for medical use of drug
active substance: 1 tablet contains S(-)amlodipine besylate equivalent to S(-)amlodipine 2.5 mg; atorvastatin calcium equivalent to atorvastatin 10 mg;
excipients: microcrystalline cellulose, lactose monohydrate, calcium carbonate, hypromellose, сroscarmellose sodium, colloidal anhydrous silica, magnesium stearate, Opadry 04F82783 yellow: polyethylene glycol, hypromellose, titanium dioxide (Е 171), iron oxide yellow (Е 172).
Pharmaceutical form. Coated tablets.
Main physico-chemical properties: round, biconvex, smooth on both sides coated tablets of yellow color..
Pharmacotherapeutic group. ATC code. C10B X03.
Hypolipidemic agents. Combinations. HMG CoA reductase inhibitors, other combinations.
Amlostat® is a combined drug which contains two medical agents: dihydropyridine calcium antagonist S(-)amlodipine and HMG-CoA reductase inhibitor atorvastatin. In this combination S(-)amlodipine is a slow calcium channel blocker in cell membranes in the smooth muscle fibers of blood vessels and heart; atorvastatin has a strong selective inhibitory effect on HMG-CoA reductase, a key enzyme converting HMG-CoA in mevalonate, a substance that is a precursor of sterols, including cholesterol.
The mechanism of antihypertensive action of S(-)amlodipine consists in relaxation of smooth muscle fibers of blood vessels. S(-)amlodipine a) is a peripheral arterial vasodilator, it decreases TPR (afterload). As the heart rate does not change, reducing the load on the heart leads to lower consumption of energy and myocardial oxygen demand; b) promotes dilatation of large coronary arteries and coronary arterioles in unchanged and in ischemic areas of myocardium. This dilatation increases the flow of oxygen to the myocardium in patients with vasospastic angina (Prinzmetal's angina or variant angina) and prevents coronary vasoconstriction.
In patients with arterial hypertension, single dose of S(-)amlodipine provides clinically significant reduction in arterial blood pressure for 24 hours in a prone position as well as standing. Due to slow beginning of action, S(-)amlodipine does not cause acute arterial hypotension. In patients with angina S (-) amlodipine enhances exercise tolerance, reduces the incidence of strokes and the need for taking nitroglycerin tablets.S (-) amlodipine does not cause metabolic disorders or changes in plasma lipids, so the drug can be administered in patients with asthma, diabetes or gout.
Atorvastatin is a strong HMG-CoA reductase inhibitor, which regulates the rate of converting HMG-CoA in mevalonate, a substance that is a precursor of sterols (including cholesterol). In patients with homozygous and heterozygous hereditary and non-hereditary form of hypercholesterolemia and mixed dyslipidemia, atorvastatin reduces the concentration of total cholesterol, LDL-C and apolipoprotein B, VLDL-C and TG concentrations, and slightly increases HDL-C level. It also reduces plasma levels of cholesterol due to inhibition of HMG-CoA reductase and cholesterol synthesis in liver, and increased number of hepatic LDL receptors on the cell surface, which leads to increasing capture and catabolism of LDL.
Atorvastatin decreases LDL synthesis and reduces the number of LDL particles. It causes pronounced and stable increased in LDL-receptors activity in combination with positive changes in quality of circulating LDL-particles.Atorvastatin reduces LDL in patients with homozygous hereditary hypercholesterolemia, in whom conventional therapy with hypolipidemic means is often ineffective.
In human models atorvastatin shows pharmacological activity as well as some of its metabolites.The primary site of effect of atorvastatin is the liver that plays a central role in cholesterol synthesis and clearance of LDL. Decrease in LDL-C correlates with the drug dose and concentration. Individual dosage adjustment is based at therapeutic efficacy.
Atorvastatin (10-80 mg) decreases total cholesterol level (30-46%), LDL-C (41-61%); apolipoprotein B (34-50%) and T (14-33). Such result is stable in patients with heterozygous hereditary and non-hereditary forms of hypercholesterolemia and mixed hyperlipidemia form, including patients with insulin dependent diabetes mellitus.
In patients with isolated hypertriglyceridemia, atorvastatin reduces total cholesterol, LDL-C, VLDL-C, apolipoprotein B, TG, LDL-C, and increases LDL-C. In patients with dysbetalipoproteinemia, atorvastatin reduces LDL-C. In patients with hyperlipoproteinemia type IIa and IIb according to Fredrickson, the average proportion of increase in HDL-C in the application of atorvastatin 10–80 mg is 5.1-8.7% regardless of dose. Besides, there is a significant dose-dependent reduction in ratio of total cholesterol/HDL-C and LDL-C/HDL-C.
The effect of atorvastatin 80 mg/day for 16 weeks on the occurrence of ischemia and total mortality in patients with unstable angina or myocardial infarction without Q wave is pronounced by significant reduction in risk of myocardial ischemia and mortality, re-hospitalization for angina and myocardial ischemia confirmed. Atorvastatin reduces the risk of ischemia and fatal outcome in inverse proportion to LDL-C concentration, the risk of ischemia and fatal outcome in patients with myocardial infarction without Q wave and unstable angina patients equally in both sexes under the age of 65 years and older.
Atorvastatin significantly decreases the incidence of fatal cardiovascular disease and non-lethal myocardial infarction, the overall frequency of cardiovascular diseases, the frequency of fatal and non-lethal stroke; it reduces the need for revascularization of the myocardium. When using atorvastatin total mortality due to cardiovascular diseases had slightly reduced.The effect of therapy did not depend on sex, age or baseline LDL-C level.
Absorption. Oral administration of S(-)amlodipine/atorvastatin combination produces two peak plasma concentrations. The first peak within 1-2 hours after intake is associated with atorvastatin; the second peak within 6-12 hours after the intake is associated with S(-)amlodipine. There is no difference between the absorption rate (bioavailability) of S(-)amlodipine and atorvastatin within the combination of S(-)amlodipine/atorvastatin and bioavailability of S(-)amlodipine and atorvastatin taken separately in form of tablets, which can be seen from the values of maximum plasma concentration (Сmах) 101% and area under the curve “concentration-time” (AUC) 100% for S(-)amlodipine within the combination of S(-)amlodipine/atorvastatin, and Сmах 94% and AUC 105% for atorvastatin within the combination of S(-)amlodipine/atorvastatin. The bioavailability of S(-)amlodipine within the combination of S(-)amlodipine/atorvastatin was not decreased when taking it after meal, which is confirmed by Сmах 105% and AUC 101% compared to the values when taking the drug without meal. However, food decreases the rate and extent of absorption of atorvastatin when using the combined drug by almost 32% and 11%, respectively, which is confirmed by Сmах 68% and AUC 89% compared to the values when taking the drug without meal. Similar decrease in plasma concentration when using atorvastatin after meal is seen in monotherapy, but it is not accompanied by a reduction in effect on decrease of LDL-C.
After oral administration of therapeutic doses of S(-)amlodipine, it is well absorbed, Сmax is reached within 6-12 hours. Absolute bioavailability is 64-80%. The volume of distribution is about 21 L/kg. About 97.5% of S(-)amlodipine is bound with plasma proteins. Food does not affect absorption of S(-)amlodipine.
After oral administration, atorvastatin is rapidly absorbed; its Сmах in plasma is reached within 1-2 hours. Absorption and plasma concentration increases in proportion to the dose of the drug. The bioavailability of atorvastatin tablets is 95-99% compared to solution. the absolute bioavailability of atorvastatin is about 12%, and systemic availability of inhibitory activity aimed at HMG-CoA reductase is about 30%. Low systemic bioavailability is associated with presystemic clearance in gastrointestinal mucosa and/or biotransformation on first passage through the liver. Despite the fact that the proportion and extent of absorption of the drug is reduced when taken with food by about 25% and 9% (by Сmах and AUC), respectively, reduction of LDL-C did not depend on taking atorvastatin with or without food.When taking atorvastatin in the evening, its concentration in plasma is lower (about 30% for Сmах and AUC) than when taking it with food. However, decrease of LDL-C level does not depend on the hours of taking the drug.
Distribution of atorvastatin. The average volume of distribution is about 381 L. more than 98% of the drug is bound to plasma proteins. An erythrocyte/plasma ratio of approximately 0.25 indicates poor drug penetration into erythrocytes.
Metabolism and excretion of S(-)amlodipine. Stable steady-state plasma concentration is achieved after 7-8 days of regular administration of S(-)amlodipine. S (-) amlodipine is extensively transformed in the liver to form inactive metabolites. It is excreted with the urine: 10% of the excreted dose is unchanged, 60% is in the form of metabolites. Plasma half-life is about 35-50 hours, which allows taking the drug 1 time per day. Atorvastatin is extensively metabolized to ortho- and parahydroxylated derivatives and various beta-oxidation products. In vitro inhibition of HMG-CoA reductase by ortho- and parahydroxylated metabolites is equivalent to that of atorvastatin. Approximately 70% of circulating inhibitory activity for HMG-CoA reductase is attributed to active metabolites. In vitro studies suggest the importance of atorvastatin metabolism by cytochrome P450 3A4, consistent with increased plasma concentrations of atorvastatin in humans following co-administration with erythromycin, a known inhibitor of this enzyme. In vitro studies have also shown that atorvastatin is a weak inhibitor of cytochrome P450 3A4. Co-administration of atorvastatin and terfenadine (a compound, mainly metabolized by P450 3A4) had no significant effect of increasing concentrations of terfenadine in plasma. Atorvastatin is not likely to significantly alter pharmacokinetics of other substrates of cytochrome P450 3A4. Atorvastatin and its metabolites are eliminated primarily in bile following hepatic and/or extra-hepatic metabolism. However, the drug does not appear to undergo enterohepatic recirculation. Mean plasma elimination half-life of atorvastatin in humans is about 14 hours, but the half-life of inhibitory activity for HMG-CoA reductase is 20 to 30 hours due to the contribution of active metabolites. Less than 2% of a dose of atorvastatin is recovered in urine following oral administration.
Hepatic failure. Plasma concentration of atorvastatin is significantly increased (Сmах 16-fold, and AUC 11-fold) in patients with alcoholic cirrhosis (Child-Pugh class B).
Renal failure. Changes in plasma concentration of S(-)amlodipine do not correlate with the level of renal failure. S(-)amlodipine is not excreted in hemodialysis.
Kidney diseases do not affect plasma concentration of atorvastatin or its effect on lipids, therefore, there is no need to change the concentration of atorvastatin for patients with impaired renal function.
Sex.Plasma concentration of atorvastatin in women is different from plasma concentration in men (by about 20% higher for Сmах and by 10% less by AUC). However, no clinically significant differences in the effects on lipids were found in men and women.
Elderly patients. Time before reaching the equilibrium plasma concentrations of S(-)amlodipine is equal in elderly and younger patients.
Clearance of S(-)amlodipine. In elderly patients and in patients with congestive heart failure there is a tendency to decrease clearance of S(-)amlodipine, which leads to an increase in AUC and half-life of the drug. Equal doses of S(-)amlodipine were well tolerated both by elderly and younger patients.
Plasma concentrations of atorvastatin in healthy elderly subjects (age ≤ 65 years) were higher than in young adults (about 40 for Сmax for AUC).
Prophylaxis of cardiovascular disorders in patients with arterial hypertension with three concomitant factors of cardiovascular risk: cholesterol levels from normal to moderately elevated, with no clinical manifestations of coronary heart disease, when according to current guidelines for treatment, the use of S(-)amlodipine or low dose atorvastatin is considered appropriate
In case of inefficacy of diet and other non-pharmacological measures.
Hypersensitivity to dihydropyridines, active substances amlodipine and atorvastatin or any other excipients;
active liver diseases, or elevated for unknown reason level of serum transaminases, which is 3 times the upper limit of normal;
combinations with itraconazole, ketoconazole and telithromycin
severe arterial hypotension;
shock (including cardiogenic shock);
obstruction of the left ventricular outflow tract (severe aortic stenosis);
hemodynamically unstable heart failure after acute myocardial infarction;
in patients with unstable angina and within 8 days after myocardial infarction.
Drug interactions and other types of interactions.
Concomitant medical treatment
The combination of Amlostat® with dantrolene (infusion), gemfibrozil and other fibrates is not recommended.
As with other statins, the risk of acute necrosis of muscles and myopathies increases with co-administration of Amlostat® with some drugs which increase the plasma concentration of atorvastatin, such as immunosuppressors, such as: cyclosporine; macrolide antibiotics, such as: erythromycin; clarithromycin; azole antifungals, such as: itraconazole, ketoconazole, nefazodone; lipid-modifying dosages of niacin; gemfibrozil and other fibric acid derivatives or HIV protease inhibitors.
Combination of atorvastatin and fusidic acid is not recommended. When receiving treatment with fusidic acid, it may be advisable to discontinue atorvastatin.
Interactions related to the combination drug
Data from a drug interaction study involving 10 mg of amlodipine and 80 mg of atorvastatin in healthy volunteers, indicate that there are no changes in pharmacokinetics of amlodipine when co-administration of these drugs. No effect of amlodipine on Cmax atorvastatin was shown, but in the presence of amlodipine, AUC of atorvastatin increased by 18% (CI90% [109-127%]).
No studies of drug interaction between Amlostat® and other drugs have been performed, though there have been individual studies performed with amlodipine and atorvastatin, as described below:
Interactions related to amlodipine
Dantrolene (infusion): in animals, when intravenous administration of verapamil and dantrolene, lethal ventricular fibrillation was observed inevitably;
By extrapolation combination of amlodipine and dantrolene should be avoided.
Combinations requiring precaution
Baclofen:enhances the hypotensive effect. Arterial blood pressure should be monitored; and if necessary, the dose of hypotensive drug should be adjusted.
CYP3A4 inductors (anticonvulsant agents, such as carbamazepine, phenobarbital, phenytoin, fosphenytoin, primidone, rifampin): risk of reduction in levels of calcium channel blockers in plasma due to enhancement of hepatic metabolism by these inducers. Clinical monitoring should be performed. Dose adjustment of amlodipine in case of necessity is possible during treatment with these inducers and after stopping them.
Combination to be taken into account
Alpha-1- blockers in urology (prazosin, alfuzosin, doxazosin, tamsulosin, terazosin): increase in the hypotensive effect. Risk of severe orthostatic hypotension.
Amifostine: increase in the hypotensive effect by addition of adverse effects.
Imipramine antidepressants, neuroleptics: hypotensive effect and risk of increase in orthostatic hypotension (additive effect).
Beta-blockers in heart failure (bisoprolol, carvedilol, metoprolol): risk of arterial hypotension and heart failure in patients with latent or uncontrolled heart failure (in vitro negative inotropic effect of the dihydropyridines, variable depending on the products, which may add to the negative inotropic effects of beta-blockers). Treatment in the presence of beta-blockers can minimize the reflex sympathetic reaction set in case of excessive hemodynamic repercussion.
Corticosteroid, tetracosactide: decrease in the antihypertensive effect (water and sodium retention effect of the corticosteroids).
Other hypotensive dugs: concomitant use of amlodipine and another hypotensive drug (beta-blocker, angiotensin II blocker, diuretic, ACE inhibitor) can increase the hypotensive effect of amlodipine. Caution should be exercised when considering treatment with trinitrate, nitrates or other vasodilators.
Sildenafil: a single 100mg dose of sildenafil had no effect on the pharmacokinetic parameters of amlodipine in patients with idiopathic hypertension. When using a combination of amlodipine and sildenafil, each drug independently exerted its own blood pressure lowering effect.
In interaction studies it has also been shown that cimetidine, atorvastatin and aluminum/magnesium salts have not affected the pharmacokinetics of amlodipine
Interactions related to atorvastatin
Itraconazole, ketoconazole: increased risk of adverse effects (dose-dependent) such as acute necrosis of skeletal muscles (reduced metabolism of atorvastatin).
Telithromycin: increased risk of adverse effects (dose-dependent) such as acute necrosis of skeletal muscles (reduced metabolism of atorvastatin).
Gemfibrozil, and other fibrates: increased risk of adverse effects (dose-dependent) such as acute necrosis of skeletal muscles.
Combinations requiring precaution
Inhibitors of cytochrome P450 3A4: atorvastatin is metabolized by cytochrome P450 3A4. Interaction may occur when atorvastatin is administered with inhibitors of cytochrome P450 3A4 (e.g. immunosuppressive drugs, such as cyclosporine, macrolide antibiotics, e.g. erythromycin and clarithromycin, nefazodone, azole antifungals and HIV protease inhibitors). Co-administration can lead to increased plasma concentrations of atorvastatin. Therefore, when atorvastatin is used in combination with such drugs, special caution should be exercised.
In case if co-administration of atorvastatin and these drugs is considered advisable, it is necessary to analyze the risk/benefit ratio for such concomitant treatment. Therefore, when co-administration with the above mentioned drugs, lower starting and maintenance doses of atorvastatin should be considered.
Transporter inhibitors: atorvastatin and its metabolites are substrates of transporters that may be inhibited by concomitant medications, such as cyclosporine, which increases bioavailability of atorvastatin. Co-administration of atorvastatin 10 mg and cyclosporine 5.2 mg/kg/day resulted in a 7.7 fold increase in exposure to atorvastatin. In case if co-administration of atorvastatin and cyclosporine is considered necessary, dose of atorvastatin should not exceed 10 mg.
Inducers of cytochrome P450 3A4: co-administration of atorvastatin with inducers of cytochrome P450 3A4 (e.g. efavirenz, rifampin, carbamazepine, phenytoin, phenobarbital, rifabutin or St John’s wort) can lead to a variable decrease in plasma concentrations of atorvastatin. This decrease may achieve a maximal value of 80% with rifampin. To ensure efficacy, cholesterol levels should be monitored.
Protease inhibitors: co-administration of atorvastatin and protease inhibitors, known inhibitors of cytochrome P450 3A4, was associated with increased plasma concentrations of atorvastatin.
Warfarin: co-administration of atorvastatin can increase the anticoagulant effect of warfarin leading to risk of hemorrhage. Patients should be frequently monitored as there may be a need to adjust the dosage of the oral anticoagulant.
Colchicine. In concomitant use of atorvastatin and colchicine, cases of myopathy, rhabdomyolysis, have been reported; therefore, caution should be exercised when prescribing atorvastatin with colchicine.
Fusidic acid: from postmarketing experience with atorvastatin and fusidic acid used concomitantly, muscle-related effects have been reported, including acute necrosis of skeletal muscles, as well as for other statins. The mechanism of this interaction is unknown. Patients should undergo close monitoring and temporary stop of treatment may be appropriate.
Niacin: the risk of myopathy during treatment with HMG-CoA reductase inhibitors is increased with co-administration of lipid-modifying doses and niacin and on rare occasions has resulted in acute necrosis of skeletal muscles with renal dysfunction secondary to myoglobinuria. Therefore, it is necessary to analyze the risk/benefit ratio for such concomitant treatment
Combination to be taken into account
Antacid: co-administration of atorvastatin and oral antacid suspension (magnesium and aluminum hydroxides) decreases plasma concentrations of atorvastatin and its active metabolite approximately by 35%. However, LDL-cholesterol reduction was not altered
Grapefruit juice: increase in the plasma concentrations of the hypolipidemic drug, with risk of onset of adverse events, such as muscular events.
Oral contraceptives: co-administration of atorvastatin and oral contraceptive increases plasma concentrations of norethindrone and ethinylestradiol. These increased concentrations should be considered when selecting oral contraceptive doses.
Colestipol: when co-administration of colestipol and atorvastatin, plasma concentrations of atorvastatin and its active metabolite were lower (approximately by 25%). However, lipid effects were greater when atorvastatin and colestipol were administered concomitantly, than when either drug was taken alone.
Digoxin. Concomitant administration of multiple doses of atorvastatin and digoxin, equilibrium plasma concentrations of digoxin increased by approximately 20%. The condition of patients taking digoxin should be appropriately monitored.
Diltiazem HCl: co-administration of atorvastatin 40 mg and diltiazem 240 mg resulted in 51% increase in exposure to atorvastatin.
Phenazone: co-administration of multiple doses of atorvastatin and phenazone showed little or no detectable effect in the clearance of phenazone
No interaction was observed with NSAIDs, antibiotics, hypoglycemic agents, cimetidine and digoxin.
Effect on liver. Liver function tests should be performed before start of treatment, periodically after treatment, and in patients with any signs or symptoms of liver damage. In case of elevated transaminase levels, they must be monitored till their values are normal.
If the elevated ALT and AST levels remain 3 times above the upper limit of normal (ULN), the treatment should be discontinued.
Because of the presence of atorvastatin, caution should be exercised when using the drug in patients consuming a lot of alcohol, patients with hepatic failure and/or liver disease in the anamnesis.
Effect on skeletal muscles. As well as other HMG-CoA reductase inhibitors, atorvastatin can affect the skeletal muscles and cause myalgia, myositis and myopathy, which in rare cases can progress to acute skeletal muscles necrosis, characterized by significantly elevated CPK levels (more than 10-fold ULN), myoglobinemia and myoglobinuria, which can lead to renal failure, and in rare cases, may be lethal.
Regular monitoring of CPK levels or other muscle enzymes is not recommended in patients treated with statin who show no symptoms. Monitoring of CPK is recommended for patients with predisposition factors to acute necrosis of skeletal muscles and patients with muscle symptoms before and during any treatment with statin (see below).
Caution should be exercised when prescribing the drug to patients with predisposition to acute necrosis of skeletal muscles. Before starting statin treatment, the CPK level should be measured in the following cases:
– in elderly patients (over 70);
– in case of renal failure;
– in case of hypothyroidism;
– in case of hereditary muscular disorders in personal or family anamnesis;
– muscle toxicity associated with the use of statin or fibrate in anamnesis;
– in case of alcohol abuse.
In such cases, it is necessary to analyze the risk compared to the possible positive effect and perform clinical monitoring.
If at baseline the CPK levels are significantly elevated (more than 5 times ULN), treatment should not be started.
CPK levels should not be measured following strenuous exercise or in the presence of any other reason of possible elevation of CPK, as this complicates interpretation of the results. If at baseline the CPK levels are significantly elevated (more than 5-fold the ULN), levels should be systematically re-measured every 5-7 days to confirm the results. In case if the confirmed CPK levels at baseline are 5-fold the ULN, the treatment cannot be started.
The patients should immediately report pain in muscles, muscle cramps or weakness because of unknown reasons, especially if accompanied by malaise or fever.
If such symptoms occur during treatment, it is necessary to measure the CPK level. If it is significantly elevated (more than 5-fold the ULN), treatment should be discontinued.
If muscular symptoms are severe and cause daily discomfort, treatment discontinuation should be considered, even if the elevated CPK levels are less than 5-fold the ULN.
If symptoms resolve and the CPK levels return to normal, the possibility of re-administration of drug with close monitoring may be considered.
Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL)
For patents with prior hemorrhagic stroke or lacunar infarct, the balance of risk and positive effect when using atorvastatin 80 mg is unknown; therefore, before starting treatment, it is necessary to analyze the potential risk of hemorrhagic stroke.
Interstitial lung disease: exceptional cases of interstitial lung disease have been reported for some statins, especially in case of long-term treatment. The manifestation may include dyspnea, non-productive cough and deterioration in general health (fatigue, weight loss and fever). If development of interstitial lung disease is suspected, statin therapy must be discontinued.
The drug contains lactose, which should be taken into account when prescribing it to patients with galactose intolerance, Lapp lactase deficiency or malabsorption of glucose/galactose.
Use during pregnancy or breast feeding.
Amlostat® is contraindicated during pregnancy or breast feeding.
Women of childbearing age should use appropriate methods of contraception.
Cholesterol and its derivatives are very important for the development of fetus, therefore, during pregnancy, potential risk of HMG-CoA reductase inhibition overweighs potential benefits expected from treatment with statin.
If pregnancy is detected during treatment, Amlostat® should be discontinued.
It is not known whether amlodipine passes into breast milk, however, since amlodipine does pass into it, Amlostat® is contraindicated during breast feeding.
Effects on ability to drive and operate machinery.
There is no data on the effect of Amlostat® on ability to drive or operate other automated systems. However, on the basis of pharmacological properties of amlodipine component of the drug, when driving motor transport or when working with other automated systems, the possibility of dizziness should be taken into account.
Dosage and administration.
The drug is intended for oral administration.
The usual starting dose is 2.5 mg/10 mg 1 time per day.
The drug can be taken at any time with or without food.
Amlostat® can be used both separately and in combination with hypotensive agents, but not with other calcium channel blockers or other statin.
Avoid combinations with fibrates.
Patients with renal failure: for patients with renal dysfunction no dosage adjustment is required.
Patients with hepatic failure: the drug is contraindicated in patients with active liver diseases.
Elderly patients: no dose adjustment is required.
Safety and efficacy of drug administration in children are not established, therefore, it is not recommended in this population.
There is no information on overdose of S(-)amlodipine/atorvastatin combination.
Data for amlodipine.
Experience with intentional overdose of amlodipine is limited.
Symptoms of overdose: the available information suggests that gross overdose of amlodipine will result in excessive peripheral vasodilatation and probably in reflex tachycardia. Significant, and possibly prolonged systemic hypotension, including shock with fatal outcome.
Treatment: clinically significant hypotension due to amlodipine overdose requires active support of cardiovascular system, including frequent monitoring of cardiac and respiratory function, elevation of lower extremities, monitoring of circulating fluid and urine passage.
Vasoconstrictor drugs may be used to restore vascular tone and arterial blood pressure, but first make sure that there are no contraindications for their use. Intravenous use of calcium gluconate may be useful for leveling the effects of calcium channel blockers.
In some cases gastric lavage may be useful. The use of activated charcoal in healthy volunteers within 2 hours following administration of 10 mg of amlodipine significantly decreased the level of its absorption.
Since amlodipine is highly protein bound? The effect of dialysis is negligible.
Data for atorvastatin.
There is no specific treatment in case of overdose with atorvastatin. In case of drug overdose, symptomatic and supporting therapy should be conducted if necessary. Liver function tests should be conducted, and serum level of CK should be monitored. Since atorvastatin is extensively bound to plasma proteins, hemodialysis cannot significantly increase atorvastatin clearance.
Data foe amlodipine.
Blood and lymphatic system: leukopenia, thrombocytopenia, purpura, anemia, agranulocytosis.
Immune system: allergic reactions.
Metabolic disorders: hyperglycemia, thirst, body weight gain, body weight loss.
Mentality: insomnia, nervousness, mood changes (including anxiety, fear), depression, confusion of consciousness, loss of consciousness, sleep disorders, depersonalization.
Nervous system: drowsiness, dizziness, headache (mostly at the beginning of treatment), tremor, dysgeusia, syncope, hypoesthesia, paresthesia, hypertonus, peripheral neuropathy, extrapyramidal syndrome.
Organs of vision: visual disturbances (including diplopia), conjunctivitis, pain in the eyes.
Hearing organs and labyrinth: acuphenes, sonitus, tinnitus.
Heart: palpitation, tachycardia, myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia, atrial fibrillation), angina attacks, orthostatic (postural) hypotension, collapse, pain in chest, syncope, heart palpitation.
Vessels: hyperemia, flushes, arterial hypotension, vasculitis, peripheral ischemia.
Respiratory system: dyspnea, rhinitis, cough, nasal bleeding.
Gastrointestinal tract: anorexia, loss of appetite, discomfort in epigastric region, abdominal pain, nausea, vomiting, dyspepsia, dysperistalsis (including constipation and diarrhea), flatulence, intestinal dysfunction, dry mouth, dysphagia, pancreatitis, gastritis, gum hyperplasia, distortion of the sense of taste, hypertrophic gingivitis.
Hepatobiliary system: hepatitis, jaundice, increased liver enzymes (mostly associated with cholestasis), hyperbilirubinemia, compromised liver function.
Skin and subcutaneous tissue: alopecia, purpura, skin discoloration, dermatodyschromia, hyperhidrosis, itching, rash, exanthema, angioedema, erythema multiforme, erythematous rash, maculopapular rash, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke’s edema, photosensitivity.
Musculoskeletal system and connective tissue: swelling of lower legs, arthralgia, myalgia, cramps, backache, lumbar pain, muscle rigidity, joint swelling (including swelling of the ankle).
Kidneys and urinary tract: disorders of urination, nocturia, increased frequency of urination.
Reproductive system and mammary glands: impotence, gynecomastia, sexual dysfunction.
General disorders and conditions at the site of administration: edema, peripheral edema, increased fatigability, retrosternal pain, chest pain, asthenia, pain, malaise, fever.
Changes in laboratory data: elevated levels of liver enzymes ALT, AST (mostly associated with cholestasis).
Data for atorvastatin.
Blood and lymphatic system: thrombocytopenia.
Immune system: allergic reactions, anaphylaxis (including anaphylactic shock).
Metabolic disorders: hypoglycemia, hyperglycemia, anorexia, body weight gain, diabetes mellitus.
Mentality:depression, sleep disorders, including insomnia and nightmares.
Nervous system: headache, peripheral neuropathy, paresthesia, hypoesthesia, dizziness, dysgeusia, cognitive disorders (e.g. memory loss, forgetfulness, amnesia, memory impairment, confusion of consciousness), associated with the use of astatines, stroke.
Organs of vision: darkening of vision, blurred vision, visual disturbances, visual acuity disturbances, visual disturbances (including diplopia).
Hearing organs and labyrinth: sonitus, acuphenes, loss of hearing.
Respiratory system: nasopharyngitis, nasal bleeding, interstitial lung disease, n in the pharynx and larynx.
Gastrointestinal tract: dyspepsia, nausea, vomiting, eructation, diarrhea, constipation, meteorism, abdominal pain, pain in the upper and lower abdomen, gastric pain, gastrointestinal discomfort, pancreatitis.
Liver and gallbladder hepatitis, cholestasis, cholestatic jaundice, lethal and non-lethal liver failure.
Skin and subcutaneous tissue: alopecia, itching, skin rash, bullous rash (including erythema multiforme, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome)), urticaria, angioedema, Quincke’s edema.
Musculoskeletal system and connective tissue: myalgia, myopathy, including immune- mediated necrotizing myopathy, acute necrosis of skeletal muscles, myositis, seizures, muscle spasms, muscle weakness, increased muscle fatigue, rhabdomyolysis, arthralgia, pain in joints, backache , lumbar pain, pain in the extremities, musculoskeletal pain, neck pain, joint swelling (including swelling of the ankle), tendinopathy (sometimes complicated by tendon rupture).
Kidneys and urinary tract: urinary tract infection, leukocyturia.
Reproductive system and mammary glands: sexual dysfunction, impotence, gynecomastia.
General disorders: feeling of malaise, asthenia, pyrexia, chest pain, edema, peripheral edema, increased fatigue, fever.
Trauma, poisoning and complications of manipulations:tendon rupture.
Infections and invasions: infections.
Changes in laboratory data: elevated transaminases and liver enzymes, abnormal liver functional tests, increased alkaline phosphatase levels, increased blood creatine phosphokinase activity.
Store at the temperature not more than 25 °С in a dry place, protected from sunlight.
Keep out of reach of children.
14 tablets are in a blister, 1 or 2, or 4, or 6 blisters are in a carton pack.
Conditions of supply.
LLC “KUSUM PHARM”.
54 Skryabina St., Sumy 40030, Ukraine
Date of last revision.