Amlodipine + Atorvastatin - instructions for use, dose, side effects, contraindications

The mechanism of action of the drug is due to the action of its constituent components: amlodipine - blocker of slow calcium channels, 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 into mevalonic acid, a precursor of steroids, including cholesterol (Xc).

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 expands peripheral arterioles and thus reduces 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 start of action amlodipine does not cause acute arterial hypotension.

In patients with angina, the use of amlodipine 1 time / day.increases the time of exercise, 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 who received amlodipine, there was a significant decrease (by 31%) in 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 in doses of 5-10 mg, and the remaining patients - 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%.

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 Xc, Xc-LDL and apolipoprotein B (apo-B), and also of very low-density lipoprotein cholesterol (X-VLDL) and triglycerides (TG) and causes a variable increase in cholesterol level of HDL-C.

Atorvastatin reduces the levels of Xc and lipoproteins in the plasma by suppressing 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.

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 myocardial infarction without Q wave) 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.

Pharmacokinetics:

After ingestion of the combined preparation, two distinct peaks of C_max in the plasma. C_max atorvastatin was achieved in 1-2 h, C_maxamlodipine - after 6-12 hours. The speed and degree of absorption (bioavailability) of amlodipine and atorvastatin with the drug did not differ from that with simultaneous administration of tablets of amlodipine and atorvastatin: C_maxAmlodipine = 101%, AUC of amlodipine = 100%, C_max atorvastatin = 94%, atorvastatin AUC = 105%.

After eating, the bioavailability of amlodipine does not change (C_max = 105% and AUC = 101% compared with fasting rates). Although simultaneous ingestion of food caused a decrease in the rate and degree of absorption of atorvastatin with the use of the drug 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 at therapeutic doses, reaching C_max in the blood 6-12 hours after admission. Absolute bioavailability according to calculations is 64-80%. Food intake does not affect the absorption of amlodipine.

Atorvastatin is rapidly absorbed after ingestion, C_maxis achieved in 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 mucosa of the gastrointestinal tract and / or metabolism during the "first passage" through the liver. The food somewhat reduces the speed and degree of absorption (by 25% and 9%, respectively, as evidenced by the results of the determination of C_max and AUC), however, a decrease in X-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 (C_max and AUC approximately 30%) than after taking in the morning, the decrease in X-LDL does not depend on the time of day in which the drug is taken.

V_d Amlodipine is approximately 21 l / kg. In vitro studies have shown that circulating amlodipine approximately 97.5% binds to plasma proteins. C_ssin blood plasma is achieved after 7-8 days of constant intake of the drug.

Average V_d Atorvastatin is about 381 liters. Binding to plasma proteins is not less than 98%. The ratio of the erythrocyte / plasma content is about 0.25, i.e. atorvastatin poorly penetrates into red blood cells.

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

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 the activity of HMG-CoA reductase occurs due to the action of active circulating metabolites.The results of in vitro studies suggest that CYP3A4 of the 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. In vitro studies also showed that atorvastatin is a weak inhibitor of CYP3A4. There was no clinically significant effect of atorvastatin on the concentration in the blood plasma of terfenadine, which is metabolized mainly by CYP3A4, so it is unlikely that atorvastatin has a significant effect on the pharmacokinetics of other CYP3A4 substrates.

T_1/2 Amlodipine from the blood plasma is about 35-50 h, which allows you to prescribe the drug 1 time / day. 10% of unchanged amlodipine and 60% of metabolites are excreted by the kidneys.

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. T_1/2 is about 14 hours, while T_1/2inhibitory 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 detected in the urine.

Pharmacokinetics in special clinical cases

The concentration of atorvastatin in blood plasma is significantly increased (C_maxapproximately 16 times, AUC approximately 11 times) in patients with alcoholic liver cirrhosis (class B according to the Child-Pugh classification).

The concentrations of amlodipine in plasma do not depend on the degree of renal failure; amlodipine not output during dialysis.

Kidney disease does not affect the concentration of atorvastatin in the blood plasma, so dose adjustments in patients with impaired renal function are not required.

The concentration of atorvastatin in blood plasma in women differs (C_max about 20% higher, and AUC 10% lower) than that of men, but there were no clinically significant differences in the effect of the drug on lipid metabolism in men and women.

Time required to achieve C_max Amlodipine in blood plasma, virtually independent of age. Older people have a tendency to decrease 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, there was an increase in AUC and T_1/2. The tolerability of amlodipine in the same doses in the elderly and young people is equally good.

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

Indications:

Arterial hypertension with three or more risk factors for cardiovascular events (fatal and nonfatal IHD, the need for revascularization, fatal and nonfatal myocardial infarction, stroke and transient ischemic attack), with normal or moderately elevated level of Xs without clinically significant CHD.

The drug is used in cases when combined therapy with amlodipine and low doses of atorvastatin is recommended. It is possible to combine the drug with other antihypertensive and / or antianginal agents.

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

ICD-10

IX.I10-I15.I10 Essential [primary] hypertension

Contraindications:

Active liver disease or persistent increase in hepatic enzyme activity is more than 3 times higher than the norm of unclear etiology; severe arterial hypotension; pregnancy; lactation period (breastfeeding); use in women of reproductive age who do not use adequate methods of contraception; children and adolescents under 18 years of age (efficacy and safety not established); hypersensitivity to amlodipine and other derivatives of dihydropyridine, atorvastatin or any component of the drug. Caution should be used in patients who abuse alcohol and / or liver disease (history).

Carefully:

Caution should be used in patients who abuse alcohol and / or liver disease (history).

Pregnancy and lactation:

Contraindications in pregnancy, t. the composition of the drug is atorvastatin. Contraindicated in the period of breastfeeding, tk. 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.The safety of the use of amlodipine during pregnancy and during lactation is not established.

Dosing and Administration:

The drug is taken orally 1 tablet. 1 time / day at any time, regardless of food intake.

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

are used in combination with non-medicamentous methods of treatment, including diet, exercise, weight loss in obese patients, quitting.

The treatment should begin with the administration of tablets 5/10 mg (amlodipine / atorvastatin, respectively). In patients with hypertension, it is necessary to monitor blood pressure every 2-4 weeks and, if necessary, transfer to the administration of 10/10 mg tablets (amlodipine / atorvastatin, respectively) is possible.

With IHD, the recommended dose of amlodipine is 5-10 mg 1 time / day.

With primary hypercholesterolemia and combined (mixed) hyperlipidemia, the dose of atorvastatin for most patients is 10 mg 1once / day; The therapeutic effect manifests itself within 2 weeks and usually reaches a maximum within 4 weeks; with prolonged treatment the effect is preserved.

In patients with impaired renal function, dose adjustment is not required.

When prescribing the drug for elderly patients, dose adjustment is not required.

Side effects:

Amlodipine

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

From the musculoskeletal system: infrequently - arthralgia, muscle cramps, myalgia, back pain, arthrosis; rarely - myasthenia gravis.

From the side of the central nervous system and the peripheral nervous system: sensation of heat and tides of blood to the skin of the face, increased fatigue, dizziness, headache, drowsiness; infrequently - malaise, fainting, increased sweating, asthenia, hypoesthesia, paresthesia, peripheral neuropathy, tremor, insomnia,lability of mood, unusual dreams, nervousness, depression, anxiety; rarely - cramps, apathy, agitation; very rarely - ataxia, amnesia.

From the side of the digestive system: often - pain in the abdominal cavity, nausea; infrequent - vomiting, changes in the bowel movement (including constipation, flatulence), dyspepsia, diarrhea, anorexia, dry mouth, thirst; rarely - gingival hyperplasia, increased appetite; very rarely - gastritis, pancreatitis, hyperbilirubinemia, jaundice (usually cholestatic), increased activity of hepatic transaminases, hepatitis.

From the hemopoietic system: very rarely - thrombocytopenic purpura, leukopenia, thrombocytopenia.

Metabolic disorders: very rarely - hyperglycemia.

On the part of the respiratory system: infrequently - shortness of breath, rhinitis; very rarely - cough.

From the urinary system: infrequent urination, painful urination, nocturia, impotence; very rarely - dysuria, polyuria.

From the side of the organ of vision: infrequently - visual impairment, diplopia, accommodation disorder, xerophthalmia, conjunctivitis, pain in the eyes.

From the skin: rarely - alopecia; rarely - dermatitis; very rarely - xeroderma, a violation of skin pigmentation.

Allergic reactions: infrequent - skin itching, rash; very rarely - angioedema, erythema multiforme, urticaria.

Other: infrequent - ringing in the ears, gynecomastia, increase / decrease in body weight, taste distortion, chills, nosebleeds; very rarely - parosmia, "cold" sweat.

Atorvastatin

Usually well tolerated. Adverse reactions are usually mild and transient.

The most frequent adverse reactions (≥1%):

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

On the part of the digestive system: nausea, diarrhea, abdominal pain, indigestion, constipation, flatulence.

From the musculoskeletal system: myalgia.

Less frequent adverse reactions:

From the side of the central nervous system and peripheral nervous system: malaise, dizziness, amnesia, paresthesia, peripheral neuropathy, hypoesthesia.

On the part of the digestive system: vomiting, anorexia, hepatitis, pancreatitis, cholestatic jaundice.

From the musculoskeletal system: back pain, muscle cramps, myositis, myopathy, arthralgia, rhabdomyolysis.

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

Metabolic disorders: hypoglycemia, hyperglycemia, increased serum CK, increase in body weight.

From the hemopoietic system: thrombocytopenia.

Other: impotence, peripheral edema, chest pain, secondary renal failure, alopecia, tinnitus, fatigue.

The causal relationship with taking the drug is not established for all of the above reactions.

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

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, and a pronounced and persistent decrease in blood pressure, incl. with the development of shock and death. Symptoms of an atorvastatin overdose are not described.

Treatment of an overdose of amlodipine: taking activated charcoal immediately or within 2 hours after taking amlodipine at a dose of 10 mg leads to a significant delay in the absorption of the drug.In some cases, gastric lavage may be effective. Clinically significant arterial hypotension caused by an overdose of amlodipine requires the implementation of active measures aimed at maintaining the function of the cardiovascular system, including monitoring the performance of the heart and lungs, elevated limb position and control of bcc and diuresis. To restore the tone of blood vessels and blood pressure, it may be useful to use a vasoconstrictor, if there is no contraindication to its purpose, to eliminate the effects of calcium channel blockade - iv gluconate administration.

There are no specific agents for the treatment of atorvastatin overdose. 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 in combination with atorvastatin 10 mg in healthy volunteers does not change. Amlodipine did not influence C_max atorvastatin, but caused an increase in AUC by 18%. The interaction of the drug with other drugs has not been specifically studied, but studies of each of the components were carried out separately.

Amlodipine

It can be expected that the inhibitors of microsomal oxidation will increase the concentration of amlodipine in the plasma, increasing the risk of side effects, and inductors of microsomal liver enzymes - reduce.

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

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

Unlike other blockers of slow calcium channels, clinically significant interaction of amlodipine was not found when combined with NSAIDs, especially indomethacin.

It is possible to intensify the antianginal and hypotensive effect of slow calcium channel blockers when combined with thiazide and loop diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates, as well as increase their hypotensive effect when combined with alpha₁adrenoblockers, neuroleptics.

Although no negative inotropic effect was usually observed in the study of amlodipine, nevertheless,some slow calcium channel blockers may increase the negative inotropic effect of antiarrhythmic drugs that cause prolongation of the QT interval (for example, amiodarone and quinidine).

With the joint application of slow calcium channel blockers with lithium preparations, an increase in the manifestation of their neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, and tinnitus) is possible.

Amlodipine does not influence in vitro the degree of binding to blood proteins of digoxin, phenytoin, warfarin and indomethacin.

Aluminum / magnesium-containing antacids in a single dose did not significantly affect the pharmacokinetics of amlodipine.

A single dose of sildenafil (at a dose of 100 mg) in patients with essential hypertension does not affect the pharmacokinetics of amlodipine.

With the simultaneous use of amlodipine with digoxin in healthy volunteers, serum levels and renal clearance of digoxin do not change.

At a single and repeated application in a dose of 10 mg amlodipine has no significant effect on the pharmacokinetics of ethanol.

Amlodipine does not affect the changes in prothrombin time caused by warfarin.

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

The effect on the results of laboratory tests is not known.

Atorvastatin

The risk of developing myopathy during treatment with other drugs of this class is increased with the simultaneous use of cyclosporine, fibrolic acid derivatives, erythromycin, antifungal agents related to azoles, and nicotinic acid.

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 content of LDL-C was not changed.

Atorvastatin does not affect the pharmacokinetics of phenazone, therefore interaction with other drugs metabolized by the same isoenzymes of cytochrome P450 is not expected.

With the simultaneous use of colestipol, the concentration of atorvastatin in the blood plasma decreased by about 25%; However, the hypolipidemic effect of the combination of atorvastatin and colestipol was superior to that of each drug alone.

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.

With simultaneous use of atorvastatin and erythromycin (500 mg 4 times / day) or clarithromycin (500 mg 2 times / day), which inhibit CYP3A4, an increase in the concentration of atorvastatin in blood plasma was observed.

With the simultaneous use of atorvastatin (10 mg 1 time / day) and azithromycin (500 mg 1 time / day), the concentration of atorvastatin in plasma did not change.

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

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

Clinically significant interaction of atorvastatin with warfarin was not detected.

Clinically significant interaction of atorvastatin with cimetidine was not detected.

With simultaneous use of atorvastatin in a dose of 80 mg and amlodipine at a dose of 10 mg, the pharmacokinetics of atorvastatin did not change in the equilibrium state.

Simultaneous use of atorvastatin with protease inhibitors, known as inhibitors of CYP3A4, was accompanied by an increase in the concentration of atorvastatin in blood plasma.

In clinical trials atorvastatin were used in combination with antihypertensive agents and estrogens, which were prescribed for substitution purposes; Signs of clinically significant undesirable interaction were not observed; studies of interaction with specific drugs have not been conducted.

Special instructions:

In patients who received atorvastatin, myalgia was observed. The diagnosis of myopathy (pain or weakness in muscles, combined with an increase in CKK activity by more than 10 times compared to IGN) should be expected in patients with common myalgias, tenderness or weakness of the muscles and / or a marked increase in CKK activity. Patients should immediately consult a doctor if unexplained pain or weakness in the muscles occurs, especially if they are accompanied by malaise or fever. The drug should be discontinued in the event of a marked increase in the activity of CK 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, derivatives of fibrolic acid, erythromycin, nicotinic acid or azole antifungal drugs. Many of these drugs inhibit CYP3A4 mediated metabolism and / or drug transport. It is known that CYP3A4 - the main isoenzyme of the liver, involved in the biotransformation of atorvastatin. Assigning atorvastatin in lipid-lowering doses combined with fibrolic acid derivatives, erythromycin, immunosuppressants, azole antifungals or nicotinic acid, the expected benefit and risk of treatment should be carefully weighed and patients monitored regularly to identify pain or weakness in the muscles, especially during the first months of treatment and in period of increasing the dose of any drug. 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.

Taking the drug may cause an increase in the activity of CK. 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 drug 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 electrolyte disturbances and uncontrolled seizures). Treatment with amlodipine in an adequate dose for the purpose of controlling hypertension can be continued.

Although the available data on amlodipine and atorvastatin indicate that the combined preparation should not worsen the ability to drive and use machinery, care should be taken when driving vehicles and controlling mechanisms (considering the possible development of excessive depression of blood pressure, dizziness, fainting).

Instructions

Amlodipine + Atorvastatin (Amlodipinum + Atorvastatinum)