Amlessa (perindopril tert-butylamine) tablets 8 mg/5 mg. №30

active substances: perindopril tert-butylamine and amlodipine;

1 tablet contains 8 mg of perindopril tert-butylamine (corresponding to 6.68 mg of perindopril) and 5 mg of amlodipine (corresponding to 6.935 mg of amlodipine besylate);

excipients: microcrystalline cellulose; pregelatinized starch; sodium starch glycolate; calcium chloride, hexahydrate; sodium bicarbonate; colloidal anhydrous silicon dioxide; magnesium stearate.

Tablets.

The main physical and chemical properties:

8 mg/5 mg: white or almost white, round, biconvex tablets with beveled edges.

Combined preparations of angiotensin-converting enzyme inhibitors. ACE inhibitors in combination with calcium antagonists. ATX code C09B B04.

The rate and degree of absorption of perindopril and amlodipine as monopreparations in the composition of the drug Amlessa do not differ significantly.

Perindopril tert-butylamine

Perindopril tert-butylamine is an angiotensin-converting enzyme (ACE) inhibitor, which converts ACE. The converting enzyme, or kinase, is an exopeptidase that allows the conversion of angiotensin I to angiotensin II and also causes the breakdown of the vasodilator agent bradykinin to form an inactive heptapeptide. Inhibition of ACE activity leads to a decrease in the concentration of angiotensin II in the blood plasma, which is accompanied by an increase in the activity of renin in the plasma (by inhibiting the negative assessment of renin release) and a decrease in the secretion of aldosterone. Since ACE blocks bradykinin, inhibiting the activity of this enzyme leads to an increase in the activity of the circulating and local kallikrein-kinin system and, thereby, to the activation of the prostaglandin system.

Perindopril tert-butylamine in the body turns into an active metabolite – perindoprilat. Other metabolites do not show inhibition of ACE activity in vitro.

Amlodipine

Amlodipine is an antagonist of calcium ions, which blocks the influx of calcium ions through the membranes to the smooth muscle cells of the myocardium and blood vessels. The mechanism of the hypotensive effect of amlodipine is caused by a direct effect on vascular smooth muscles. The exact mechanism of action of amlodipine in angina has not been established, but it is known that amlodipine reduces myocardial ischemia in two ways.

Amlodipine dilates peripheral arterioles and thus reduces the total peripheral resistance (afterload) against which the heart works. Reducing the load on the heart leads to a decrease in energy consumption and myocardial oxygen demand.

The mechanism of action of amlodipine may also involve dilation of the major coronary arteries and coronary arterioles. This expansion increases the oxygen supply to the myocardium in patients with Prinzmetal’s angina. In patients with arterial hypertension, dosing once a day provides a clinically significant reduction in blood pressure (both in standing and supine positions) throughout the entire 24-hour interval.

In patients with angina pectoris, taking amlodipine 1 time per day prolongs the total active time, the time to the onset of angina pectoris, and the time to depression of the 1 mm ST segment. Amlodipine reduces the frequency of angina pectoris and reduces the need to take nitroglycerin tablets.

Perindopril

After oral administration, perindopril is rapidly absorbed, the maximum concentration in blood plasma (Cmax) is reached within 1 hour. The half-life (t1/2) of perindopril from blood plasma is 1 hour.

Perindopril is a prodrug. 27% of the accepted dose of perindopril enters the bloodstream in the form of an active metabolite of perindoprilat. In addition to active perindoprilat, perindopril forms 5 more inactive metabolites. Cmax of perindoprilat in blood plasma is reached after 3-4 hours.

Since the use of food reduces the conversion of perindopril to perindoprilat, and therefore its bioavailability decreases, perindopril tert-butylamine is recommended to be taken orally in a single daily dose in the morning before meals.

There is a linear relationship between the dose of perindopril and its concentration in blood plasma.

The volume of distribution of unbound perindoprilat is approximately 0.2 L/kg. Binding of perindoprilat to plasma proteins is 20%, mainly with ACE, but is dose-dependent. Perindoprilat is excreted in the urine, the final elimination half-life of unbound perindoprilat is approximately 17 hours. The state of equilibrium is reached after 4 days.

Excretion of perindoprilat is reduced in elderly patients and in patients with cardiac or renal failure. Therefore, it is necessary to regularly monitor the level of potassium and creatinine.

The dialysis clearance of perindoprilat is 70 ml/min.

The kinetics of perindopril changes in patients with liver cirrhosis: the hepatic clearance of the main molecule is reduced by half. However, the amount of perindoprilat formed does not decrease. Therefore, such patients do not need to adjust the dose.

Amlodipine

After oral administration in therapeutic doses, amlodipine is well absorbed and reaches Cmax 6-12 hours after administration. Absolute bioavailability is from 64 to 80%. The volume of distribution is approximately 21 l/kg. Eating food does not affect the bioavailability of amlodipine. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to blood plasma proteins.

T1/2 is approximately 35-50 hours, which allows you to prescribe the drug once a day. Amlodipine is metabolized in the liver with the formation of inactive metabolites. 60% of the dose is excreted in the urine, and 10% of the drug is unchanged.

Application to elderly patients. The time required to reach Cmax of amlodipine is the same in both elderly and younger patients. In elderly people, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in AUC (area under the concentration/time curve) and t1/2. The recommended dosage regimen for elderly patients is similar, but dose increases should be done with caution.

Use in patients with renal failure.

Use in patients with impaired liver function. T1/2 of amlodipine, like all calcium antagonists, increases in patients with impaired liver function.

Arterial hypertension and/or coronary heart disease (if treatment with perindopril and amlodipine is necessary).

• hypersensitivity to perindopril (or to any other ACE inhibitors), to amlodipine (or to other dihydropyridines) or to any auxiliary substance of the drug;
• angioedema in the anamnesis after the use of any ACE inhibitors;
• idiopathic or hereditary angioedema;
• severe arterial hypotension;
• shock, including cardiogenic shock;
• obstruction of the outflow tract of the left ventricle (for example, severe stenosis of the aorta);
• unstable angina pectoris;
• heart failure after an acute myocardial infarction (within the first 28 days);
• pregnant women or women who plan to become pregnant);
• simultaneous use with drugs containing the active ingredient aliskiren, in patients with diabetes or in patients with renal failure (glomerular filtration rate < 60 ml/min/1.73 m2).

When driving a car or working with various mechanisms, it is necessary to take into account the possibility of developing such side effects of the drug as dizziness or weakness.

Start treatment with 1 tablet per day once, preferably in the morning before eating.

Tablets are not subject to division. The dosage range of the drug allows you to flexibly choose the ratio of components depending on clinical needs. The dose should be selected individually for each patient, taking into account the indication for use, the course of the disease and blood pressure indicators.

The use of a fixed combination is not suitable for initial therapy.

The maximum daily dose is 1 tablet of Amlessa 8 mg/10 mg per day.

Patients with renal insufficiency and elderly patients

Elimination of perindoprilat slows down in elderly patients and patients with renal insufficiency. Therefore, during treatment, it is necessary to monitor the level of creatinine and potassium frequently. Amlessa can be prescribed to patients with CK ≥ 60 ml/min. Amlessa is contraindicated in patients with CC < 60 mL/min in this dosage form. For such patients, individual selection of doses of perindopril and amlodipine is recommended.

The change in the concentration of amlodipine in blood plasma does not correlate with the degree of severity of renal failure.

Patients with liver failure

The dosage scheme for patients with liver failure has not been established, therefore Amlessa should be used with caution in such patients.

The drug is not recommended for children (under 18 years of age) due to the lack of studies involving this group of patients.

There is no information on overdose of the drug Amlessa when used for the treatment.

Overdose (taking large doses) of amlodipine can lead to excessive peripheral vasodilatation and, as a result, to significant and possibly prolonged systemic arterial hypotension, including with the development of shock up to a fatal outcome. Amlodipine is not removed by hemodialysis.

Treatment

Clinically significant arterial hypotension caused by an overdose of amlodipine requires the implementation of active measures aimed at supporting the functions of the cardiovascular system, including monitoring of heart and lung performance indicators, ensuring the position of the patient lying down with raised lower limbs, control of the volume of circulating blood, diuresis.

Vasoconstrictors are prescribed to restore blood vessel tone and normal blood pressure. In order to eliminate the consequences of blocking calcium channels, calcium gluconate should be administered intravenously.

In some cases, gastric lavage may be useful.

Since amlodipine is largely bound to blood proteins, the effectiveness of dialysis is unlikely.

Data on perindopril overdose in humans are limited. Symptoms of an overdose of ACE inhibitors are arterial hypotension, shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, rapid heartbeat, bradycardia, dizziness, agitation, cough. Treatment should be carried out by intravenous administration of physiological solution. When arterial hypotension occurs, the patient should be placed in a horizontal position with a low headboard. Intravenous angiotensin II and/or catecholamines may also be used. It is possible to remove perindopril from the systemic circulation by hemodialysis. To eliminate bradycardia, which is not amenable to treatment, the issue of pacemaker implantation is being considered. It is necessary to constantly monitor the main indicators of vital activity.