Amlostat tablets №28

Amlostat (AMLOSTAT) instructions for use

Composition

active ingredient: 1 tablet contains S (-) amlodipine besylate in terms of S (-) amlodipine 2.5 mg atorvastatin calcium in terms of atorvastatin 10 mg;
auxiliary substances: cellulose microcrystalline, lactose, calcium carbonate, hypromellose, sodium croscarmellose, silicon dioxide colloid, magnesium stearate, Opadry 04F82783 yellow: polyethylene glycol, hypromellose, titanium dioxide (E 171), iron oxide yellow (E 172).

Dosage form

The tablets covered with a cover.

Basic physical and chemical properties:

round, biconcave, smooth on both sides of the tablet, coated with a yellow coating.

Pharmacological group

Lipid-lowering drugs, combination. Inhibitors of HMG-CoA reductase, other combinations. Code ATX C10B X03.

Pharmacological properties

Pharmacological.

Amlostat is a combined drug that combines two medicines: dihydropyridine calcium antagonist - S (-) amlodipine and an inhibitor of HMG-CoA reductase - atorvastatin. In this combination, S (-) amlodipine is a blocker of the slow calcium channels of cell membranes in the smooth muscle fibers of the vessels and heart; Atorvastatin has a powerful selective inhibitory effect on HMG-CoA reductase, the key enzyme for converting HMG-CoA to mevalonate, a substance that is a precursor of styrenes, including cholesterol.

The mechanism of antihypertensive action of S (-) amlodipine is to relax the smooth muscle fibers of the vessels. S (-) amlodipine: a) dilates the peripheral arterioles and, as a result, reduces OPSS (postload). Since the heart rate does not change much, a decrease in heart burden leads to a reduction in energy consumption and myocardial oxygen demand;b) promotes the expansion of large coronary arteries and coronary arterioles both in unchanged and in ischemic zones of the myocardium. This 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.

In patients with arterial hypertension, a single dose of S (-) amlodipine provides a clinically significant BP reduction for 24 hours in the supine and standing position. Due to the slow onset of S (-) action, amlodipine does not cause acute arterial hypotension. In patients with angina pectoris, S (-) amlodipine increases exercise tolerance, reduces the incidence of angina attacks and the need for nitroglycerin tablets.

S (-) amlodipine does not cause metabolic disturbances or lipid changes in the blood plasma, so that the drug can be prescribed to patients with bronchial asthma, diabetes mellitus or gout.

Atorvastatin is a selective potent inhibitor of HMG-CoA reductase regulating the conversion rate of HMG-CoA to mevalonate, the precursor of styrenes (including cholesterol). In patients with homozygous and heterozygous hereditary and non-hereditary forms of hypercholesterolemia and mixed dyslipidemias, atorvastatin reduces the concentration of total cholesterol, LDL cholesterol and apolipoprotein B, the concentration of cholesterol-VLDL and TG, and slightly increases the level of HDL-C. Also reduces the level of cholesterol and lipoproteins in the blood plasma due to the inhibition of HMG-CoA reductase and the synthesis of cholesterol in the liver and the increase in the number of hepatic LDL receptors on the cell surface, which leads to an increase in the uptake and catabolism of LDL.

Atorvastatin reduces the synthesis of LDL and reduces the number of LDL particles. It causes a pronounced and persistent increase in the activity of LDL receptors in combination with positive changes in the quality of circulating LDL particles. Atorvastatin reduces the level of LDL in patients with homozygous hereditary hypercholesterolemia, in which therapy with conventional lipid-lowering agents is often ineffective.

In humans, pharmacological activity manifests as atorvastatin, and some of its metabolites. The primary site of atorvastatin is the liver, which plays a major role in the synthesis of cholesterol and the clearance of LDL. Reducing the level of LDL cholesterol is well correlated with the dose of the drug and its concentration in the body. Individual dosage of the drug is based on therapeutic effectiveness.

Atorvastatin (10-80 mg) reduces the level of total cholesterol (30-46%), LDL cholesterol (41-61%), apolipoprotein B (34-50%) and TG (14-33%). This result is stable in patients with heterozygous hereditary and non-hereditary forms of hypercholesterolemia and a mixed form of hyperlipidemia, including patients with insulin-dependent diabetes mellitus.

In patients with isolated hypertriglyceridemia, atorvastatin reduces total cholesterol, LDL cholesterol, cholesterol-VLDL, apolipoprotein B, TG, LDL-C and increases HDL-C. In patients with disbetalipoproteinemia, atorvastatin reduces the level of LDL cholesterol. In patients with hyperlipoproteinemia type Iaa and Iib according to Fredrickson, the average percentage of increase in HDL-C with 10-80 mg of atorvastatin is 5.1-8.7% regardless of the dose. In addition, there is a significant dose-related decrease in the ratio of total cholesterol / HDL-C and LDL-C-HDL-C.

The effect of atorvastatin at a dose of 80 mg per day for 16 weeks on the occurrence of ischemia and overall mortality in patients with unstable angina or myocardial infarction without Q wave is manifested by a significant decrease in the risk of myocardial ischemia and mortality, the risk of rehospitalization cases of angina and confirmed myocardial ischemia.Atorvastatin reduces the risk of developing ischemia and death in patients with myocardial infarction without Q wave and unstable angina in inverse proportion to LDL cholesterol, equally in patients of both sexes before the age of 65 and older.

Atorvastatin significantly reduced the incidence of lethal cardiovascular diseases and non-lethal myocardial infarction, the overall incidence of cardiovascular diseases, the incidence of lethal and non-lethal stroke, and reduced the need for revascularization of the myocardium. At application of atorvastatin the general lethality owing to cardiovascular diseases slightly decreased. The effect of therapy was independent of sex, age or baseline LDL cholesterol.

Pharmacokinetics.

Absorption. When administered orally, combinations of S (-) amlodipine / atorvastatin show two separate plasma concentration maxima. The first, within 1-2 hours after taking, is associated with atorvastatin; second, within 6-12 hours after administration, associated with S (-) amlodipine. The rate of absorption (bioavailability) of S (-) amlodipine and atorvastatin in the combination of S (-) amlodipine / atorvastatin does not differ from the bioavailability of S (-) amlodipine and atorvastatin, which were taken separately in the form of tablets, (C max) 101% and the area under the concentration-time curve (AUC) of 100% for S (-) amlodipine in the combination of S (-) amlodipine / atorvastatin and C max 94% and AUC 105% for atorvastatin in the composition combination of S (-) amlodipine / atorvastatin.

The bioavailability of S (-) amlodipine in the combination of S (-) amlodipine / atorvastatin does not worsen with the use of the drug after meals, as confirmed by C max - 105% and AUC - 101% compared to fasting. Although the intake of food reduces the rate and volume of absorption of atorvastatin with the use of the drug by almost 32% and 11% respectively, which is confirmed by C max - 68% and AUC - 89% compared with the indices when taking the drug on an empty stomach. A similar decrease in plasma concentration when atorvastatin is used after taking is noted also with monotherapy with atorvastatin, but this is not accompanied by a decrease in the effect on the decrease in LDL cholesterol.

After oral administration at therapeutic doses of S (-), amlodipine is well absorbed, reaching C max after 6-12 hours.Bioavailability reaches 64-80%. The distribution volume is approximately 21 l / kg. Approximately 97.5% of S (-) amlodipine binds to plasma proteins. The intake of food does not affect the absorption of S (-) amlodipine.

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

Distribution of atorvastatin. The average volume of atorvastatin distribution is approximately 381 liters. More than 98% of the drug binds to blood plasma proteins. The ratio of erythrocyte / plasma ratio is approximately 0.25, which indicates a weak penetration of the drug into erythrocytes.

Metabolism and excretion of S (-) amlodipine. Stand equilibrium concentration in blood plasma is achieved after 7-8 days of regular intake of S (-) amlodipine. S (-) amlodipine is extensively transformed in the liver with the formation of inactive metabolites. Output with urine 10% of the administered dose - in unchanged form, 60% - in the form of metabolites. The half-life of the plasma is approximately 35-50 hours, which allows prescribing the drug once a day.

Atorvastatin is metabolized to ortho- and para-hydroxylated derivatives and various beta-oxidized products. In vitro inhibition of HMG-CoA reductase due to ortho- and parahydroxylated metabolites is practically equal to that of atorvastatin. The inhibitory effect of the drug against HMG-CoA reductase is approximately 70% realized by the activity of circulating metabolites. The results of in vitro studies have shown the importance of cytochrome P450AA4 for the metabolism of atorvastatin, which may affect the increase in the concentration of atorvastatin in human plasma as a result of simultaneous use with erythromycin, an inhibitor of the enzyme. In vitro studies also found that atorvastatin is a weak inhibitor of cytochrome P450 3A4. Simultaneous use of atorvastatin and terfenadine - a compound that is mainly metabolized by cytochrome P450 3A4 - did not produce a significant effect of increasing the concentration of terfenadine in the blood plasma. It is unlikely that atorvastatin will significantly alter the pharmacokinetics of other cytochrome P450 substrates. Atorvastatin and its metabolites are excreted mainly with bile as a result of hepatic and / or extrahepatic metabolism. However, the preparation does not undergo significant enterohepatic recirculation. The half-life of atorvastatin is approximately 14 hours, but the average period of inhibitory activity against 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.

Liver failure. The level of concentration of atorvastatin in plasma significantly increases (C max about 16 times, and AUC - 11 times) in patients with alcoholic cirrhosis of the liver (degree of severity according to the Child-Pugh class, class B).

Renal failure. Changes in the plasma concentration of S (-) amlodipine do not correlate with the degree of renal failure.S (-) amlodipine is not excreted by hemodialysis.

Kidney disease does not affect the concentration in the blood plasma of atorvastatin or its effect on lipids, so adjust the dose of atorvastatin for patients with impaired renal function is not required.

Floor. The level of concentration of atorvastatin in blood plasma in women differs from the level of plasma concentration in men (about 20% higher for C max and 10% less for AUC). However, there was no clinically significant difference in the effect on lipids in men and women.

Patients of advanced age. The time to reach the equilibrium concentration of S (-) amlodipine in the blood plasma is similar to that in elderly patients and adults.

Clearance of S (-) amlodipine. In elderly patients and patients with congestive heart failure, there is a tendency to decrease the clearance of S (-) amlodipine, which leads to an increase in AUC and half-life of the drug. Identical doses of S (-) amlodipine were well tolerated by both young and elderly patients.

The level of concentration of atorvastatin in blood plasma in healthy elderly (over 65 years) is higher (about 40% for C max and 30% for AUC) than for young people.

Indications

To prevent cardiovascular disorders in patients with hypertension with three concomitant factors of cardiovascular risk: with normal to moderately elevated cholesterol levels, without clinical manifestations of coronary heart disease, when the combined use of S (-) is deemed appropriate according to the current treatment guidelines, Amlodipine and a low dose of atorvastatin.

In case of ineffectiveness of diet and other non-pharmacological measures.

Contraindications

• Hypersensitivity to dihydropyridines, active amlodipine and atorvastatin or other excipients;
• active liver diseases or constantly elevated serum transaminases for an unknown reason, which is 3 times higher than the upper limit of the norm;
• combinations with itraconazole, ketoconazole and telithromycin;
• severe arterial hypotension
• shock (including cardiogenic shock);
• obstruction of the outflow pathway of the left ventricle (eg, aortic stenosis of a high degree)
• hemodynamically unstable heart failure after acute myocardial infarction
• in patients with unstable angina and within 8 days after myocardial infarction
• pregnancy and lactation;
• age to 18 years.

Interaction with other drugs and other interactions

Interactions associated with a combination drug.

Data on the study of drug interactions, which included the administration of 10 mg of amlodipine and 80 mg of atorvastatin in healthy subjects, suggest that the pharmacokinetics of amlodipine do not change when these drugs are taken together. No effect of amlodipine on C max of atorvastatin has been demonstrated, but atorvastatin AUC in the presence of amlodipine increased by 18% (CI 90% [109-127%]).

Studies of the drug interaction of the combination of amlodipine and atorvastatin with other drugs have not been carried out, although studies have been conducted on individual amlodipinovim and atorvastatinov components, as described below.

Interactions associated with amlodipine.

Incompatible (not recommended) combinations.

Dantrolene (infusion). The animals had ventricular fibrillation with a fatal outcome and cardiovascular collapse, which was associated with hyperkalemia, after the administration of verapamil and dantrolene intravenously. Because of the risk of developing hyperkalemia, it is recommended to avoid the use of calcium channel blockers, such as amlodipine, prone to malignant hyperthermia in patients and in the treatment of malignant hyperthermia.

Extrapolation concluded that combination of amlodipine and dantrolene should be avoided.

Combinations that require caution.

Baclofen: enhances the hypotensive effect. It is necessary to monitor blood pressure and adjust if necessary the dose of an antihypertensive drug.

CYP 3A4 inhibitors: simultaneous use of amlodipine with strong or moderate inhibitors of CYP 3A4 (protease inhibitors, antimycotics of the azole group, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) can cause a significant increase in the action of amlodipine. The clinical shift of these changes in pharmacokinetics may be more pronounced in elderly patients. Therefore, there may be a need for clinical monitoring and dose adjustment.

Inductors CYP 3A4.

Information on the effect of CYP 3A4 inducers on amlodipine is not available. The simultaneous use of amlodipine and substances that are inducers of CYP 3A4 (for example, rifampicin, St. John's wort), can lead to a decrease in the concentration of amlodipine in the blood plasma, so use such combinations with caution.

It is not recommended to use amlodipine together with grapefruit or grapefruit juice, as some patients can increase its bioavailability, which will lead to an increase in the hypotensive effect.

Combinations that should be considered.

Alpha-1-blockers in urology (prazosin, alfuzozin, doxazosin, tamsulosin, terazosin): increased hypotensive effect. The risk of severe orthostatic hypotension.

Amifostin: increased hypotensive effect through additional side effects.

Imipraminovye antidepressants, neuroleptics: increased antihypertensive effect and risk of orthostatic hypotension (additive effect).

Beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol) in patients with latent or uncontrolled cardiac failure risk of hypotension and heart failure (in vitro: negative inotropic effect of dihydropyridines that varies depending on the drugs which can increase the negative inotropic effect of beta blockers). Treatment of a beta-blocker can minimize pretty reflex reaction which is operated at excessive hemodynamic reperkusii.

Corticosteroids, tetracosactide: reduced antihypertensive effect (effect of corticosteroids on detention of water and sodium).

Other antihypertensive agents: amlodipine simultaneous use with other antihypertensive agents (beta-blockers, blockers of angiotensin II, diuretics, ACE inhibitors) may enhance the hypotensive effect of amlodipine. Treatment trinitrate, nitrates or other vasodilators requires caution.

Sildenafil: a single dose of 100 mg sildenafil for hypertension had no effect on the pharmacokinetic parameters of amlodipine. When amlodipine and sildenafil were used in combination, each of the drugs were his independent hypotensive effect.

Tacrolimus.

There is a risk of increase tacrolimus levels in the blood while the use of amlodipine, but pharmacokinetic mechanism of this interaction is not fully set. To avoid the toxicity of tacrolimus with simultaneous application of amlodipine need regular monitoring of tacrolimus in the blood and, if appropriate, dose adjustment.

Cyclosporine.

Studies interactions of cyclosporine and amlodipine when applied to healthy volunteers and the other groups was not performed, except that the patients with kidney transplant, in which there was an increase of residual volatile concentrations of cyclosporine (an average of 0-40%). For patients with a transplanted kidney, which is used amlodipine, consider monitoring cyclosporine concentration and, if necessary, reduce the dose of cyclosporin.

Simvastatin.

The simultaneous use of multiple doses of amlodipine and 10 mg simvastatin 80 mg resulting in increased exposure of simvastatin by 77% compared with the application of simvastatin. For patients who apply amlodipine, simvastatin dose should be limited to 20 mg per day.

Interactions related to atorvastatin.

The risk of myopathy during treatment with statins is increased in the case of simultaneous use of fibric acid derivatives, lipidomodifikatsiynih doses of niacin, cyclosporin or potent inhibitors of CYP 3A4 (e.g. clarithromycin, HIV protease inhibitors and itraconazole).

Potent inhibitors of CYP 3A4. Atorvastatin is metabolized by cytochrome P450 3A4. Simultaneous use of atorvastatin with potent CYP 3A4 inhibitor may lead to increased concentrations of atorvastatin in the blood plasma. The degree of interaction and potentiation of dependent variation effects on CYP 3A4. It is possible to avoid the simultaneous application of potent inhibitors of CYP 3A4 (e.g. cyclosporin, telithromycin, clarithromycin, delavirdine, stiripentolom, ketoconazole, voriconazole, itraconazole, posaconazole and HIV protease inhibitors including ritonavir, lopinavir, atazanavir, indinavir, darunavir). If it is impossible to avoid the simultaneous application of these drugs with atorvastatin should consider applying a lower initial and maximum doses of atorvastatin.Also recommended adequate clinical patient monitoring. Moderate inhibitors of CYP 3A4 (e.g. erythromycin, diltiazem, verapamil and fluconazole) can increase the concentration of atorvastatin in plasma. Concomitant use of erythromycin and statins is accompanied by an increased risk of myopathy. Investigation of the interaction of drugs to assess the influence of amiodarone or verapamil on atorvastatin not conducted. It is known that amiodarone, and verapamil inhibit the activity of CYP 3A4, and therefore co-administration of these drugs with atorvastatin may result in increased exposure of atorvastatin. Thus, while the use of atorvastatin and these moderate CYP 3A4 inhibitors should consider destination lower maximum doses of atorvastatin.Also clinical patient monitoring is recommended. After initiation of treatment or inhibitor after correction its dose recommended clinical patient monitoring.

Grapefruit juice. Comprises one or more components which inhibit CYP 3A4 and can increase the concentration of atorvastatin in plasma, especially when excessive consumption of grapefruit juice (more than 1.2 liters per day).

Clarithromycin. Meaning atorvastatin AUC increased significantly while applying atorvastatin 80 mg and clarithromycin (500 mg twice per day) as compared to using only atorvastatin. Thus, patients who take clarithromycin, should be used with caution atorvastatin 20 mg.

A combination of protease inhibitors. Meaning atorvastatin AUC increased significantly, while the application of atorvastatin with several combinations of HIV protease inhibitors, as well as with an inhibitor of hepatitis C virus protease telaprevir as compared to using only atorvastatin. Therefore, for patients taking HIV protease inhibitor ritonavir, tipranavir + or an inhibitor of hepatitis C virus protease telaprevir, avoid the simultaneous application of the drug Amlostat. The drug should be used with caution in patients who are taking an HIV protease inhibitor lopinavir + ritonavir and apply the most necessary dose. For patients taking HIV protease inhibitors ritonavir + saquinavir, ritonavir + darunavir, fosamprenavir + ritonavir or fosamprenavir,atorvastatin dose should not exceed 20 mg, and used with caution. When applied in patients taking HIV protease inhibitor nelfinavir or an inhibitor of hepatitis C virus protease boceprevir, atorvastatin dose should not exceed 40 mg, and recommends a thorough clinical patient monitoring.

Itraconazole.Meaning atorvastatin AUC increased significantly, while the application of atorvastatin 40 mg itraconazole and 200 mg. Thus, patients taking itraconazole should be cautious when atorvastatin dose exceeds 20 mg.

Cyclosporine. Atorvastatin and its metabolites are substrates of OATP1B1 transporter. OATP1B1 inhibitors (e.g. Ciclosporin) may increase the bioavailability of atorvastatin. Meaning atorvastatin AUC increased significantly, while the application of atorvastatin and 10 mg cyclosporin in a dose of 5.2 mg / kg / day as compared to using only atorvastatin. Avoid the simultaneous application Amlostat and cyclosporine.

Medical recommendations for the use of drugs interacting summarized in Table 1.

Table 1.

Drug interactions associated with an increased risk of myopathy / rhabdomyolysis.

Drugs that interact	Medical recommendations for application
Cyclosporin, HIV protease inhibitors (tipranavir + ritonavir), an inhibitor of hepatitis C virus protease (telaprevir)	Avoid the use of atorvastatin
HIV protease inhibitor (lopinavir + ritonavir)	Be used with caution and at the required dose
Clarithromycin, itraconazole, HIV protease inhibitors (saquinavir, ritonavir + * + ritonavir, darunavir, fosamprenavir, ritonavir, fosamprenavir +)	Exceed the dose of 20 mg of atorvastatin per day
HIV protease inhibitor (nelfinavir) Protease inhibitor of hepatitis C virus (boceprevir)	Exceed 40 mg atorvastatin dose per day

* Use with caution and at lower dose required.

Gemfibrozil. Due to the increased risk of myopathy / rhabdomyolysis while taking inhibitors of HMG-CoA reductase inhibitor with gemfibrozil avoid joint use drug Amlostat with gemfibrozil.

Other fibrates. Since it is known that the risk of myopathy during treatment with HMG-CoA reductase increases while receiving other fibrates Amlostat should be used with caution when combined with other fibrates.

Niacin. The risk of side effects from the skeletal muscle may be increased by use of atorvastatin in combination with niacin, and hence under these conditions should be considered the possibility of reducing the dose of atorvastatin.

Rifampicin or other inducers of cytochrome P450 3A4. Simultaneous use of the drug Amlostat with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampicin) can lead to an unstable reduction atorvastatin plasma concentration. Through the mechanism of interaction of rifampin dual simultaneous application Amlostat rifampin, since it has been shown that delayed administration of the preparation after administration of rifampin is associated with a significant reduction of atorvastatin concentrations in plasma.

Diltiazem hydrochloride.

Simultaneous treatment with atorvastatin (40 mg), and diltiazem (240 mg) was accompanied by increased concentrations of atorvastatin in the blood plasma.

Cimetidine.

As a result of evidence of studies of the interaction of cimetidine and atorvastatin was not revealed.

Antacids.

Simultaneous atorvastatin and oral antacid formulation a suspension containing magnesium and aluminum hydroxide, accompanied by a decrease in blood plasma concentration of atorvastatin for 35%. In this case, lipid-lowering effect of atorvastatin unchanged.

Kolestipol.

plasma concentration of atorvastatin lower (approximately 25%), while taking atorvastatin and colestipol. Thus hypolipidemic effect of the combination of atorvastatin and colestipol exceed effect, which allows the reception of each of the drugs individually.

Azithromycin.

Simultaneous administration of atorvastatin (10 mg 1 time per day) and azithromycin (500 mg 1 time per day) was not accompanied by changes in the concentration of atorvastatin in plasma.

Inhibitors of transport proteins.

Inhibitors of transport proteins (e.g. cyclosporin) can increase the level of systemic exposure of atorvastatin. The effect of suppressing accumulation of transport proteins on the concentration of atorvastatin in liver cells is unknown. If you avoid the simultaneous administration of these drugs can not be recommended to decrease the dose and clinical monitoring of the effectiveness of atorvastatin.

Ezetimibe.

The use of ezetimibe as a monotherapy has been associated with effects from the musculoskeletal system, including rhabdomyolysis. Thus, while the use of ezetimibe and atorvastatin risk of these events is increased. It is recommended to carry out appropriate clinical monitoring of these patients.

Fusidic acid.

interaction and atorvastatin acid fuzidovoi study were not conducted. As is the case with other statins, a post-marketing period while taking atorvastatin and fuzidovoi acid phenomena observed by the muscular system (including rhabdomyolysis). The mechanism of this interaction is unknown. Patients need to be carefully monitored, may require the temporary suspension of treatment with atorvastatin.

Digoxin.With simultaneous use of multiple doses of atorvastatin and digoxin Digoxin equilibrium plasma concentrations increased by approximately 20%. It is necessary to properly monitor the status of patients taking digoxin.

Oral contraceptives.Simultaneous use of atorvastatin with oral contraceptives increased the AUC value for ethinylestradiol and norethisterone. These increases should be considered when selecting an oral contraceptive for a woman who takes Amlostat.

Warfarin. Atorvastatin had no clinically significant effect on prothrombin time when used in patients receiving long-term warfarin therapy.

Colchicine. With simultaneous use of atorvastatin with colchicine reported cases of myopathy, including rhabdomyolysis, should therefore be used with caution atorvastatin with colchicine.

Other drugs.

Clinical studies have shown that the concurrent use of atorvastatin and antihypertensive drugs and their use in the course of estrogen replacement therapy was not associated with clinically significant side effects. Interaction studies with other drugs have not been conducted.

Application features

Patients with heart failure.

Patients with congestive heart failure Calcium channel blockers, including amlodipine, should be used with caution as they may increase the risk of cardiovascular events and deaths in the future.

Patients with impaired liver function.

These patients should begin use of the drug at a low dose. It should be careful at the beginning of the drug, and by increasing the dose.

Patients of advanced age.

Increase the dose of the drug in these patients with caution.

Patients with renal insufficiency.

These patients should use the usual dose. Changes in amlodipine plasma concentrations are not correlated with the degree of renal dysfunction. Amlodipine is not removed by dialysis.

Amlodipine does not affect the results of laboratory tests.

Not recommended for use with amlodipine with grapefruit or grapefruit juice, as some patients bioavailability can be increased, which will result in increased hypotensive effect of the drug.

Fertility.

It reported current biochemical changes in the sperm head in some patients when used calcium channel blockers. Clinical information about the potential effect of amlodipine on fertility is not enough.

Effect on the liver. Results liver tests necessary to determine before the beginning of treatment, periodically after treatment, as well as patients who show any signs or symptoms suggestive of liver injury. In the case of elevated levels of transaminases is necessary to conduct their monitoring to the normalization of.

If found elevated levels of ALT or AST by more than 3 times more than the upper limit of normal (ULN), treatment should be stopped.

Due to the presence of the atorvastatin component, the drug should be used with caution in patients who consume alcohol in significant amounts, patients with hepatic insufficiency and / or liver disease in the history.

There are rare post-registration reports of cases of lethal and non-lethal hepatic insufficiency in patients taking drugs of the statin group, including atorvastatin. In case of severe liver damage with clinical symptoms and / or hyperbilirubinemia or jaundice with the drug Amlostat should be discontinued immediately. If an alternative etiology is not defined, do not re-initiate treatment with the drug.

Influence on skeletal muscles. Like other HMG-CoA reductase inhibitors, atorvastatin can affect skeletal muscle and cause myalgia, myositis, and myopathies, which can sometimes progress to acute skeletal muscle necrosis, which is characterized by markedly elevated levels of CKM (more than 10 times the upper limit of normal ), myoglobinemia and myoglobinuria, which can lead to kidney failure and in rare cases can be lethal.

In the absence of symptoms in patients who are treated with statins, regular monitoring of the level of CKK or other muscle enzymes is not recommended. For patients with risk factors for acute necrosis of skeletal muscles and patients with muscle symptoms, monitoring of CPK is recommended before starting any treatment with statins, as well as in the treatment of statins (see below).

Before treatment.

Patients with a tendency to acute necrosis of skeletal muscle drug should be administered with caution. Before starting treatment with statins, the level of CK should be measured in the following cases:

• elderly people (from 70 years);
• with renal insufficiency
• hypothyroidism;
• in hereditary muscle disorders in a personal or family history
• with muscular toxicity associated with the use of statins or fibrates in an anamnesis
• at abusing alcohol.

In such cases, it is necessary to analyze the risk in comparison with a possible positive effect and conduct clinical monitoring.

If at the initial stage, the level of CK is significantly increased (more than 5 times higher than the upper limit of the norm), treatment can not be started.

Measurement of CK.

You can not measure CK after intensive physical exertion or if there is any other reason for a possible increase in CK, as this makes it difficult to interpret the results. If the levels of CK at the initial stage are significantly increased (more than 5 times higher than the upper limit of the norm), they must be systematically measured after 5-7 days to confirm the results. If the level of CK is confirmed, which is 5 times higher than the initial stage, treatment can not be started.

During treatment.

Patients should immediately report muscle pain, muscle cramps, or weakness for unexplained reasons, especially if these symptoms are accompanied by weakness or fever.

If such symptoms occur during treatment, it is necessary to measure the level of CK. If it turns out that this level is significantly elevated (more than 5 times the upper limit of the norm), treatment should be stopped.

If the muscle symptoms are severe and cause daily discomfort, it is necessary to consider cessation of treatment, even if elevated levels of CK do not exceed ULN less than 5-fold.

If the symptoms have disappeared and the CK levels have returned to normal, you may consider re-administering the drug with careful monitoring.

Therapy Amlostat should be temporarily or completely discontinued in any patient with an acute, serious condition, indicates the development of myopathy, or if there is a risk factor for developing renal failure due to rhabdomyolysis (eg severe acute infection, arterial hypotension, surgery, trauma, severe metabolic, endocrine and electrolytic disorders, as well as uncontrolled convulsions).

Prevention of stroke by aggressively lowering cholesterol levels (SPARCL).

For patients with a previous hemorrhagic stroke or lacunar infarction, the balance of risk and benefit with the use of 80 mg of atorvastatin is unknown, so before starting treatment, the potential risk of hemorrhagic stroke must be carefully analyzed.

Interstitial lung disease: for some statins, exceptional cases of interstitial lung disease have been reported, especially with prolonged treatment. Features of the manifestation may include shortness of breath, dry cough and deterioration in overall health (fatigue, weight loss and fever). If there is a suspicion that the patient develops interstitial lung disease, treatment with statins should be discontinued.

Endocrine function.

It is known about an increase in the level of HbA1c and the concentration of glucose in the blood serum fasting with the use of inhibitors of HMG-CoA reductase, including atorvastatin.

Statins interfere with the synthesis of cholesterol and theoretically can weaken the secretion of adrenal and / or gonadal steroids.

Caution should be exercised when using the drug group of statins simultaneously with drugs that may reduce the levels or activity of endogenous steroid hormones, such as ketoconazole, spironolactone and cimetidine.

The preparation contains lactose. If you have intolerance to some sugars, consult a doctor before taking this medication.

Use during pregnancy or lactation

Amlostat is contraindicated during pregnancy and lactation.

Pregnancy.

Women of reproductive age should take appropriate contraceptives.

Cholesterol and its derivatives are very important for the development of the fetus, therefore during pregnancy the potential risk of oppression of HMG-CoA reductase predominates over the benefit that is expected from statin treatment.

If pregnancy is detected during treatment, admission to Amlostat should be discontinued.

Breastfeeding.

It is not known whether amlodipine penetrates into breast milk, but as atorvastatin penetrates into breast milk, Amlostat is contraindicated during breastfeeding.

The ability to influence the reaction rate when driving vehicles or other mechanisms

There is no information about the influence of Amlostat on the ability to drive vehicles or work with other automated systems. However, on the basis of the pharmacological properties of the amlodipine component of the drug when driving vehicles or working with other automated systems, it is necessary to take into account the possibility of dizziness.

Dosing and Administration

The drug is intended for oral administration.

The initial dose is 2.5 mg / 10 mg once a day.

The drug can be taken at any time of the day with or without food.

Amlostat can be used alone or in combination with antihypertensive drugs, but it can not be used with another calcium channel blocker or with other statins.

It is necessary to avoid the combination of the drug with fibrates.

Patients with renal insufficiency for patients with impaired renal function are not required to adjust the dose.

Patients with hepatic insufficiency the drug is contraindicated in patients with active liver disease.

Elderly patients do not need dose adjustment.

Children

Safety and effectiveness of the drug in children are not established, so it is not recommended to assign this age category of patients.

Overdose

Information on the overdose of the combination S (-) amlodipine / atorvastatin is absent.

Data for amlodipine.

The experience of deliberate overdose of amlodipine is limited.

Symptoms of overdose: the available information gives grounds to believe that a significant overdose of amlodipine will lead to excessive peripheral vasodilation and, possibly, reflex tachycardia. A significant and possibly prolonged systemic hypotension has been reported, including a fatal shock.

Treatment of clinically significant hypotension due to an overdose of amlodipine requires active support of cardiovascular activity, including frequent monitoring of heart and respiratory function, increased lower extremities, monitoring of circulating fluid volume and urination.

To restore the vascular tone and arterial pressure, vasoconstrictive drugs can be used, making sure that there are no contraindications to their use. The use of calcium gluconate intravenously can be useful for leveling the effects of calcium channel blockade.

In some cases, gastric lavage may be beneficial. The use of activated carbon in healthy volunteers within 2 hours after the administration of 10 mg of amlodipine significantly reduced the level of its absorption.

Since amlodipine of high degree binds to proteins, the dialysis effect is insignificant.

Data for atorvastatin.

There is no specific treatment for overdose of atorvastatin. In cases of drug overdose, symptomatic and supportive therapy should be provided if necessary. It is necessary to conduct functional tests of the liver and monitor the level of CC in the blood serum. Because atorvastatin extensively binds to blood plasma proteins, hemodialysis can not significantly increase the clearance of atorvastatin.

Adverse Reactions

Data for amlodipine.

On the part of the blood system and lymphatic system: leukopenia, thrombocytopenia, purpura, anemia, agranulocytosis.

From the immune system: allergic reactions.

Metabolic disorders: hyperglycemia, thirst, weight gain, weight loss.

On the part of the psyche: insomnia, nervousness, mood changes (including anxiety, fear), depression, confusion, loss of consciousness, sleep disturbance, depersonalization.

From the nervous system: drowsiness, dizziness, headache (mainly at the beginning of treatment), tremor, dysgeusia, syncope, hypesthesia, paresthesia, hypertonia, peripheral neuropathy, extrapyramidal symptoms.

From the side of the organ of vision: visual impairment (including diplopia), conjunctivitis, pain in the eyes.

From the organs of hearing and the labyrinth: ringing in the ears, noise in the ears, tinnitus.

From the heart: tachycardia, tachycardia, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation, atrial fibrillation), angina attacks, orthostatic (postural) hypotension, collapse, chest pain, fainting, palpitation of the heart.

From the vessels: hyperemia, hot flashes, arterial hypotension, vasculitis, peripheral ischemia.

On the part of the respiratory system: dyspnea, rhinitis, cough, nosebleeds.

On the part of the gastrointestinal tract: anorexia, loss of appetite, discomfort in the epigastric region, abdominal pain, nausea, vomiting, dyspepsia, violation of intestinal motility (including constipation and diarrhea), flatulence, intestinal dysfunction, dry mouth, dysphagia, pancreatitis, gastritis, gingival hyperplasia, changes in taste, hypertrophic gingivitis.

On the part of the digestive system: hepatitis, jaundice, increased levels of hepatic enzymes (most often associated with cholestasis), hyperbilirubinemia, impaired liver function.

From the skin and subcutaneous tissue: alopecia, purpura, skin discoloration, skin pigmentation disorder, increased sweating, itching, rash, exanthema, angioedema, erythema multiforme, skin rash, maculopapular rash, urticaria, exfoliative dermatitis, Stevens Johnson syndrome, edema Quincke, photosensitization.

From the musculoskeletal and connective tissues: edema of the shins, arthralgia, myalgia, muscle cramps, back pain, back pain, muscle stiffness, joint swelling (including ankle swelling).

From the side of the kidneys and urinary tract: violation of urination, nocturia, increased frequency of urination.

On the part of the reproductive system and mammary glands: impotence, gynecomastia, sexual dysfunction.

General disorders and conditions at the site of administration: edema, peripheral edema, fatigue, chest pain, chest pain, asthenia, pain, malaise, fever.

Changes in the results of laboratory tests: elevated levels of hepatic enzymes ALT, AST (mostly consistent with cholestasis).

Data for atorvastatin.

On the part of the blood system and lymphatic system: thrombocytopenia.

From the side of the immune system: allergic reactions, anaphylactic shock (including anaphylactic shock).

Metabolic disorders: hypoglycemia, hyperglycemia, anorexia, weight gain, diabetes.

From the side of the psyche: depression, sleep disturbances, including insomnia and nightmares.

From the side of the nervous system: headache, peripheral neuropathy, paresthesia, hypoesthesia, dizziness, dysgeusia, cognitive disorders (eg memory loss, amnesia, memory impairment, confusion) associated with the use of statins, stroke.

From the side of the organ of vision: blurred vision, blurred vision, visual impairment, visual acuity, visual impairment (including diplopia).

From the organs of hearing and the labyrinth: noise in the ears, ringing in the ears, loss of hearing.

On the part of the respiratory system: nasopharyngitis, epistaxis, interstitial lung disease, sore throat and larynx.

On the part of the digestive tract: dyspepsia, nausea, vomiting, belching, diarrhea, constipation, flatulence, abdominal pain, pain in the upper and lower abdominal areas, stomach pain, gastrointestinal discomfort, pancreatitis.

From the liver and gallbladder: hepatitis, cholestasis, cholestatic jaundice, lethal and non-lethal hepatic insufficiency.

From the skin and subcutaneous tissue: alopecia, itching, skin rashes, bullous eruptions (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)), urticaria, angioedema, Quincke's edema.

From the musculoskeletal system and connective tissue: myalgia, myopathy, including immunologically mediated necrotizing myopathy, acute necrosis of skeletal muscles, myositis, convulsions, muscle spasms, muscle weakness, fatigue of muscles, rhabdomyolysis, arthralgia, joint pain, pain back pain, back pain, pain in the extremities, musculoskeletal pain, neck pain, swelling of the joints (including ankle swelling), tendonopathy (sometimes difficult with a rupture of the tendon).

From the side of the kidneys and urinary tract: infection of the urinary tract, leukocyturia.

On the part of the reproductive system and mammary glands: a disorder of sexual function, impotence, gynecomastia.

Common disorders: malaise, asthenia, pyrexia, chest pain, edema, peripheral edema, increased fatigue, fever.

In school, poisoning and complications of procedures: a rupture of the tendon.

Infections and infestations: infections.

Changes in the results of laboratory tests: an increase in the level of transaminases and hepatic enzymes, deviations from the norm of functional liver samples, an increase in the level of alkaline phosphatase in the blood, an increase in the activity of the CKK of blood.

Shelf life

2 years.

Storage conditions

Store at a temperature of no higher than 25 ° C in the original packaging. Keep out of the reach of children.

Packaging

For 14 tablets in a blister pack, 1 or 2 or 4 or 6 blisters each in a cardboard box.

Category of leave

On prescription.