Composition, form of production and packaging
The tablets covered with a film shell of white color, oval, on one side it is put "Pfizer", on another - "CDT" and "051".
1 tab.
amlodipine besylate * 6.94 mg,
which corresponds to the content of amlodipine 5 mg
atorvastatin calcium 10.85 mg,
which corresponds to the content of atorvastatin 10 mg
Auxiliary substances: calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80 (tween 80), giprolase, silicon dioxide colloid, magnesium stearate, film coat Opadrai II white 85F28751 (polyvinyl alcohol, titanium dioxide, macrogol (PEG) 3000, talc).
10 pieces. - blisters (3) - packs of cardboard.
The tablets covered with a film shell of blue color, oval, on one side it is put "Pfizer", on another - "CDT" and "101".
1 tab.
amlodipine besylate * 13.87 mg,
which corresponds to the content of amlodipine 10 mg
atorvastatin calcium 10.85 mg,
which corresponds to the content of atorvastatin 10 mg
Auxiliary substances: calcium carbonate, croscarmellose sodium, microcrystalline cellulose, pregelatinized starch, polysorbate 80 (tween 80), giprolase, silicon dioxide colloid, magnesium stearate, film membrane Opadrai II blue 85F10919 (polyvinyl alcohol, titanium dioxide, macrogol (PEG) 3000, talc, lacquer aluminum indigo carmine).
10 pieces. - blisters (3) - packs of cardboard.
* Nonproprietary international name recommended by WHO - amlodipine besylate.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Combined drug used to treat combined cardiovascular diseases (arterial hypertension / angina and dyslipidemia).
The mechanism of action of the drug is due to the action of its constituent components: amlodipine - a derivative of dihydropyridine, a blocker of slow calcium channels, and atorvastatin - a hypolipidemic agent, an inhibitor of HMG-CoA reductase. Amlodipine inhibits calcium flow through membranes into smooth muscle cells and cardiomyocytes. Atorvastatin selectively and competitively inhibits HMG-CoA reductase, which catalyzes the conversion of 3-hydroxy-3-methylglutarylcoenzyme A to mevalonic acid, a precursor of steroids, including cholesterol (Xc).
Clinical studies in patients with arterial hypertension and dyslipidemia
In the RESPOND study, 1,600 patients with a combination of arterial hypertension and dyslipidemia were compared with amlodipine monotherapy and monotherapy with atorvastatin or placebo. In addition to hypertension and dyslipidemia, 15% of patients had diabetes mellitus, 22% smokers, and 14% had a hereditary anamnesis for cardiovascular disease. After 8 weeks, combination therapy in all 8 doses resulted in a statistically significant and dose-dependent decrease in systolic and diastolic blood pressure and low-density lipoprotein cholesterol (LDL-C) cholesterol compared with placebo. In terms of the effect on systolic blood pressure and diastolic blood pressure or the level of LDL-C, the drug Caduet did not differ significantly from monotherapy with amlodipine and atorvastatin.
In the GEMINI study, 1220 patients with a combination of hypertension and dyslipidemia received amlodipine / atorvastatin for 14 weeks. Patients with uncontrolled arterial hypertension (who received and did not receive antihypertensive drugs, patients could continue taking other antihypertensive drugs, in addition to slow calcium channel blockers, during the 14-week period of titration of the dose) and normal or elevated LDL-C. All patients had elevated blood pressure or LDL-C, and 62% had both. Treatment with Cadet resulted in a decrease in systolic and diastolic blood pressure by an average of 17.1 and 9.6 mm Hg. Art. respectively, and the level of Xc-LDL on average by 32.7%. Control of blood pressure and the level of LDL-C was achieved in 58% of patients (criteria for control of blood pressure and LDL-C were less than 140/90 mm Hg and less than 160 mg / dL in patients with a combination of hypertension and dyslipidemia, less than 140/90 mmHg and less than 130 mg / dL in patients with a combination of hypertension and dyslipidemia and another cardiovascular risk factor, but without CHD or diabetes, less than 130/85 mm Hg and less than 100 mg / dl in patients with a combination of arterial hypertension and dyslipidemia, as well as CHD, diabetes and other diseases, the cause atherosclerosis). It was shown that a decrease in blood pressure and a level of LDL-C was achieved in 65% of patients who received Cadet at the initial stage of therapy for the treatment of hypertension and dyslipidemia, and 55-64% of patients who had been added amlodipine for the correction of blood pressure (55 % of patients receiving other hypolipidemic drugs other than atorvastatin, 58% of patients who received atorvastatin before the study, and 64% of patients who did not take lipid-lowering drugs).
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, but amlodipine reduces ischemia in the following two ways:
1. Amlodipine dilates the peripheral arterioles and thus lowers the OPSS, i.e. heart afterload. Since the heart rate does not change, reducing the load on the heart leads to a reduction in energy consumption and oxygen demand.
2. 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 arterial hypertension, the administration of amlodipine in a single daily dose provides a clinically significant reduction in blood pressure for 24 hours in both the prone position and the standing position. Due to the slow onset of action, amlodipine does not cause acute arterial hypotension.
In patients with angina, the use of amlodipine 1 time / day increases the exercise time, prevents the development of an attack of angina and ST depression (by 1 mm), reduces the frequency of angina attacks and the use of nitroglycerin tablets.
Amlodipine does not adversely affect the metabolism and lipids of the blood plasma and can be used in patients with bronchial asthma, diabetes and gout.
Use in patients with ischemic heart disease
The effects of amlodipine on cardiovascular morbidity and mortality, the progression of coronary atherosclerosis and the course of carotid artery atherosclerosis have been studied in the PREVENT study. In this study, patients with angiographically confirmed coronary atherosclerosis were observed for 3 years. In patients receiving amlodipine, there was a significant reduction (by 31%) of the total incidence of cardiovascular mortality, myocardial infarction, stroke, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass grafting, hospitalization for unstable angina and progression of chronic heart failure . In addition, it was noted that amlodipine prevented the progressive thickening of the intima-media of the carotid arteries.
The CAMELOT study examined the efficacy of amlodipine in the prevention of adverse outcomes in patients with coronary artery disease, approximately half of whom received amlodipine at doses of 5-10 mg, and the remaining patients received placebo in combination with standard therapy. The duration of therapy was 2 years. Amlodipine therapy was accompanied by a decrease in cardiovascular mortality, nonfatal myocardial infarction, fatal and nonfatal stroke or transient ischemic attacks and other serious cardiovascular complications by 31%, hospitalizations for angina by 42%.
Pharmacodynamics of atorvastatin
Atorvastatin is a selective competitive inhibitor of HMG-CoA reductase, which converts HMG-CoA to mevalonic acid, a precursor of steroids, including Xc. In patients with homozygous and heterozygous familial hypercholesterolemia, non-family forms of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces the levels of total cholesterol, LDL-C and apolipoprotein B (apo-B) as well as cholesterol of very low density lipoproteins (X-VLDL) and triglycerides (TG) and causes a variable increase in the level of cholesterol Xc-HDL.
Atorvastatin reduces the levels of Xc and lipoproteins in the plasma by inhibiting HMG-CoA reductase and the synthesis of Xc in the liver and increasing the number of hepatic LDL receptors on the cell surface, which leads to an increase in the capture and catabolism of LDL.
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 level of LDL-C in patients with homozygous familial hypercholesterolemia, which usually does not respond to lipid-lowering therapy.
Atorvastatin and some of its metabolites are pharmacologically active in humans. The primary site of atorvastatin is the liver, where the synthesis of cholesterol is carried out and the clearance of LDL. The degree of decrease in the level of LDL-C 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.
In a clinical study that examined the dose-response of the effect, atorvastatin 10-80 mg reduced the level of total cholesterol (by 30-46%), Xc-LDL (by 41-61%), apo-B (by 34-50%) and TG (by 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 the levels of total Xc, Xc-LDL, Xc-VLDL, apo-B, TG and Xc-LPneVP and increases the level of Xc-HDL. In patients with disbetalipoproteinemia, atorvastatin reduced the level of Xp of intermediate-density lipoproteins.
In patients with hyperlipoproteinemia IIa and IIb types according to Frederickson, who participated in 24 controlled studies, the median increase in the level of X-HDL in the treatment with atorvastatin (10-80 mg) was 5.1-8.7%. The changes in this indicator did not depend on the dose. In the analysis of these patients, a dose-dependent decrease in the total Xc / Xc-HDL and Xc-LDL / Xc-HDL cholesterol rates was also found to be 29-44% and 37-55%, respectively.
The 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 Q-free myocardial infarction) who received standard therapy, including diet, in combination with atorvastatin 80 mg / day or placebo for 16 weeks (median). Treatment with atorvastatin resulted in a marked reduction in the risk of ischemic outcomes and lethality by 16%. The risk of re-hospitalization for angina and confirmed myocardial ischemia decreased by 26%. The effect of atorvastatin on the risk of ischemic outcomes and mortality was independent of the baseline level of LDL-C and was comparable in patients with Q-wave myocardial infarction and unstable angina, men and women, patients younger than 65 years of age.
Prevention of the risk of developing cardiovascular diseases
In the Anglo-Scandinavian cardiovascular outcome, the lipid-lowering branch (ASCOT-LLA), the effect of atorvastatin on fatal and nonfatal outcomes of IHD (cardiovascular mortality, hospitalization for unstable angina) was assessed in patients aged 40-80 years without infarction myocardial history and baseline total cholesterol more than 6.5 mmol / l (251 mg / dL). At least 3 cardiovascular risk factors were present in all patients: male sex, age over 55 years, smoking, diabetes mellitus, IHD of the 1st functional class in history, the ratio of total cholesterol level to HDL-C level is more than 6, peripheral vascular disease, left ventricular hypertrophy, cerebral circulation history, specific ECG changes, proteinuria and albuminuria. In the study, patients with hypertension concomitant with prescribed antihypertensive therapy (target blood pressure less than 140/90 mm Hg for all patients in patients without diabetes mellitus and less than 130/80 for patients with diabetes mellitus) was prescribed atorvastatin at a dose of 10 mg / day or placebo.
Due to the fact that according to the data of the intermediate analysis the effect of the drug therapy was much higher than the placebo effect, it was decided to terminate the study ahead of schedule 3.3 years instead of the expected 5 years. Atorvastatin significantly reduced the development of the following complications:
Complications Risk Reduction
Coronary complications (IHD with fatal outcome and non-fatal myocardial infarction) 36%
General cardiovascular complications and revascularization procedures 20%
Common coronary events 29%
Stroke (fatal and nonfatal) 26%
There was no significant reduction in overall and cardiovascular mortality, although there was a positive trend.
In a combined study of atorvastatin in diabetes mellitus (CARDS), its effect on fatal and nonfatal outcomes of cardiovascular disease was assessed in patients aged 40-75 years with type 2 diabetes without cardiovascular disease in history and with an LDL of no more than 4.14 mmol / l (160 mg / dL) and TG not more than 6.78 mmol / L (600 mg / dL). All patients had at least one of the following risk factors: hypertension, smoking, retinopathy, micro- or macroalbuminuria. Patients received atorvastatin 10 mg / day or placebo for an average of 3.9 years. Due to the fact that according to the data of the intermediate analysis the effect of the drug treatment was much higher than the effect of placebo application, it was decided to finish the study ahead of schedule 2 years earlier than the target date.
The effect of atorvastatin on the development of cardiovascular complications is given below:
Complications 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%
Myocardial infarction (fatal and nonfatal acute myocardial infarction, latent myocardial infarction) 42%
Stroke (fatal and nonfatal) 48%
Atherosclerosis
In the study of reverse development of atherosclerosis with aggressive lipid lowering therapy (REVERSAL), the effect of atorvastatin (80 mg) and pravastatin on coronary atherosclerosis with intravascular ultrasound angiography (IVUS) in patients with ischemic heart disease was evaluated. IVUS was carried out at the beginning of the study and 18 months later, at the end of the study. In the atorvastatin group, the mean decrease in the total volume of atheroma (the primary test) from the start of the study was 0.4% (P = 0.98). In the atorvastatin group, the level of Xc-LDL decreased on average to 2.04 В± 0.8 mmol / L (78.9 В± 30 mg / dL) compared with the initial level of 3.89 В± 0.7 mmol / L (150 В± 28 mg / dL), with a decrease in the mean the level of total cholesterol by 34.1%, TG - by 20%, apo-B - by 39.1%. an increase in HDL-C level by 2.9%, and a decrease in the level of C-reactive protein by an average of 36.4%.
PHARMACOKINETICS
Suction
After ingestion of the combined preparation Caduette, two distinct peaks of C max in the plasma were recorded. C max atorvastatin was achieved in 1-2 h, C max of amlodipine - after 6-12 hours. The speed and degree of absorption (bioavailability) of amlodipine and atorvastatin with the use of the drug Cadet did not differ from that with simultaneous administration of tablets of amlodipine and atorvastatin: Cmax amlodipine = 101%, AUC amlodipine = 100%, C max atorvastatin = 94%, atorvastatin AUC = 105%.
After eating, the bioavailability of amlodipine does not change ( Cmax = 105% and AUC = 101% compared to fasting rates). Although simultaneous intake of food caused a decrease in the rate and extent of absorption of atorvastatin with the use of the preparation Kaduet by approximately 32% and 11% respectively (C max = 68% and AUC = 89%), but similar changes in bioavailability were detected using one atorvastatin. At the same time, eating did not affect the degree of decrease in the level of LDL-C.
Amlodipine is well absorbed after oral administration in therapeutic doses, reaching C max in the blood 6-12 hours after ingestion. Absolute bioavailability according to calculations is 64-80%. Food intake does not affect the absorption of amlodipine.
Atorvastatin is rapidly absorbed after ingestion, C max is reached 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 inhibitors - about 30%. The low systemic bioavailability due to first pass metabolism (suction) in the mucosa of the gastrointestinal tract and / or metabolism of the "first pass" through the liver. Food somewhat reduces the rate and extent of absorption (25% and 9%, respectively, as evidenced by the results of determination of C max and AUC), but LDL-C reduction is similar to that when receiving atorvastatin fasting. Despite the fact that after its evening atorvastatin plasma concentration lower (C max and AUC by about 30%) than after ingestion of the morning, LDL-C reduction is independent of the time of day that take medication.
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 dosing.
Middle V d atorvastatin is about 381 liters. Binding to plasma proteins is not less than 98%. The ratio of the erythrocyte / plasma is about 0.25, i.e., Atorvastatin does not penetrate into erythrocytes.
Metabolism
Amlodipine is metabolized in the liver to inactive metabolites.
Atorvastatin is largely metabolized with formation of ortho- and para-hydroxylated derivatives, and various products of beta-oxidation. In vitro ortho and para-hydroxylated metabolites have an inhibitory effect on HMG-CoA reductase, comparable to that of atorvastatin. Approximately 70% reduction in the activity of HMG-CoA reductase is due to actions of active circulating metabolites. The results of in vitro studies provide evidence to suggest that CYP3A4 liver plays an important role in the metabolism of atorvastatin. In favor of this fact is evidenced by the increasing concentration of atorvastatin in human plasma while taking erythromycin, which is an inhibitor of this isoenzyme. in vitro studies have also shown that atorvastatin is a weak inhibitor of CYP3A4. There was no clinically significant effect of atorvastatin on blood levels of terfenadine plasma, which is metabolized primarily by CYP3A4, it is unlikelythat atorvastatin has a significant effect on the pharmacokinetics of other substrates of CYP3A4.
Excretion
T 1/2 amlodipine plasma of blood is about 35-50 hours, allowing the drug to assign 1 time / day. 10% of unchanged amlodipine and 60% of the metabolites excreted by the kidneys.
Atorvastatin and its metabolites are excreted mainly in the bile as a result of hepatic and / or extrahepatic metabolism, atorvastatin does not undergo pronounced enterohepatic recirculation. T 1/2 of about 14 h, the T 1/2 of the inhibitory activity against HMG-CoA reductase due to the presence of the active metabolite is about 20-30 hours. After oral administration found in the urine of less than 2% of the dose.
Pharmacokinetics in specific clinical situations
blood plasma concentration of atorvastatin significantly increased (Pmax approximately 16 times, AUC of about 11-fold) in patients with alcoholic liver cirrhosis (class classification Child-Pugh).
The concentration of amlodipine in plasma does not depend on the degree of renal failure; Amlodipine is not displayed during dialysis.
Kidney disease does not affect the concentration of atorvastatin in the blood plasma, in connection with this dose adjustment for patients with impaired renal function is not required.
The concentration of atorvastatin in the blood plasma of women different (C max of about 20% higher, a AUC is 10% lower) from that of men, however, clinically significant differences of the drug effect on lipid metabolism in men and women were not identified.
The time required to reach the C maxamlodipine in plasma, practically independent of age. In elderly people the tendency to reduce the clearance of amlodipine, which leads to an increase in AUC and T 1/2 . In patients of different age groups with chronic heart failure was observed increase in AUC and T 1/2 . Tolerability of amlodipine in the same doses in elderly and young people are equally good.
The concentration of atorvastatin in the blood plasma of people aged 65 years and older above (the C max by approximately 40%, the AUC by approximately 30%) than in adults younger patients; differences in the evaluation of the safety, effectiveness, or the achievement of the objectives of lipid-lowering therapy in the elderly compared with the general population have been identified.
INDICATIONS
- hypertension with three or more risk factors for cardiovascular events (fatal and nonfatal coronary heart disease, the need for revascularization, fatal and nonfatal myocardial infarction, stroke and transient ischemic attack), with normal or mildly elevated cholesterol level without clinically evident coronary heart disease.
The drug is used in cases where the recommended combination therapy with amlodipine and low doses of atorvastatin. Perhaps a combination of Kadueta with other antihypertensive and / or antianginal agents.
Kaduet applies in cases where the lipid-lowering diet and other non-pharmacological treatments for dyslipidemia are small- or ineffective.
DOSING MODE
The drug is taken orally for 1 tablet. 1 time / day at any time, regardless of the meal.
The initial and maintenance doses are selected individually considering both effectiveness and tolerance of the components in the treatment of hypertension / angina and dyslipidemia. Kaduet can be administered to patients who are already taking one of the components of the drug as monotherapy.
Kaduet used in combination with non-drug therapies, including diet, exercise, weight loss in patients with obesity, smoking cessation.
Treatment should begin with the reception of tablets 10.5 mg (amlodipine / atorvastatin, respectively). Patients with hypertension need to control blood pressure every 2-4 weeks and, if necessary, it is possible to transfer pills 10.10 mg (amlodipine / atorvastatin, respectively).
When CHD recommended dose is 5-10 mg amlodipine 1 time / day.
When primary hypercholesterolaemia and combined (mixed) hyperlipidemia atorvastatin dose for most patients - 10 1 mg once / day; therapeutic effect is apparent within 2 weeks, and typically reaches a maximum for 4 weeks; long-term treatment effect remains.
In patients with impaired renal function dose adjustment is required.
When administering the drug in elderly patients a dose adjustment is required.
SIDE EFFECT
In clinical studies, the safety of amlodipine and atorvastatin has been studied in patients with a combination of hypertension and dyslipidemia, with no unexpected adverse effects in combination therapy have been reported.
Undesirable effects consistent with previously identified in the treatment with amlodipine and / or atorvastatin. Overall, tolerability of combination therapy was good. Most undesirable effects were mild to moderate. In controlled clinical trials due to adverse effects or laboratory abnormalities treatment with amlodipine and atorvastatin was discontinued in 5.1% of patients and placebo - 4.0%.
amlodipine
Further, under frequency of side reactions means: frequent (> 1%), infrequent (<1%), rare (<0.1%), very rare (<0.01%).
Cardio-vascular system: often - peripheral edema (ankles and feet), palpitations; rare - an excessive fall in blood pressure, orthostatic hypotension, vasculitis; rarely - the development or exacerbation of congestive heart failure; very rarely - cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), heart attack, chest pain, migraine.
On the part of the musculoskeletal system : rarely - arthralgia, muscle cramps, myalgia, back pain, arthritis; rarely - myasthenia gravis.
On the part of the central nervous system and peripheral nervous system: sensation of heat and rush of blood to the skin, fatigue, dizziness, headache, drowsiness; infrequently - malaise, fainting, sweating, asthenia, hypesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, abnormal dreams, nervousness, depression, anxiety; rarely - seizures, lethargy, agitation; very rarely - ataxia, amnesia.
From the digestive system: often - pain in the abdomen, nausea; rarely - vomiting, defecation regime changes (including constipation, flatulence), indigestion, diarrhea, anorexia, dry mouth, thirst; rarely - gingival hyperplasia, increased appetite; very rarely -gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), elevated liver enzymes, hepatitis.
From hemopoiesis system: very rarely - thrombocytopenic purpura, leukopenia, and thrombocytopenia.
Metabolic disorders: very rarely - hyperglycemia.
From the side of respiratory system: rarely - dyspnea, rhinitis; very rarely - cough.
From the urinary system: rarely - frequent urination, painful urination, nocturia, impotence; very rarely - dysuria, polyuria.
From a sight organ:rarely - blurred vision, diplopia, disturbance of accommodation, xerophthalmia, conjunctivitis, eye pain.
For the skin: rare - alopecia; rarely - dermatitis; very rarely - dermatoxerasia, violation of skin pigmentation.
Allergic reactions: rarely - itching, rash; very rarely - angioedema, erythema multiforme, urticaria.
Other: rarely - ringing in the ears, gynecomastia, increase / decrease in body weight, taste perversion, chills, nasal bleeding; very rarely - parosmiya, "cold" sweat.
Atorvastatin
is generally well tolerated. Adverse reactions are usually mild and transient.
The most frequent adverse reactions (1%?):
On the part of the central nervous system: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:
CNS and peripheral nervous system: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia.
From the digestive system: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.
On the part of the musculoskeletal system : back pain, muscle cramps, myositis, myopathy, arthralgia, rhabdomyolysis.
Allergic reactions:urticaria, itching, skin rash, anaphylaxis, bullous rashes, erythema multiforme, toxic epidermal necrolysis (Lyell's syndrome), malignant exudative erythema (Stevens-Johnson syndrome).
Metabolic disorders: hypoglycemia, hyperglycemia, increased serum CPK, increased body mass index.
From hemopoiesis system: thrombocytopenia.
Other: impotence, peripheral edema, chest pain, secondary renal failure, alopecia, tinnitus, fatigue.
A causal relationship to drug intake is not installed for all of the above reactions.
Not all of these effects have established a causal relationship to atorvastatin therapy.
CONTRAINDICATIONS
- Active liver disease or persistent elevation of liver enzymes more than 3 times higher than normal unclear etiology;
- severe hypotension;
- Pregnancy;
- lactation (breast feeding);
- the use in women of reproductive age who do not use adequate methods of contraception;
- child and adolescence to 18 years (effectiveness and safety have been established);
- increased sensitivity to amlodipine and other dihydropyridine derivatives, atorvastatin or any component of the formulation.
With caution should be used on patients abusing alcohol and / or with liver disease (disorder).
PREGNANCY AND LACTATION
Kaduet is contraindicated in pregnancy because of the drug include atorvastatin.
Women of reproductive age during treatment should use adequate contraception methods. The drug can be administered to women of childbearing age only when the probability of pregnancy is low and the patient informed of the potential risk to the fetus.
Kaduet contraindicated during lactation since it is part of the atorvastatin. Information about the excretion of atorvastatin in breast milk does not. Given the possibility of adverse reactions in infants, women receiving the drug should stop breastfeeding.
Safety of application of amlodipine during pregnancy and lactation has not been established.
APPLICATION FOR FUNCTIONS OF THE LIVER
In patients with impaired renal function dose adjustment is required.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
Contraindications: active liver disease or persistent elevation of liver enzymes more than 3 times higher than normal unclear etiology.
With caution should be used on patients with liver disease (disorder).
APPLICATION FOR CHILDREN
Contraindications: childhood and adolescence to 18 years (effectiveness and safety have been established).
APPLICATION IN ELDERLY PATIENTS
When administering the drug in elderly patients a dose adjustment is required.
SPECIAL INSTRUCTIONS
Patients treated with atorvastatin was observed myalgia. The diagnosis of myopathy (pain or weakness in muscles, combined with an increase in CPK activity more than 10 times compared with FHG) should be considered in patients with advanced myalgia, muscle tenderness or weakness, and / or markedly elevated CK activity. Patients should seek medical advice immediately if the appearance of unexplained pain or weakness in muscles, especially if accompanied by malaise or fever. Kaduet drug therapy should be stopped in case of pronounced increase of CPK activity in the presence or confirmed or suspected myopathy.
The risk of myopathy in the treatment of other drugs in this class is increased while the application of cyclosporine, fibric acid derivatives, erythromycin, nicotinic acid or azole antifungals. Many of these drugs inhibit metabolism mediated by CYP3A4, and / or transport of drugs. It is known that CYP3A4 - primary liver isoenzyme involved in the biotransformation of atorvastatin. Assigning atorvastatin lipid-lowering doses in combination with a fibric acid derivatives, erythromycin, immunosuppressants, azole antifungals or niacin should be carefully weigh the potential benefits and risks of treatment and regularly monitor patients to detect pain or weakness in muscles, especially during the first months of treatment and during the increase of the dose of any drug.In such situations, we can recommend periodic determination of CPK activity, although such control does not prevent the development of severe myopathy.
Admission Kadueta can cause elevation of CK activity. In the application of atorvastatin, as well as other drugs of this class are described in rare cases of rhabdomyolysis with acute renal failure caused by myoglobinuria. Therapy with Kaduet should suspend or abolish the appearance of signs of possible myopathy or presence of risk factors of renal failure development against the background of rhabdomyolysis (eg, severe acute infection, hypotension, surgery, trauma, metabolic, endocrine, and electrolyte disorders, and uncontrolled seizures). Treatment of amlodipine in an adequate dose for the purpose of control of hypertension can be extended
