Eclamise
Eclamise is a combination antihypertensive drug. It has a hypotensive and antianginal effect.
Lisinopril in the drug is an ACE inhibitor, reducing the formation of angiotensin II and aldosterone, while simultaneously increasing the formation of bradykinin (a vasodilator mediator). Affects tissue RAAS. Reduces OPSS, blood pressure, preload and afterload, pressure in the pulmonary capillaries, does not affect heart rate, while it is possible to increase the IOC and increase blood flow in the kidneys. Arteries dilate to a greater extent than veins. Treatment with the drug improves blood supply to the ischemic myocardium. With long-term use of the drug, it reduces hypertrophy of the myocardium and the walls of resistant arteries. Slows the progression of LV dysfunction after myocardial infarction not complicated by HF. Effective for arterial hypertension with low renin activity, reduces albuminuria (by reducing blood pressure, changing the hemodynamics of the glomerular apparatus). Does not affect blood glucose concentrations in patients with diabetes. The hypotensive effect develops 1 hour after administration, the maximum effect is after 6 hours, the duration of action is 24 hours. When treatment is stopped, no syndrome occurs (sharp increase in blood pressure).
Amlodipine contained in the drug, a third-generation BMCC, has antianginal and hypotensive effects. Reduces the entry of Ca2+ into myocardial cells and smooth muscle cells of the vascular wall (to a greater extent). Reduces OPSS, blood pressure. The antianginal effect is due to the expansion of arteries and arterioles, reducing afterload. Increases the oxygen supply to intact (especially with vasospastic angina) myocardium and ischemic areas of the myocardium. Does not cause reflex tachycardia, prevents the formation of the ischemic ST interval, does not affect the conductivity and contractility of the myocardium. Reduces the frequency of angina attacks and the need for nitroglycerin. The use of the drug has a long-term dose-dependent hypotensive effect. Does not reduce the LV ejection fraction, reduces the degree of LV myocardial hypertrophy, and has an antiatherosclerotic and cardioprotective effect in ischemic heart disease. Does not increase the risk of death in patients with CHF (NYHA grade III-IV) during therapy with digoxin, diuretics, and ACE inhibitors. Inhibits platelet aggregation, enhances glomerular filtration, and has a weak natriuretic effect; in diabetic nephropathy does not increase microalbuminuria. Does not have a negative effect on metabolic processes and does not change plasma lipids. Can be used in patients with concomitant bronchial asthma, diabetes mellitus, gout.
The onset of action of the drug is 2-4 hours after taking the drug (more effective in a sitting and lying position), duration is 24 hours.
The combination of lisinopril with amlodipine helps prevent the development of undesirable effects caused by counterregulation of the active substances. BMCC dilating arterioles can lead to Na+ and water retention, therefore, it can activate the RAAS. An ACE inhibitor blocks this process.
Treatment with the drug is recommended in cases where taking individual components in the same doses is not effective.
Long-term circulation of both active ingredients makes it possible to take the drug once a day.
Eklamiz
The drug Eclamise should not be used to relieve a hypertensive crisis.
To determine the optimal maintenance dose, it is necessary to determine the dosage regimen on an individual basis, using lisinopril and amlodipine separately, while simultaneously monitoring renal function. The combination drug Eclamise is indicated only for those patients whose optimal maintenance dose of amlodipine and lisinopril is titrated to 5 mg and 10 mg or 10 mg and 20 mg, respectively.
If renal function decreases, Eclamise should be discontinued and replaced with monotherapy with drugs in adequate doses. In addition, dose reduction or discontinuation of diuretics may be required.
The drug Eclamise does not have any adverse effects on metabolism and plasma lipids and can be used in the treatment of patients with bronchial asthma, diabetes mellitus and gout.
The use of Eclamise in patients with myocardial infarction is not recommended due to the lack of sufficient experience in clinical use.
Aortic stenosis/mitral stenosis/hypertrophic obstructive cardiomyopathy
Like all vasodilators, Eclamise should be used with caution in patients with left ventricular outflow tract obstruction and mitral valve stenosis. In case of hemodynamically significant obstruction of the left ventricular outflow tract, the use of Eclamise is contraindicated.
Amlodipine
Cardiovascular diseases
In rare cases, in patients with coronary heart disease (especially with severe obstructive lesions of the coronary arteries), an increase in the frequency, duration and/or severity of angina attacks was observed after starting the use of BMCC or after increasing their dosage.
Although BMCC should generally be used with caution in patients with chronic heart failure, amlodipine did not increase mortality or the incidence of cardiovascular events in patients with CHF in short- and long-term clinical studies. During the use of amlodipine in patients with chronic heart failure (functional class III and IV according to the NYHA classification) of non-ischemic origin, an increase in the incidence of pulmonary edema was observed, despite the absence of signs of progression of heart failure.
Syndrome of “hepatic” enzymes, the drug should be discontinued with subsequent monitoring of their condition.
Kidney transplant
There is no experience with the use of lisinopril in patients who have recently undergone kidney transplantation.
Neutropenia/agranulocytosis/thrombocytopenia/anemia
In rare cases, neutropenia, agranulocytosis, thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia is rare. Neutropenia and agranulocytosis are reversible and disappear after discontinuation of the ACE inhibitor. Eclamise should be used with extreme caution in patients with connective tissue diseases, those receiving immunosuppressive therapy, during treatment with allopurinol or procainamide, or a combination of these aggravating factors, especially in the presence of pre-existing renal impairment. Some of these patients developed severe infections, which in several cases did not respond to antibiotic therapy. During treatment with Eclamise, it is necessary to periodically monitor the level of leukocytes (blood test with leukocyte count) in such patients, and also warn them of the need to report the first signs of an infectious disease.
Cough
Cough has been frequently reported during the use of ACE inhibitors. As a rule, the cough is non-productive, constant and stopped after discontinuation of the drug. When making a differential diagnosis of cough, cough caused by the use of ACE inhibitors must also be taken into account.
Surgery/general anesthesia
In patients undergoing major surgery or during general anesthesia with drugs that lead to hypotension, lisinopril may block the formation of angiotensin II after compensatory renin release. If arterial hypotension develops, probably as a result of the above mechanism, correction can be made by increasing the volume of blood volume.
Elderly patients
In elderly patients, the use of standard doses leads to higher concentrations of lisinopril in the blood, so special care is required when determining the dose, despite the fact that differences in the antihypertensive effect of lisinopril in elderly and young patients were not identified.
Hyperkalemia
An increase in serum potassium levels was observed in some patients receiving ACE inhibitors. The risk group for the development of hyperkalemia includes patients with renal failure, diabetes mellitus, acute heart failure, dehydration, metabolic acidosis, or while taking potassium-sparing diuretics, potassium-containing food supplements, potassium-containing salt substitutes or any other drugs that lead to an increase in serum potassium levels (for example, heparin). If it is necessary to take it simultaneously with the above drugs, it is necessary to monitor the potassium content in the blood serum.
Double blockade of the RAAS
The simultaneous use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients.
Concomitant use of ACE inhibitors with ARB II is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.
Primary hyperaldosteronism
In primary hyperaldosteronism, antihypertensive drugs whose effects are based on inhibition of the renin-angiotensin system are often ineffective, so the use of Eclamise is not recommended.
Diabetes
In patients with diabetes mellitus taking oral hypoglycemic agents or insulin, blood glucose concentrations should be regularly monitored during the first month of therapy with ACE inhibitors.
Ethnic differences
It should be taken into account that patients of the Negroid race have a higher risk of developing angioedema. Like other ACE inhibitors, lisinopril is less effective in lowering blood pressure in black patients. This effect may be associated with a pronounced predominance of low-renin status in black patients with arterial hypertension.
Instructions for use NOCLAUD®
Platelet aggregation inhibitors
Cilostazol is a PDE III inhibitor with antiplatelet activity. In clinical studies in healthy volunteers, cilostazol 150 mg twice daily for five days did not prolong the duration of bleeding.
Acetylsalicylic acid (ASA)
Short-term (4 days or less) concomitant use of ASA with cilostazol resulted in a 23-25% increase in inhibition of ADP-induced platelet aggregation ex vivo
compared to ASA used as monotherapy.
In patients receiving cilostazol and ASA, there was no apparent evidence of an increase in the incidence of bleeding adverse events compared with patients receiving placebo and equivalent doses of ASA.
Clopidogrel and other antiplatelet drugs
Concomitant use of cilostazol with clopidogrel had no effect on platelet levels, prothrombin time (PT) and activated partial thromboplastin time (aPTT). All healthy study participants experienced an increase in bleeding time when taking clopidogrel alone, and taking it concomitantly with cilostazol did not have a significant additional effect on bleeding time. Caution is recommended when using cilostazol concomitantly with any drug that inhibits platelet aggregation. Periodic monitoring of bleeding duration should be considered. Treatment with cilostazol is contraindicated in patients taking two or more additional antiplatelet/anticoagulant agents (see Contraindications).
A higher incidence of bleeding events was observed with concomitant use of clopidogrel, ASA and cilostazol in the CASTLE trial.
Oral anticoagulants such as warfarin
In a single-dose clinical study, cilostazol did not suppress the metabolism of warfarin and did not affect coagulation parameters (PT, aPTT, bleeding time). However, cilostazol should be used with caution in patients receiving concomitant treatment with any anticoagulant agents, and frequent monitoring is necessary to reduce the risk of bleeding.
Treatment with cilostazol is contraindicated in patients taking two or more additional antiplatelet/anticoagulant agents (see Contraindications).
Cytochrome P-450 (CYP) enzyme inhibitors
Cilostazol is extensively metabolized by enzymes of the cytochrome CYP system, especially CYP3A4 and CYP2C19, and to a lesser extent by CYP1A2. The dihydro-metabolite, which inhibits platelet aggregation 4-7 times more actively than cilostazol, is apparently formed with the participation of CYP3A4. The 4'-trans-hydroxy metabolite, five times less active than cilostazol, appears to be formed with the participation of CYP2C19. Therefore, drugs that inhibit the activity of CYP3A4 (for example, some macrolides, azole antifungals, protease inhibitors) or CYP2C19 (such as proton pump inhibitors (PPIs)) increase the overall pharmacological activity and may potentially increase the undesirable effects of cilostazol. Therefore, the recommended dose for patients concomitantly taking strong CYP3A4 or CYP2C19 inhibitors is 50 mg twice daily (see Dosage Regimen).
Taking cilostazol with erythromycin (a CYP3A4 inhibitor) resulted in a 72% increase in the AUC of cilostazol, accompanied by a 6% increase in the AUC of the dihydrometabolite and a 119% increase in the AUC of the 4'-trans-hydroxy metabolite.
Taking into account AUC values, the total pharmacological activity of cilostazol increases by 34% when taken together with erythromycin. Based on these data, the recommended dose of cilostazol is 50 mg twice daily when coadministered with erythromycin and similar agents (eg, clarithromycin).
Co-administration of ketoconazole (a CYP3A4 inhibitor) with cilostazol resulted in a 117% increase in the AUC of cilostazol, accompanied by a 15% decrease in the AUC of the dihydro metabolite and an 87% increase in the AUC of the 4'-trans-hydroxy metabolite. Taking into account AUC values, the overall pharmacological activity of cilostazol increases by 35% when used simultaneously with ketoconazole. Based on these data, the recommended dose of cilostazol is 50 mg twice daily when coadministered with ketoconazole and similar agents (eg, itraconazole).
Administration of cilostazol with diltiazem (a weak CYP3A4 inhibitor) resulted in a 44% increase in the AUC of cilostazol, accompanied by a 4% increase in the AUC of the dihydrometabolite and a 43% increase in the AUC of the 4'-trans-hydroxy metabolite.
Taking into account AUC values, the total pharmacological activity of cilostazol increases by 19% when administered concomitantly with diltiazem. Based on these data, no dose adjustment is required.
A single dose of 100 mg of cilostazol with 240 ml of grapefruit juice (an inhibitor of intestinal CYP3A4) did not have a significant effect on the pharmacokinetics of cilostazol. Based on these data, no dose adjustment is required. However, drinking large volumes of grapefruit juice may have a clinically significant effect on the pharmacokinetics of cilostazol.
Taking cilostazol with omeprazole (a CYP2C19 inhibitor) resulted in a 22% increase in cilostazol AUC, accompanied by a 68% increase in the AUC of the dihydrometabolite and a 36% decrease in the AUC of the 4'trans-hydroxy metabolite. Taking into account AUC values, the total pharmacological activity of cilostazol increases by 47% when administered concomitantly with omeprazole. Based on these data, the recommended dose of cilostazol is 50 mg twice daily when taken concomitantly with omeprazole.
Substrates for cytochrome P-450 enzymes
Cilostazol increased the AUC of lovastatin (a sensitive CYP3A4 substrate) and its β-hydroxy acid by 70%.
Cilostazol is recommended to be used with caution when coadministered with CYP3A4 substrates with a narrow therapeutic index (for example, cisapride, halofantrine, pimozide, ergot derivatives). Caution should be exercised when cilostazol is used concomitantly with statins metabolized by CYP3A4 enzymes, such as simvastatin, atorvastatin and lovastatin.
Inducers of cytochrome P-450 enzymes
The effect of inducers of CYP3A4 and CYP2C19 (such as carbamazepine, phenytoin, rifampicin and St. John's wort) on the pharmacokinetics of cilostazol has not been studied. There is a theoretical possibility of a change in the antiplatelet effect, which should be carefully monitored when taking cilostazol concomitantly with inducers of CYP3A4 and CYP2C19.
In clinical trials, smoking (which induces CYP1A2 enzyme activity) resulted in a 18% decrease in cilostazol plasma concentrations.
Other potential interactions
Caution should be exercised when simultaneous use of cilostazol with any other drug that can lower blood pressure, due to the possibility of developing an additive hypotensive effect accompanied by reflex tachycardia.
