Caduet, 10 mg+10 mg 30 pcs

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Indications

Hypertension with three or more risk factors for cardiovascular events (fatal and non-fatal CHD, need for revascularization, fatal and non-fatal myocardial infarction, stroke and transient ischemic attack), with normal to moderately elevated CHD levels without clinically significant CHD.

The drug is used in cases where combination therapy with amlodipine and low-dose atorvastatin is recommended.

Caduet may be combined with other antihypertensive and/or antianginal agents.

Caduet is used in cases where hypolipidemic diet and other non-pharmacological methods of treatment of dyslipidemia prove to be little or ineffective.

Active ingredient

Composition

1 tablet contains amlodipine 10 mg and atorvastatin 10 mg;

excipients:

calcium carbonate,

croscarmellose sodium,

microcrystalline cellulose,

pregelatinized starch,

polysorbate 80 (tween 80),

hyprolose,

colloidal silicon dioxide,

magnesium stearate,

Opadray II white film jacket 85F28751 (polyvinyl alcohol, titanium dioxide, macrogol (PEG) 3000, talcum)

Magnesium stearate

How to take, the dosage

Caduet is taken orally 1 tablet once daily at any time, regardless of meals.

The starting and maintenance doses are adjusted individually, taking into account the efficacy and tolerability of both components in the treatment of arterial hypertension/stenocardia and dyslipidemia. Caduet may be administered to patients who are already taking one component of the drug in monotherapy.

Caduet is used in combination with nonmedicamental therapies including diet, exercise, weight loss in obese patients and smoking cessation.

Caduet should be started with 5/10 mg tablets (amlodipine/atorvastatin, respectively). In patients with arterial hypertension, BP should be monitored every 2-4 weeks and, if necessary, it is possible to transfer to 10/10 mg tablets (amlodipine/atorvastatin, respectively).

In CHD, the recommended dose of amlodipine is 5-10 mg once daily.

Interaction

The data regarding drug interactions of amlodipine and atorvastatin in healthy subjects indicate that the pharmacokinetics of amlodipine is not altered when these drugs are used in combination. Amlodipine has no effect on Cmax for atorvastatin: 91% (90% confidence interval: 80-103%), but increases AUC of atorvastatin by 18% (90% CI: 109-127%).
Studies of drug interaction between amlodipine/atorvastatin concentration and other drugs have not been conducted, but there are studies regarding the effects of amlodipine and atorvastatin separately. These findings are summarized below.

Amlodipine can be safely used together with thiazide diuretics, β- and α-adrenoreceptor blockers, ACE inhibitors, long-acting nitrates, sublingual forms of nitroglycerin, NSAIDs, antibiotics and oral hypoglycemic agents. In vitro data from human plasma studies indicate that amlodipine does not affect the protein binding of digoxin, phenytoin, warfarin or indomethacin. Cimetidine – Combined use of amlodipine and cimetidine does not alter the pharmacokinetics of amlodipine.

Grapefruit juice – Combined use of 240 mL of grapefruit juice and a single oral dose of 10 mg amlodipine in 20 healthy volunteers had no effect on amlodipine pharmacokinetics.

Aluminum/magnesium (antacid) – Combined use of aluminum/magnesium (antacid) and a single dose of amlodipine had no effect on amlodipine pharmacokinetics.

Sildenafil – A single dose of 100 mg of sildenafil in subjects with essential hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil are used in combination, each agent independently manifests its hypotensive effect.

Digoxin – Combined use of amlodipine and digoxin does not change the serum concentration and renal clearance of digoxin in healthy volunteers.

Ethyl alcohol (alcohol) – Single and multiple doses of 10 mg amlodipine do not affect the pharmacokinetics of ethyl alcohol.

Warfarin – Combined use of amlodipine and warfarin does not alter the warfarin-dependent prothrombin time.
Cyclosporine – Pharmacokinetic studies of cyclosporine indicate that amlodipine does not alter the pharmacokinetics of cyclosporine.

The effect on laboratory test values is not known.

The risk of myopathy during treatment with HMG-CoA reductase inhibitors (including atorvastatin) increases with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, azole antifungals or nicotinic acid.

Antacids – combined use of atorvastatin and oral suspensions of antacids containing magnesium and aluminum hydroxides reduces plasma concentrations of atorvastatin by approximately 35%; however, the magnitude of decrease in LDL-C levels does not change.

Phenazone (antipyrine) – Since atorvastatin does not affect pharmacokinetics of phenazone, interaction with other drugs that are metabolized by the same cytochrome isoenzymes is unlikely.

Colestipol – when combined use of colestipol and atorvastatin, plasma concentrations are reduced by almost 25%. However, the effects on lipids are more pronounced when used in combination than when used separately.

Digoxin – When combined repeated use of digoxin and 10 mg atorvastatin, the equilibrium plasma concentration of digoxin is not changed. However, when combined use of digoxin and 80 mg atorvastatin per day, digoxin concentration is increased by almost 20%. Patients taking digoxin require appropriate monitoring.

Eritromycin/clarithromycin – combined use of atorvastatin and erythromycin (500 mg 4 times daily) or clarithromycin (500 mg 2 times daily) – known cytochrome P450 WA4 inhibitors – increases the plasma concentration of atorvastatin.
Azithromycin – combined use of atorvastatin (10 mg once daily) and azithromycin (500 mg once daily) does not change the plasma concentration of atorvastatin.

Terfenadine – combined use of atorvastatin and terfenadine does not cause clinically significant changes in terfenadine pharmacokinetics.

Peroral contraceptives – combined use with oral contraceptives containing norethindrone and ethinylestradiol increases equal AUCs for norethindrone and ethinylestradiol by approximately 30 and 20%. This increase should be considered when choosing an oral contraceptive for women taking atorvastatin.

Warfarin – No clinically significant interaction was found in studies of atorvastatin and warfarin interactions when used in combination.

Cimetidine – no clinically significant interaction has been observed in the study of atorvastatin and cimetidine interaction in combined use.

Protease inhibitors – combined use of atorvastatin and protease inhibitors – known cytochrome P450 ZA4 inhibitors – leads to a decrease in plasma concentration of atorvastatin.

Attorvastatin has been used with antihypertensive agents and estrogen replacement therapy in clinical trials. No clinically significant adverse interactions have been identified. No study of interaction with specific agents has been conducted.

Special Instructions

Myalgia has been observed in patients receiving atorvastatin. The diagnosis of myopathy (pain or weakness in muscles combined with an increase in CPK activity of more than 10 times that of IGN) should be assumed in patients with widespread myalgia, muscle soreness or weakness and/or a marked increase in CPK activity. Patients should immediately consult a physician if unexplained muscle pain or weakness occurs, especially if accompanied by malaise or fever. Therapy with Kaduet should be discontinued if there is a marked increase in CPK activity or if there is confirmed or suspected myopathy.

The risk of myopathy during treatment with other drugs of this class increases with concomitant use of cyclosporine, fibric acid derivatives, erythromycin, nicotinic acid or azole antifungals. Many of these drugs inhibit CYP3A4-mediated metabolism and/or drug transport. CYP3A4 is known to be the main liver isoenzyme involved in the biotransformation of atorvastatin. When prescribing atorvastatin in hypolipidemic doses in combination with fibric acid derivatives, erythromycin, immunosuppressants, azole antifungal drugs or nicotinic acid, the expected benefits and risks of treatment should be carefully weighed and patients should be regularly observed to detect muscle pain or weakness, especially during the first months of treatment and during dose increases of any drug. Periodic determination of CPK activity may be recommended in such situations, although such monitoring does not prevent the development of severe myopathy.

The administration of Caduet may cause an increase in CPK activity. Rare cases of rhabdomyolysis with acute renal failure due to myoglobinuria have been described with atorvastatin and other drugs of this class. Therapy with Kaduet should be temporarily stopped or completely discontinued if there are signs of possible myopathy or if there are risk factors of renal failure due to rhabdomyolysis (such as severe acute infection, arterial hypotension, surgical intervention, trauma, metabolic, endocrine and electrolyte disorders and uncontrolled convulsions). Treatment with amlodipine at an adequate dose to control arterial hypertension may be continued.

Impact on driving and operating machinery

While available data on amlodipine and atorvastatin suggest that the combined drug should not impair the ability to drive and operate machinery, caution should be exercised when driving and operating machinery (given the possible development of excessive BP decrease, dizziness, fainting).

Contraindications

Known hypersensitivity to dihydropyridine, amlodipine, atorvastatin, or any component of the drug; active liver disease or elevated serum transaminase levels that are three times greater than normal; pregnancy and lactation or childbearing age in the absence of adequate contraception.

Side effects

The safety of amlodipine and atorvastatin has been studied in clinical trials in patients with a combination of arterial hypertension and dyslipidemia, and no unexpected adverse effects have been reported with the combined therapy.
Adverse effects were consistent with those previously identified with amlodipine and/or atorvastatin treatment. In general, tolerability of combined therapy was good. Most of the adverse effects were mild to moderate. In controlled clinical trials due to adverse effects or abnormal laboratory values, treatment with amlodipine and atorvastatin was discontinued in 5.1% of patients and placebo in 4.0%.
Amlodipine
The following refers to the frequency of adverse reactions: frequent (> 1%), infrequent (< 1%), rare (< 0.1%), very rare (< 0.01%).
Cardio-vascular system: common – peripheral edema (ankles and feet), palpitation; infrequent – excessive decrease of BP, orthostatic hypotension, vasculitis; rare – development or worsening of heart failure; very rare – cardiac arrhythmias (including bradycardia, ventricular tachycardia and atrial fibrillation), myocardial infarction, chest pain, migraine.
Musculoskeletal system: infrequent – arthralgia, muscle cramps, myalgia, back pain, arthrosis; rarely – myasthenia.
CNS and peripheral nervous system disorders: Feeling of fever and blood rush to the face, increased fatigue, dizziness, headache, drowsiness; infrequently – malaise, fainting, increased sweating, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia, mood lability, unusual dreams, nervousness, depression, anxiety; rarely – convulsions, apathy, agitation; very rarely – ataxia, amnesia.
Digestive system disorders: frequent – abdominal pain, nausea; infrequent – vomiting, changes in defecation mode (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dry mouth, thirst; rare – gum hyperplasia, increased appetite; very rare – gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased activity of liver transaminases, hepatitis.
Blood system: very rarely – thrombocytopenic purpura, leukopenia, thrombocytopenia.
Metabolic disorders: very rarely – hyperglycemia.
Respiratory system: infrequent – shortness of breath, rhinitis, very rare – cough.
Urinary system: infrequent – frequent urination, painful urination, nycturia, impotence, very rare – dysuria, polyuria.
Visually: infrequent – visual disturbances, diplopia, accommodation disorders, xerophthalmia, conjunctivitis, pain in the eyes.
Skin: infrequent – alopecia, rare – dermatitis, very rare – xeroderma, pigmentation disorders.
Allergic reactions: infrequent – skin itching, rash, very rare – angioedema, erythema multiforme, urticaria.
Other: infrequent – tinnitus, gynecomastia, weight gain/decrease, perversion of taste, chills, nosebleed; very rare – parosmia, “cold” sweat.
Atorvastatin
Usually well tolerated. Adverse reactions are usually mild and transient.
The most common adverse reactions (≥1%):
CNS side: insomnia, headache, asthenic syndrome.
Digestive system: nausea, diarrhea, abdominal pain, dyspepsia, constipation, flatulence.
Musculoskeletal system: myalgia.
Less frequent adverse reactions:
CNS and peripheral nervous system: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia.
Digestive system: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.
Musculoskeletal system: back pain, muscle cramps, myositis, myopathy, arthralgia, rhabdomyolysis.
Allergic reactions: urticaria, pruritus, skin rash, anaphylaxis, bullous rash, erythema multiforme, toxic epidermal necrolysis (Lyell’s syndrome), erythema malignant exudative (Stevens-Johnson syndrome).
Metabolic disorders: hypoglycemia, hyperglycemia, increased serum CPK, weight gain.
Blood system: thrombocytopenia.
Other: impotence, peripheral edema, chest pain, secondary renal failure, alopecia, tinnitus, fatigue.

Overdose

There are no data on overdose of the drug.

Both amlodipine and atorvastatin actively bind to blood plasma proteins, therefore a significant increase in clearance of the combined drug in hemodialysis is unlikely.

The symptoms of amlodipine overdose: excessive peripheral vasodilation leading to reflex tachycardia, and pronounced and persistent decrease of BP, including with the development of shock and death.

The symptoms of atorvastatin overdose have not been described.

Treatment of amlodipine overdose: Administration of activated charcoal immediately or within 2 hours after taking amlodipine in dose of 10 mg leads to significant delay in absorption of the drug. In some cases gastric lavage may be effective. Clinically significant arterial hypotension caused by amlodipine overdose requires active measures aimed at maintaining cardiovascular function, including control of heart and lung function, elevation of extremities and control of CPR and diuresis. For restoration of vascular tone and BP it may be useful to use a vasoconstrictor, if there are no contraindications for its prescription, for elimination of the consequences of calcium channel blockade – IV administration of calcium gluconate.

There are no specific remedies for treatment of atorvastatin overdose. In case of overdose symptomatic and supportive treatment should be carried out as needed.

Pregnancy use

It is contraindicated in pregnant women and during lactation.