: infrequently - impaired vision, diplopia, accommodation disorder, xerophthalmia, conjunctivitis, pain in the eyes.

    Violations from the organ of hearing and labyrinthine disturbances: infrequently - "ringing" in the ears.

    Disorders from the digestive system: often - abdominal pain, nausea; infrequent - changes in the bowel movement (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dryness of the oral mucosa, thirst, gingival hyperplasia, increased appetite, gastritis, pancreatitis, vomiting.

    Disturbances from the liver and bile ducts: very rarely - hyperbilirubinemia, jaundice (usually cholestatic), increased activity of "liver" transaminases, hepatitis.

    Violations from the side of the kroen and lymphatic system: infrequently - leukopenia, thrombocytopenia; very rarely - thrombocytopenic purpura.

    Disorders from the metabolism and nutrition: infrequently - hyperglycemia.

    Disturbances from the respiratory system, chest and mediastinum: infrequently - shortness of breath, rhinitis, cough.

    Disorders from the kidneys and urinary tract: infrequent pollakiuria, frequent urination, painful urination, nocturia; very rarely - dysuria, polyuria.

    Violations of the genitals and mammary glands: infrequently-gynecomastia, impotence.

    Disturbances from the skin and subcutaneous tissues: infrequently - alopecia, increased sweating, purpura, a violation of skin pigmentation, urticaria; rarely - skin itching, rash, angioedema, erythema multiforme, dermatitis.

    General disorders and disorders at the injection site: often - peripheral edema, increased fatigue; infrequent - general weakness, malaise, pain of unspecified localization, taste distortion, chills, nosebleeds; very rarely - parosmia, xeroderma, "cold" sweat.

    Laboratory and instrumental data: infrequently - increase or decrease in body weight.

    Atorvastatin

    The most frequent adverse reactions

    From the central nervous system: insomnia, headache, asthenic syndrome.

    Disturbances from the respiratory, thoracic and mediastinal organs: sore throat, nosebleed.

    Disorders from the gastrointestinal tract: nausea, diarrhea, abdominal pain, indigestion, constipation, flatulence.

    Disorders from the musculoskeletal and connective tissue: arthralgia, pain in the limbs, musculoskeletal pain, muscle cramps, myalgia, swelling of the joints. Infectious and parasitic diseases: nasopharyngitis.

    Disorders from the metabolism and nutrition: hyperglycemia.

    Labortion and instrumental data: deviation from the norm of the results of "liver" tests. increased serum creatine phosphokinase (CK) activity.

    Less pure adverse reactions (<I%>):

    Disorders of the psyche: unusual dreams.

    Disturbances from the nervous system: dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia, a violation of taste perception.

    Disorders from the side of the organ of vision: the appearance of a "swaddle" before the eyes. Hearing disorders and labyrinthine disturbances: tinnitus.

    Disorders from the side of the digestive system: vomiting, anorexia, hepatitis, abdominal discomfort, belching, pancreatitis.

    Disorders from the liver and bile ducts: hepatitis, cholestatic jaundice.

    Disorders from the musculoskeletal and connective tissue: back pain, myositis, immune-mediated necrotizing myopathy, muscle weakness, neck pain, rhabdomyolysis.

    Injuries, intoxications and complications of manipulation: tendopathy (in some cases with a rupture of the tendon).

    Laboratory and instrumental data: leukocyturia.

    Disturbances from the skin and subcutaneous tissues: urticaria, skin itch, rash, bullous rash, polymorphic exudative erythema (including Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

    Disorders from the metabolism and nutrition: weight gain, hypoglycemia.

    Violations from the blood and lymphatic system: thrombocytopenia.

    Immune system disorders: allergic reactions (including anaphylaxis).

    General disorders and disorders at the site of administration: malaise, impotence, peripheral edema, chest pain, secondary renal failure, fatigue, fever.The causal relationship with taking the drug is not established for all of the above reactions.

    Overdose:

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

    Symptoms of an overdose of amlodipine:

    excessive peripheral vasodilation leading to reflex tachycardia;

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

    Symptoms of an overdose of atorvastatin: not described.

    Treatment of an overdose of amlodipine:

    reception of activated carbon immediately or within 2 hours after taking amlodipine at a dose of 10 mg leads to a significant delay in absorption of the drug. 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 limb position, monitoring the volume of circulating blood and diuresis.

    for the restoration of blood pressure and vascular tone can be useful application of vasoconstrictor, if there is no contraindication to its purpose.

    to eliminate the effects of calcium channel blockade - intravenous calcium gluconate.

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

    Interaction:

    It has been shown that the pharmacokinetics of amlodipine 10 mg with combined therapy with atorvastatin 80 mg in healthy volunteers does not change.

    Amlodipine had no effect on CmAtorvastatin, but caused an increase in AUC by 18%.

    Interaction of the drug KADUET® with other drugs has not been specifically studied. The following information is provided for each component individually.

    Amlodipine

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

    Inhibitors of the isoenzyme CYP3A4: with the simultaneous use of diltiazem 180 mg and amlodipine at a dose of 5 mg in elderly patients (69 to 87 years) with arterial hypertension, an increase in the system exposure of amlodipine by 57%.The simultaneous use of amlodipine and erythromycin in healthy volunteers (from 18 to 43 beds) does not lead to significant changes in the exposure of amlodipine (an increase in the area under the concentration-time curve (AUC) by 22%). Despite the fact that the clinical significance of these effects is not fully understood, they can be more pronounced in elderly patients. Strong inhibitors of the isoenzyme CYP3A4 (for example, ketoconazole, itraconazole, ritonavir) can lead to an increase in the concentration of amlodipine in the blood plasma to a greater extent than diltiazem. It should be used with caution amlodipine and inhibitors of the isoenzyme CYP3A4.

    Clarithromycin: clarithromycin is an inhibitor of the isoenzyme CYP3A4. There is an increased risk of developing arterial hypotension in patients receiving clarithromycin simultaneously with amlodipine. With simultaneous use of amlodipine with clarithromycin, it is recommended to carefully monitor the condition of patients.

    Inductors of the isoenzyme CYP3A4: there is no evidence of the effect of CYP3A4 isoenzyme inducers on the pharmacokinetics of amlodipine. Simultaneous application of inducers of the isoenzyme CYP3A4 (for example, rifampicin, St. John's wort perforated) and amlodipine can lead to a decrease in the concentration of amlodipine in the blood plasma. It should be used with caution amlodipine and inductors of the isoenzyme CYP3A4.

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

    Grapefruit juice: simultaneous single intake of 240 ml of grapefruit juice and 10 mg of amlodipine inwards is not accompanied by a significant change in the pharmacokinetics of amlodipine, however, the possibility of genetic polymorphism of the isoenzyme CYP3A4 should be considered. In this regard, the simultaneous use of the drug KADUET® and grapefruit or grapefruit juice ns is recommended, in view of 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 BCCC, clinically significant interaction of amlodipine was not found when combined with non-steroidal anti-inflammatory drugs (NG1NP), especially indomethacin. It is possible to strengthen the anti-anginal and hypotensive action of BCCC when combined with thiazide and loop diuretics,verapamil, angiotensin converting enzyme (AG1F) inhibitors, beta-adrenoblockers and nitrates, as well as intensifying their hypotensive effect when combined with alpha 1-adrenergic blockers, neuroleptics. Although no negative inotropic effect was usually observed in the study of amlodipine, nevertheless, some BCCI can enhance the expression of the negative inotropic effect of antiarrhythmic drugs that cause an elongation of the RT interval (for example, amiodarone and quinidine). With the joint use of BCCC with lithium preparations, it is possible to enhance the neurotoxicity of lithium (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus). Amlodipine does not influence in vitro the degree of binding to blood proteins of digoxin, phenytoin, warfarin and indomethacin.

    Aluminum- and magnesium-containing antacids: their single administration does not significantly affect the pharmacokinetics of amlodipine.

    Sildenafil: a single dose of 100 mg of sildenafil in patients with essential hypertension does not affect the pharmacokinetics of amlodipine. With simultaneous use, each drug independently reduces blood pressure.

    Digoxin: with the simultaneous use of amlodipine with digoxin in healthy volunteers, the serum concentration and renal clearance of digoxin ns change.

    Ethanol (alcohol containing drinks): with a single and repeated application in a dose of 10 mg amlodipine has no significant effect on the pharmacokinetics of ethanol.

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

    Cyclosporin: studies of the interaction of amlodipine and cyclosporine were performed only in patients after kidney transplantation. These studies have shown that amlodipine can either not influence the minimum concentration of cyclosporine in the blood plasma, or increase it up to 40%. Consideration should be given to monitoring the plasma cyclosporin concentration in patients after kidney transplantation with this combination of drugs.

    Tacrolimus: There is a risk of increasing tacrolimus concentration in the blood with simultaneous use with amlodipine. In order to avoid the development of tacrolimus toxicity with amlodipine in patients receiving tacrolimus treatment, it is necessary to monitor its concentration in the blood and dose adjustment if necessary.

    Dantrolene: in cases of animals with simultaneous application of verapamil and dantrolene intravenously, cases of lethal atrial fibrillation and cardiovascular insufficiency were observed in connection with the development of hyperkalemia. In view of the risk of hyperkalemia, it is recommended to avoid the use of BCCC, such as amlodipine, in patients with suspected or confirmed malignant hyperthermia, as well as during treatment of this condition.

    Simvastatin: repeated simultaneous use of amlodipine in a dose of 10 mg and simvastatin 80 mg leads to an increase in the concentration of simvastatin by 77% compared with simvastatin monotherapy. Limit the dose of simvastatin to 20 mg per day.

    Influence on the results of laboratory tests: unknown.

    Atorvastatin

    Because the atorvastatin is metabolized by the isoenzyme CYP3A4, the combined use of atorvastatin with inhibitors of the isoenzyme CYP3A4 can lead to an increase in the concentration of atorvastatin in the blood plasma. The degree of interaction and potentiation effect is determined by the variability of the effect on the isoenzyme CYP3A4.

    Inhibitors of transport protein OATP1B1: atorvastatin and its metabolites are substrates of the transport protein OATP1B1. Inhibitors of OATP1B1 (for example, ciclosporin) may increase the bioavailability of atorvastatin. Thus, the simultaneous use of atorvastatin 10 mg and cyclosporine at a dose of 5.2 mg / kg / day leads to an increase in the concentration of atorvastatin in blood plasma by 7.7 times (see section "Method of administration and dose"). The risk of myopathy during treatment with other drugs of this class is increased by the simultaneous use of cyclosporine, fibrin acid derivatives, erythromycin, antifungal preparations of azoles, and nicotinic acid in lipid-lowering doses (more than 1 g / day) (see section "Special instructions" - "Action on skeletal muscles ").

    Antacids: simultaneous ingestion of a suspension containing magnesium and aluminum hydroxides, reduced the concentration of atorvastatin in the blood plasma by approximately 35%, but the degree of decrease in the concentration of LDL-C was not changed.

    Phenazone: atorvastatin does not affect the pharmacokinetics of phenazone, therefore interaction with other drugs metabolized by the same isoenzymes of cytochrome is not expected.Itraconazole: simultaneous use of atorvastatin in doses of 20 mg to 40 mg and itraconazole at a dose of 200 mg led to an increase in the value of AUC atorvastatin.

    Grapefruit juice: Since grapefruit juice contains one or more components that inhibit the isoenzyme CYP3A4, its excessive intake (more than 1.2 liters per day) can cause an increase in the concentration of atorvastatin in the blood plasma.

    CYP3A4 isoenzyme inductors: the combined use of atorvastatin with CYP3A4 isoenzyme inducers (eg, efavirenz or rifampicin) can lead to a decrease in the concentration of atorvastatin in the blood plasma. Because of the dual mechanisms of interaction with rifampicin (isoenzyme CYP3A4 inducer and an inhibitor of the transport protein OATR1V1 hepatocytes), the simultaneous application of atorvastatin and rifampicin as atorvastatin delayed after receiving rifampicin significantly reduces the concentration of atorvastatin in plasma.

    Colestipol: with simultaneous application of colestipol, the concentration of atorvastatin in the blood plasma decreased by approximately 25 %; However, the hypolipidemic 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 using digoxin in combination with atorvastatin at a dose of 80 mg / day, the digoxin concentration increased by about 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) that inhibit the isoenzyme CYP3A4, an increase in the concentration of atorvastatin in the blood plasma was observed (see section "Special instructions" "Action on skeletal muscles").

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

    Terfenadine: with simultaneous use of atorvastatin and terfenadine, clinically significant changes in the pharmacokinetics of terfenadine have not been identified.

    Oral contraceptives: with simultaneous use of atorvastatin and an oral contraceptive containing norethindrone and ethinyl estradiol, there was a significant increase in AUC of norethindrone and ethinyl estradiol by approximately 30% and 20%, respectively. This effect should be considered when choosing an oral contraceptive for a woman receiving atorvastatin.

    Warfarin: no signs of a clinically significant interaction of atorvastatin with warfarin were found.

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

    Cimetidine: Signs of clinically significant interaction of atorvastatin with cimetidine were not detected.

    Amlodipine: with the simultaneous use of atorvastatin 80 mg and amlodipine 10 mg, the pharmacokinetics of atorvastatin in the equilibrium 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, there was an increase in the concentration of atorvastatin with simultaneous use 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 these drugs are used concomitantly, and the lowest effective dose of atorvastatin should be used.

    Fusidic acid: during post-marketing studies, cases of rhabdomyolysis in patients taking both fusidic acid and atorvastatin. Patients should be carefully monitored and accounted for that the temporary cancellation of atorvastatin may be appropriate.

    Colchicine: Despite the fact that no simultaneous application of colchicine and atorvastatin has been performed, there are reports of myopathy developing with this combination. Care should be taken when using atorvastatin and colchicine concomitantly.

    Other concomitant therapy: in clinical trials atorvastatin applied in combination with antihypertensives and estrogens, which were prescribed with a substitution purpose; Signs of clinically significant undesirable interaction were not observed; studies of interaction with specific drugs have not been conducted.

    Phenazone (Antipyrine): since atorvastatin does not affect the pharmacokinetics of phenazone, it is not expected to interact with other drugs that are metabolized by the same isoenzyme.

    Special instructions:

    Action on skeletal muscles

    In patients who received atorvastatin, myalgia was observed (see section "Side effect"). The diagnosis of myopathy (pain or weakness in muscles combined with an increase in CKK activity by more than 10 times compared with the upper limit of normal) should be expected in patients with common myalgias, tenderness or weakness of the muscles and / or a marked increase in CKK activity. Patients should consult a doctor immediately if unexplained pain, tension or weakness occurs in the muscles, especially if accompanied by malaise or fever. Therapy with KADUET® should be discontinued in the event of a marked increase in the activity of CKK or in the presence of confirmed or suspected myopathy. The risk of myopathy when treated with other drugs of this class increases with the simultaneous use of cyclosporine, fibrin acid derivatives, erythromycin, nicotinic acid in lipid-lowering doses (more than 1 g / day) or antifungal preparations of azole derivatives, colchicine, telaprevir, boceprevir or ritonavir / tipranavir combination.Many of these drugs inhibit metabolism mediated by cytochrome P450 ZA4, and / or transport of drugs. It is known that cytochrome P450 ZA4 - the main isoenzyme of the liver, involved in the biotransformation of atorvastatin. Assigning atorvastatin in combination with fibrin acid derivatives, erythromycin, immunosuppressants, antifungal drugs with azole derivatives or nicotinic acid in lipid-lowering doses (more than 1 g / day), the physician should carefully weigh the expected benefit and risk of treatment and regularly observe patients for pain, tension or weakness in the muscles, especially during the first months of treatment and during the period of increasing the dose of any drug. If combination therapy is required, consideration should be given to the possibility of using lower initial and maintenance doses of the above. Temporary cancellation of atorvastatin may be appropriate during treatment with fusidic acid. In such situations, it is possible to recommend a periodic determination of the activity of CKK, although such control does not prevent the development of severe myopathy (cf.section "Interaction with other drugs"), CADOET® can cause an increase in the activity of CK (see section "Side effect").

    When using atorvastatin, as well as other drugs of this class, rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria are described. The risk factor for rhabdomyolysis may be a previous impairment of kidney function. Such patients should be provided with more careful monitoring of the condition of the musculoskeletal system. KADUET® therapy should be temporarily discontinued or completely discontinued if there is evidence of possible myopathy or the presence of a risk factor for renal failure against rhabdomyolysis (eg, severe acute infection, arterial hypotension, surgery, trauma, metabolic, endocrine and water-electrolyte disorders and uncontrolled convulsions). Treatment with amlodipine in an adequate dose for the purpose of controlling hypertension can be continued.

    As with the use of other hypolipidemic drugs of this class, after treatment with atorvastatitis, moderate (more than 3 times compared with the upper limit of the norm)increased activity of "hepatic" transaminases aspartate aminotransferase (ACT) and alanine aminotransferase (ALT). A persistent increase in serum activity of "liver" transaminases (more than 3 times compared with the upper limit of normal) was observed in 0.7% of patients who received atorvastatin. The incidence of such changes with 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 usually was not accompanied by jaundice or other clinical manifestations. With a decrease in the dose of atorvastatin, a temporary or complete abolition, the activity of "hepatic" transaminases returned to its original level. Most patients continued to take atorvastatin at a reduced dose without any clinical consequences.

    Before the start of therapy, after 6 weeks and 12 weeks after the beginning of the application of the drug KADUET® or after increasing its dose, it is necessary to monitor the indicators of liver function. The liver function should also be monitored when there are clinical signs of liver damage. In the case of increased activity of "hepatic" transaminases, their activity should be monitored until it is normalized.If the increase in activity ACT or ALT more than 3 times compared with the upper limit of the norm is maintained, it is recommended to reduce the dose of atorvastatin or to cancel the drug KADUET® (see section "Side effect"), Atorvastatin Caution 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 constantly increased activity of "hepatic" transaminases of blood plasma of unknown origin is a contraindication to the use of the drug KADUET® (see the section "Contraindications"),

    In patients with CHF (III-IV functional class by classification NYHA) not ischemic etiology in the use of amlodipine, there is a possibility of pulmonary edema.

    When using inhibitors of HMG-CoA reductase, including atorvastatin, there were cases of increased glycosylated hemoglobin (HLA1) and fasting plasma glucose concentration. However, the risk of hyperglycaemia is lower than the degree of reduction in the risk of vascular complications in patients receiving statins.

    It is necessary to maintain dental hygiene and supervision at the dentist (to prevent soreness, bleeding and gingival hyperplasia).

    Effect on the ability to drive transp. cf. and fur:During the treatment period, care must be taken when driving vehicles and engaging in potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions.
    Form release / dosage:

    Tablets, film-coated, 5 mg + 10 mg and 10 mg + 10 mg.

    Packaging:

    7 or 10 tablets in a blister of polyamide / aluminum foil / PVC. 1, 2, 4 or

    8 blisters for 7 tablets or 1, 2, 3, 5, 6, 10 or 20 blisters of 10 tablets together with the instruction for use are placed in a cardboard box on the front side of which a perforated line resembling the shape of semirings is applied to control the first opening; the side surfaces of the pack tightly adhere to the packaging of the preparation.

    Storage conditions:

    At a temperature of no higher than 25 ° C.

    Keep out of the reach of children!

    Shelf life:

    3 years.

    Do not use after the expiration date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LSR-007557/08
    Date of registration:18.09.2008
    The owner of the registration certificate:Pfizer Manufakchuring Deutschland GmbH Pfizer Manufakchuring Deutschland GmbH Germany
    Manufacturer: & nbsp
    Representation: & nbspPfizer LtdPfizer LtdUSA
    Information update date: & nbsp23.03.2015
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