Hartil-AM 5 mg / 5 mg capsule №10

Hartil AM 5/5 (HARTIL AM 5/5) user's manual

Composition

active ingredients: 1 capsule contains 2.5 mg of ramipril and 2.5 mg of amlodipine (corresponding to 3,475 mg of amlodipine besylate) or 5 mg of ramipril and 5 mg of amlodipine (corresponding to 6.95 mg of amlodipine besylate) or 5 mg of ramipril and 10 mg Amlodipine (corresponding to 13.9 mg of amlodipine besylate) or 10 mg of ramipril and 5 mg of amlodipine (corresponding to 6.95 mg of amlodipine besylate) or 10 mg of ramipril and 10 mg of amlodipine (corresponding to 13.9 mg of amlodipine besylate)

Excipients: crospovidone, hypromellose, microcrystalline cellulose, glycerol dibehenate;

the composition of the capsule (lid and base);

• capsules 2.5 mg / 2.5 mg iron oxide red (E172), titanium dioxide (E 171), gelatin;
• capsules 5 mg / 5 mg brilliant blue FCF + FD and C blue 1 (E 133), gait red AC + FD and C red 40 (E 129), titanium dioxide (E 171), gelatin;
• capsules of 5 mg / 10 mg of iron oxide red (E172), titanium dioxide (E 171), azorubin, carmosein (E 122), indigo (E 132), gelatin;
• capsules of 10 mg / 5 mg of iron oxide red (E172), titanium dioxide (E 171), diamond blue FCF + FD and C blue 1 (E 133), gait red AC + FD and C red 40 (E 129), gelatin ;
• capsules of 10 mg / 10 mg azorubin, carmosein (E 122), indigo (E 132), titanium dioxide (E172), gelatin.

Dosage form

Capsules.

Pharmacological group

ACE inhibitors and calcium channel blockers.

ATC code C09BB07.

Indications

For the treatment of arterial hypertension in patients whose blood pressure is properly controlled by individual drugs, which are administered concomitantly at the same dose as in combination, but in the form of individual tablets.

Contraindications

Contraindications associated with the use of ramipril:

• angioedema (hereditary, idiopathic or due to previous use of ACE inhibitors or angiotensin II receptor antagonists) in anamnesis
• extracorporeal treatment, which leads to blood contact with negatively charged surfaces;
• marked bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney
• Arterial hypotension or hemodynamically unstable conditions;
• hypersensitivity to the active substance.

Contraindications associated with the use of amlodipine:

• hypersensitivity to the active substance;
• severe arterial hypotension
• shock (including cardiogenic shock);
• narrowing of the output of the left ventricle (for example, pronounced stenosis of the aortic aorta);
• hemodynamically unstable heart failure after acute myocardial infarction.

Contraindications associated with the use of ramipril / amlodipine:

Hypersensitivity to ramipril or ACE inhibitors (angiotensin enzyme) or to the auxiliary components of the drug, amlodipine, dihydropyridine derivatives.

Dosing and Administration

Hartil-AM is indicated to patients whose blood pressure is properly controlled by separately prescribed monocomponent drugs at the same doses recommended for a fixed combination.

The recommended daily dose is 1 capsule dosage of 2.5 mg / 2.5 mg.

Hartil-AM should be taken daily once a day at the same time, regardless of food intake.

Do not chew or grind the capsule.

Fixed combination is not suitable for initial therapy.

If necessary, the dose of Hartilu-AM can be changed or individually titrated with components of the free combination.

The daily dose can be increased to a maximum of 10 mg / 10 mg (1 capsule Hartil-AM 10 mg / 10 mg once a day)

Adults

Patients who are treated with diuretics should be careful, as these patients may have excessive excretion of liquid and / or sodium chloride from the body. The function of the kidneys and the level of potassium in the serum should be controlled.

Special groups of patients.

Patients with impaired hepatic function

Patients with impaired liver function, treatment with ramipril should be started only under the supervision of a doctor.

The maximum daily dose should be 2.5 mg of ramipril.

Doses of the drug for use in patients with mild to moderate hepatic insufficiency are not established, so the dose should be selected with caution and start with a low dose.

Patients with impaired renal function

The optimal initial and maintenance dose for patients with renal insufficiency should be adjusted individually by separately titrating the dose of ramipril and amlodipine.

The daily dose of ramipril for patients with renal insufficiency should be calculated on the basis of creatinine clearance values:

• if the creatinine clearance is ≥ 60 ml / min, there is no need to adjust the initial dose, the maximum daily dose is 10 mg
• if creatinine clearance is 30-60 ml / min, there is no need to correct the initial dose (2.5 mg per day), and the maximum daily dose is 5 mg
• if the creatinine clearance is 10-30 ml / min, the initial daily dose is 1.25 mg per day, and the maximum daily dose is 5 mg
• for patients with arterial hypertension on hemodialysis: Ramodril is slightly excreted in hemodialysis; the initial dose is 1.25 mg, and the maximum daily dose - 5 mg the drug should be taken for several hours after the hemodialysis session.

Patients with renal insufficiency correction dose of amlodipine is not required.

Amlodipine is not dialyzed. Amlodipine should be administered with caution to patients who are on dialysis.

During treatment with Hartil-AM, kidney function and serum potassium levels should be monitored. In the case of impaired renal function, the use of Hartilu-AM should be discontinued, and the dose of its components must be adequately corrected.

Patients of advanced age.

Initial doses of ramipril should be as low as possible; Further titration of the dose should be carried out more gradually due to the likelihood of developing adverse reactions. The use of Hartilu-AM is not recommended for patients after 75 years of age or very weak patients.

Older patients can be given regular doses of amlodipine, but with caution, care should be taken when increasing the dose.

Adverse Reactions

Adverse reactions that were observed with the use of active components separately, indicated according to the frequency of occurrence: very often (≥1 / 10), often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1000 to <1/100), rarely (from ≥1 / 10000 to <1/1000), very rarely (<1/10000), the frequency is unknown (can not be estimated from available data).

ramipril:

On the part of the blood system and lymphatic system: rarely - eosinophilia; rarely - a decrease in the number of leukocytes (including neutropenia and agranulocytosis), a decrease in the number of erythrocytes, a decrease in the level of hemoglobin, a decrease in the number of platelets; unknown - bone marrow insufficiency, pancytopenia, hemolytic anemia.

From the side of the immune system: it is not known - anaphylactic and anaphylactoid reactions, an increase in the level of antinuclear antibodies.

Metabolic disorders: often - increased potassium levels in the blood infrequently: anorexia, decreased appetite; it is unknown - a decrease in the level of sodium in the blood.

Mental disorders: sometimes - depressed mood, anxiety, nervousness, anxiety, sleep disturbances, including drowsiness rarely - confusion; unknown - violation of attention.

From the side of the nervous system: often - headache, dizziness, infrequently -vertego, paresthesia, agevzia, dysgeusia; rarely - tremor, imbalance; it is not known - cerebral ischemia, including ischemic stroke and transient cerebral blood flow disorder, disorders of psychomotor functions, burning, parosmia.

From the side of the organ of vision: rarely - impaired vision, including blurred vision; rarely - conjunctivitis.

From the organ of hearing and balance: rarely - hearing impairment, tinnitus.

From the cardiovascular system: often - arterial hypotension, orthostatic lowering of blood pressure, fainting; rarely - myocardial ischemia, including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitation, peripheral edema, flushing to the face, rarely - stenosis of vessels, hypoperfusion, vasculitis is unknown - Raynaud's syndrome.

From the respiratory system: often - an unproductive irritant cough, bronchitis, sinusitis, dyspnea rarely - bronchospasm, including exacerbation of asthma, nasal congestion.

On the part of the digestive tract: often - inflammation in the digestive tract, digestive disorders, gastrointestinal discomfort, dyspepsia, diarrhea, nausea, vomiting infrequently-pancreatitis (single cases with fatal outcome with the use of ACE inhibitors), increased levels of pancreatic enzymes, angioedema small intestine, pain in the upper abdomen, including gastritis, constipation, dry mouth, glaucitosis; unknown - stomatitis.

On the part of the digestive system: rarely - increased levels of hepatic enzymes and / or conjugated bilirubin rarely - cholestatic jaundice, hepatocellular damage, unknown - acute liver failure, cholestatic or cytolytic hepatitis (in rare cases, fatal).

From the skin and subcutaneous tissues: often - rash, in particular maculopopulosis;

• rarely - angioedema, in exceptional cases, airway obstruction due to angioedema may be fatal; itching, excessive sweating, rarely - exfoliative dermatitis, urticaria, onycholysis;
• very rarely photosensitivity reaction; unknown - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoidal exanthema or enanthema, alopecia.

From the musculoskeletal system: often - muscle spasms, myalgia infrequently - arthralgia.

From the urinary system: rarely - a violation of kidney function, including acute renal failure, increased diuresis, exacerbation of existing proteinuria, increased levels of urea and creatinine in the blood.

On the part of the reproductive system: sometimes - transient erectile impotence, a decrease in libido is unknown - gynecomastia.

Common disorders and disorders at the site of the implantation are pain in the chest, weakness, sometimes pyrexia;rarely - asthenia.

Amlodipine

With the use of amlodipine, adverse reactions such as drowsiness, dizziness, headache, palpitation, blood flushing, abdominal pain, nausea, edema of the legs, swelling and fatigue were most often reported.

On the part of the blood system and lymphatic system: very rarely - leukopenia, thrombocytopenia.

Metabolic disorders: rarely - hyperglycemia.

Mental disturbances: rarely - a change in mood (including anxiety), insomnia, depression, sometimes confusion.

From the nervous system: often - headache, dizziness, drowsiness (especially at the beginning of treatment) rarely - tremor, taste disorders, fainting, hypoesthesia, paresthesia very rarely - arterial hypertension, peripheral neuropathy.

From the side of the organ of vision: rarely - visual impairment (including diplopia).

From the organs of hearing: rarely - ringing in the ears.

From the cardiovascular system: often - heart palpitations, blood rushes are rare - arterial hypotension is very rare - myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), vasculitis.

From the respiratory system: rarely - shortness of breath, rhinitis very rarely - cough.

From the side of the digestive tract: often - pain in the abdomen, nausea infrequent - vomiting, indigestion, violation of intestinal motility (including constipation and diarrhea), dry mouth very rarely - pancreatitis, gastritis, gingival hyperplasia.

From the side of the digestive system: very rarely - jaundice *, hepatitis *.

From the skin and subcutaneous tissues: infrequently - alopecia, purpura, discoloration, increased sweating, itching, rash, exanthema; very rarely angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity.

From the musculoskeletal system: often - swelling of the ankle joint is rare - arthralgia, myalgia, muscle spasms, back pain.

From the urinary system: rarely - a violation of urination, nocturia, an increase in the frequency of urination.

From the side of the reproductive system: sometimes - impotence, gynecomastia.

Common disorders and conditions at the injection site are often swelling, fatigue; infrequently - pain behind the breastbone, asthenia, pain malaise.

Laboratory indicators: rarely - an increase or decrease in body weight is very rare - an increase in the level of hepatic enzymes *.

* In most cases, cholestasis.

Overdose

Ramipril

Symptoms caused by an overdose of ACE inhibitors may include excessive peripheral vasodilation (with severe arterial hypotension, shock), bradycardia, electrolyte imbalance, kidney failure. The patient's condition should be carefully monitored. Symptomatic and supportive treatment is prescribed. The proposed measures include primary detoxification (gastric lavage, sorbent administration), and means for restoring hemodynamic stability, including the administration of alpha 1-adrenergic agonists or angiotensin II (angiotensinamide) agonists. Ramiprilate, an active metabolite of ramipril, is poorly excreted from the general circulation by hemodialysis.

Amlodipine

Data on cases of intentional overdose in humans are limited.

Symptoms. Based on the available data, it is suggested that a severe overdose can lead to excessive peripheral vasodilation and, possibly, reflex tachycardia, severe and prolonged systemic arterial hypotension, including cardiogenic shock with a lethal outcome, are not documented.

Treatment. Clinically significant arterial hypotension due to an overdose of amlodipine requires active treatment measures, including frequent monitoring of cardiac and respiratory function, elevated limb position and control of circulating blood volume and diuresis. To restore the vascular tone and blood pressure level, it may be useful to use a vasoconstrictor, if there are no contraindications to its appointment. In order to eliminate the effects of calcium channel blockade, it may be effective to administer calcium gluconate.

In some cases, it may be effective to wash the stomach. In healthy volunteers, taking activated charcoal 2:00 after taking 10 mg of amlodipine reduced the rate of absorption of amlodipine.

Since amlodipine is largely associated with blood proteins, the effectiveness of dialysis is unlikely.

Use during pregnancy and lactation

Ramipril

Ramipril is not recommended in the first trimester of pregnancy and is contraindicated during the II and III trimesters of pregnancy.

Epidemiological data on the risk of teratogenicity after the use of ACE inhibitors in the first trimester of pregnancy were not convincing; However, we can not exclude a slight increase in risk. If continued therapy with an ACE inhibitor is considered necessary, patients planning a pregnancy need to switch to an alternative antihypertensive drug that has an established safety profile for use during pregnancy. If pregnancy is diagnosed, treatment with ACE inhibitors should be stopped immediately and an alternative therapy initiated.

It is known that the use of ACE inhibitors in the II and III trimesters of pregnancy causes a person fetotoxicity (decreased kidney function, oligohydramnion, delayed ossification of the skull) and neonatal toxicity (kidney failure, arterial hypotension, hyperkalemia). If an ACE inhibitor is used in the second trimester of pregnancy, ultrasound examination of kidney and skull function is recommended. Newborns, whose mothers took ACE inhibitors, should be carefully examined for arterial hypotension, oliguria, and hyperkalemia. Since there is insufficient information on the use of ramipril during breastfeeding, it is not recommended to be used and is preferred to alternative treatments, especially in the case of a newborn or prematurely born child.

Amlodipine

Pregnancy.

Use during pregnancy is recommended only when there is no safer alternative and when the disease itself carries a greater risk to the mother and fetus.

Breastfeeding.

It is not known whether amlodipine is excreted in breast milk. The decision to prolong / stop breastfeeding or continue / discontinue amlodipine treatment should be made taking into account the benefits of breastfeeding for the baby and the benefits of using amlodipine for the mother.

Given the above information, the use of Hartil-AM during pregnancy and lactation is contraindicated.

Children

Hartil-AM is not recommended for children because of the lack of data on the safety and efficacy of its use in this age group of patients.

Application features

Ramipril.

Patients in whom there is a particular risk of hypotension.

Patients with a significant increase in the activity of the renin-angiotensin. Patients with a significant increase in the activity of the renin-angiotensin-there is a risk of sudden considerable lowering blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or concomitant diuretic is prescribed for the first time or the first dose increase. A significant increase in the activity of the renin-angiotensin requiring medical supervision, including permanent control of blood pressure can be expected, such as in patients:

• with severe hypertension;
• with decompensated congestive heart failure,
• with hemodynamically significant obstacle to the inflow or outflow of blood from the left ventricle (e.g. aortic stenosis or mitral valve)
• with unilateral renal artery stenosis in the presence of a second-functioning kidney
• in which there is or may develop a lack of liquid or electrolytes (including those receiving diuretics);
• with cirrhosis and / or ascites;
• that perform extensive surgery or during anesthesia with the use of drugs that cause hypotension.

As a rule, it is recommended to correct dehydration, hypovolemia, or lack of electrolyte before treatment (but in patients with heart failure, such corrective action must be carefully weighed in terms of the risk of volume overload).

Transient persistuvalna or cardiac insufficiency after myocardial infarction.

Patients in whom there is a risk of cardiac or cerebral ischemia in case of acute hypotension. In the initial phase of treatment requires special medical supervision.

Patients of advanced age. See. See "Dosing and dose."

If surgery is possible, treatment with ACE inhibitors such as ramipril should be discontinued one day prior to surgery.

Monitoring of renal function Renal function should be assessed prior to and during treatment and dosage adjusted especially in the first weeks of treatment. Especially careful control is needed in patients with impaired renal function (see. Section "Dosage and Administration"). There is a risk of deterioration of renal function, particularly in patients with congestive heart failure or after renal transplantation.

Angioedema patients treated with ACE inhibitors, including ramipril, angioneurotic edema was observed (see. Section "Adverse reactions"). In the case of angioedema receiving the drug should be discontinued am Hart. It is necessary to immediately start emergency treatment. The patient must be under medical observation for at least 12-24 hours, and may be discharged after the complete disappearance of symptoms.

In patients treated with ACE inhibitors, including ramipril, bowel angioneurotic edema was observed (see. Section "Adverse reactions"). These patients complained of pain in the stomach (nausea / vomiting or without them).

Anaphylactic reactions during desensitizing When using ACE inhibitors likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom allergens and other increases. Before the desensitization should temporarily stop taking ramipril.

Hyperkalemia Some patients treated with ACE inhibitors, including ramipril observed occurrence hyperkalemia. The group risk of hyperkalemia include those with renal insufficiency, patients aged 70 years, patients with uncontrolled diabetes, patients who are taking potassium salts, potassium-sparing diuretics, as well as other active substances that increase potassium in the blood plasma, or patients with conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If a combined use of the aforementioned drugs is deemed advisable, it is recommended to regularly monitor the level of potassium in the blood plasma (see. Section "interaction with other drugs and other types of interactions").

Neutropenia / agranulocytosis cases neutropenia / agranulocytosis, as well as thrombocytopenia and anemia are rare. It was also reported about the oppression of bone marrow function. In order to identify possible leukopenia recommended to control the number of leukocytes in the blood. More frequent monitoring is desirable to conduct at the beginning of the treatment, and patients with impaired renal function, accompanying collagen diseases (e.g. systemic lupus erythematosus or scleroderma) or those who are taking other medications which may cause changes in the blood picture (see. Sections "Interaction with other medicaments and other forms of interaction "and" Adverse reactions ").

Ethnic differences ACE inhibitors often cause angioedema in patients blacks than in other races. Like other ACE inhibitors, ramipril hypotensive effect may be less severe in blacks compared to patients with other races. This may be due to the fact that black patients with hypertension is more common in hypertension with low renin activity.

Cough. In applying the ACE inhibitors were reported occurrence of cough. Characteristically, the cough unproductive, long and disappears after discontinuation of therapy. In the differential diagnosis of cough should be aware of the possibility of cough caused by ACE inhibitors.

Amlodipine.

Safety and effectiveness of amlodipine have not been established for the relief of hypertensive crisis.

Patients with heart failure.

Patients with heart failure require a special approach. In the long, placebo-controlled study of patients with severe heart failure (class III and IV of NYHA classification) the incidence of lung edema was higher in the group treated with amlodipine than in the placebo group, but this was not associated with worsening of heart failure.

The use in patients with impaired liver function.

In patients with impaired liver function the half-life of amlodipine is increased, however, the drug dosage recommendations have not yet been developed. For this reason the use of amlodipine in these patients with caution.

Use in elderly patients.

In elderly patients an increase in dose should be made 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.

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

Some side effects (such as blood pressure reducing symptoms such as dizziness) may interfere with the ability to focus and react, so this may affect the reaction rate at a driving or operating other mechanisms.

These adverse reactions were observed at the start of treatment or during the transition from other drugs. After the first dose, or increasing doses are not recommended to drive vehicles or work with other mechanisms for several hours.

Interaction with other drugs and other interactions

ramipril

Contraindicated combination.

Extracorporeal treatments which result in contacting the blood with negatively charged surfaces, such as dialysis or hemofiltration with certain membranes with high hydraulic permeability (e.g., polyacrylonitrile), and low density lipoprotein apheresis with dextran sulfate, increased risk of severe anaphylactic reactions. If you want such treatment, you should consider using a different type of dialysis membrane or different class of antihypertensive agents.

Use with caution

Potassium salts, heparin, potassium-sparing diuretics and other active ingredients that increase the potassium level in blood plasma (including angiotensin II, trimethoprim, tacrolimus, cyclosporine) can cause hyperkalemia, however requires careful monitoring the level of potassium in the blood plasma.

Antihypertensive drugs (e.g. diuretics), and other means that can lower blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin) may increase the risk of hypotension.

Vasopressor sympathomimetics and other substances (e.g., isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril: recommended to control blood pressure.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may change the number of blood cells: increased likelihood of haematological reactions.

Lithium salts of ACE inhibitors may reduce the excretion of lithium, and can therefore increase its toxicity. It is recommended to control the lithium levels in the blood.

Antidiabetic agents including insulin: possible hypoglycemic reactions. It is recommended to monitor blood glucose levels.

Nonsteroidal anti-inflammatory drugs and aspirin may reduce the antihypertensive effect ramipril. Therefore, the combined use of ACE inhibitors and NSAIDs may lead to an increased risk of renal impairment and increased potassium level in the blood.

Amlodipine

Amlodipine is safe when used in conjunction with thiazide diuretics, β-blockers, long-acting nitrates, nitroglycerin sublingual, nonsteroidal anti-inflammatory drugs, antibiotics and oral hypoglycemic agents.

The effect of other drugs on amlodipine

• Inhibitors of CYP3A4: in the combined use of amlodipine with an inhibitor of CYP3A4, erythromycin in young patients and diltiazem in elderly patients amlodipine plasma concentrations were increased by approximately 22% and 50% respectively. However, the clinical relevance of these indicators is not clear. We can not exclude the fact that strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine more than diltiazem. Amlodipine should be used with caution with CYP3A4 inhibitors. However, the side effects associated with this interaction has not been reported.
• Induktry CYP3A4: data on the effect of CYP3A4 inducers on amlodipine absent. Simultaneous use of inducers of CYP3A4 (rifampicin, Hypericum drugs) may lead to a reduction in the plasma concentration of amlodipine. It should be used with caution amlodipine together with inducers of CYP3A4.

Clinical interaction studies have shown that grapefruit juice, cimetidine, aluminum / magnesium (antacid) and sildenafil did not affect the pharmacokinetics of amlodipine.

Dantrolene (infusion)

The animals were observed ventricular fibrillation deaths and cardiovascular collapse, which have been associated with hyperkalemia after administration of verapamil and dantrolene intravenously. Because of the risk of hyperkalemia is recommended to avoid the use of calcium channel blockers such as amlodipine, prone to malignant hyperthermia patients and in the treatment of malignant hyperthermia.

Effect of amlodipine on other drugs

Amlodipine may potentiate the effect of other antihypertensive drugs.

Clinical studies showed no interaction of amlodipine on the pharmacokinetics of atorvastatin, digoxin, ethanol, warfarin or cyclosporin.

Amlodipine has no effect on laboratory parameters.

Pharmacological properties

Pharmacodynamics.

The mechanism of action of ramipril.

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase (synonyms: ACE kininaza II). In plasma and tissues this enzyme catalyzes the conversion of angiotensin I into the active vasoconstrictor substance angiotensin II, as well as degradation of the active vasodilator bradykinin. Reducing the formation of angiotensin II and breakdown of bradykinin inhibition leads to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat reduces secretion of aldosterone. The median responses to monotherapy with ACE inhibitors was lower in black patients (Africans) with hypertension (usually a low-renin) than white-skinned patients.

Pharmacodynamic effects.

The use of ramipril causes a significant decrease in peripheral resistance of the arteries. In general, no significant changes in renal plasma flow and glomerular filtration rate were observed. The use of ramipril in patients with hypertension leads to a decrease in blood pressure in the horizontal and vertical positions, without compensatory increase in the heart rate.

In most patients, the onset of antihypertensive action of a single dose of ramipril occurs 1-2 hours after ingestion. The maximum effect after a single dose is usually achieved 3-6 hours after ingestion. The antihypertensive effect persists for 24 hours.

The maximum antihypertensive effect with prolonged treatment with ramipril generally becomes evident after 3-4 weeks.It is shown that the antihypertensive effect with prolonged therapy persists for 2 years.

A sudden stopping of ramipril does not lead to a rapid and excessive ricochet increase in blood pressure

The mechanism of action of amlodipine:

Amlodipine inhibits the transmembrane flow of calcium ions in the heart cells and smooth muscle vessels (slow calcium channel blocker or calcium ion antagonist).

The mechanism of antihypertensive action is due to the direct relaxation effect of amlodipine on the smooth muscle of the vessels, which contributes to a decrease in systemic peripheral vascular resistance.

The exact mechanism by which amlodipine removes angina is not fully understood, but it can have the following two actions:

1) amlodipine dilates the peripheral arterioles, thereby reducing the overall peripheral resistance (after the load).

Since it does not cause reflex tachycardia, myocardial consumption of energy and the need for oxygen will decrease.

2) Due to the above described mechanism of action, amlodipine increases the flow of oxygen into the myocardium even in the case of coronary artery spasm (Prinzmetal angina or variant angina).

Pharmacodynamic properties

In patients with arterial hypertension, a single dose of amlodipine provides a clinically significant reduction in blood pressure for 24 hours in the supine position and standing. Due to the slow onset of action, amlodipine does not cause acute arterial hypotension.

In patients with angina pectoris, the use of amlodipine once a day increases the total time of possible physical activity, delays the onset of an angina attack and prolongs the time to significant depression of the ST segment, reduces the frequency of angina attacks and the need for tablets of glyceryl trinitrate.

Amlodipine does not adversely affect the metabolism and lipids of blood plasma, so it is suitable for the treatment of patients with bronchial asthma, diabetes and gout.

Pharmacokinetics.

Ramipril

Absorption

After taking ramipril quickly absorbed in the digestive tract: the maximum concentration of ramipril in the blood plasma is reached within 1:00. Given the withdrawal of ramipril with urine, the degree of absorption is at least 56%, and it is not significantly affected by the presence of food in the digestive tract. Bioavailability of the active metabolite ramiprilata after oral administration of ramipril in a dose of 2.5 mg and 5 mg is 45%.

The maximum concentration in the blood plasma of ramiprilata, a single active metabolite of ramipril is achieved in 2-4 hours after taking ramipril. The equilibrium concentration of ramiprilate in blood plasma at the usual dose (1 time per day) is reached on the 4th day of treatment.

Distribution

The binding of ramipril with blood proteins is approximately 73%, and ramiprilata - 56%.

Metabolism

Ramipril is almost completely metabolized to ramiprilate, diketopiperazine ether, diketopiperazinovoy acid and glucuronide ramipril and ramiprilata.

Conclusion

Excretion of metabolites is mainly carried out by the kidneys.

The decrease in the concentration of ramiprilate in the blood plasma occurs in several phases. Due to the powerful saturating binding with ACE and slow dissociation from the enzyme, ramiprilat is characterized by a prolonged terminal elimination phase at very low plasma concentrations.

After taking multiple doses of ramipril, the effective half-life of ramiprilata is 13-17 hours after taking the dose of 5-10 mg and longer after taking low doses of 1.25-2.5 mg. The difference is due to the saturating ability of the enzyme to bind to ramiprilat.

After a single dose, ramipril and its metabolite did not appear in breast milk. However, the effect of multiple doses is unknown.

Patients with impaired renal function.

Renal excretion of ramiprilate is reduced in patients with impaired renal function, and renal clearance of ramiprilate is proportionally associated with creatinine clearance. This leads to an increase in plasma concentrations of ramiprilate, which decrease more slowly than in individuals with normal renal function.

Patients with impaired liver function.

In patients with impaired liver function, ramipril metabolism in ramiprilata is slowed due to a decreased activity of hepatic esterases, and ramipril plasma levels in these patients are increased. However, the maximum concentration of ramiprilate in these patients did not differ from that in individuals with normal liver function.

Amlodipine

Absorption

After ingestion, amlodipine is almost completely absorbed, reaching a maximum concentration in the blood plasma 6-12 hours after ingestion. Eating does not affect the bioavailability of the drug. Bioavailability is 64 - 80%.

Distribution

The volume of distribution is 21 l / kg body weight. The equilibrium concentration in the blood plasma (5-15 ng / ml) is achieved within 7-8 days of application of the drug. In in vitro studies, it was found that 93-98% of the blood circulating amlodipine binds to blood plasma proteins.

Metabolism and excretion

Amlodipine is actively metabolized in the liver (about 90%) to inactive pyridine derivatives. 10% of the starting compound and 60% of the inactive metabolites are excreted in the urine, 20-25% with feces.

The decrease in plasma concentration has a two-phase character. The final half-life from the plasma is about 35-50 hours, taking into account the administration of the drug 1 time per day.

The total clearance is 7 ml / min / kg body weight (for patients with a body weight of 60 kg - 25 l / h). In elderly patients - 19 l / hour.

Application in the elderly

The time required to achieve the maximum concentration of amlodipine in the blood plasma is the same as in elderly patients, and in younger patients. In elderly people, there is a tendency to decrease the clearance of amlodipine, which leads to an increase in the area under the concentration / time curve (AUC) and half-life. There was an increase in AUC and half-life of the drug in patients with congestive heart failure.

Patients with impaired renal function

Amlodipine is extensively metabolized into inactive metabolites. 10% of the original compound is excreted unchanged in the urine. Changes in the concentration of amlodipine in the blood plasma are not related to the degree of impaired renal function. These patients can be treated with the usual dose of amlodipine. Amlodipine is not dialyzed.

Patients with impaired liver function.

The half-life of amlodipine is prolonged in patients with impaired hepatic function.

Basic physical and chemical properties

capsules of 2. 5 mg / 2. 5 mg
hard gelatin capsules without labeling, they themselves are closed, with an opaque, flesh-colored body and an opaque flesh-colored lid, filled with a mixture of granules and powder, free of mechanical impurities, white or almost white, without or almost odorless

capsules 5 mg / 5 mg each
hard gelatin capsules without labeling, they themselves are closed, with an opaque, light-burgundy body and an opaque light-burgundy lid, filled with a mixture of granules and powder, free of mechanical impurities, white or almost white, without or almost odorless

capsules of 5 mg / 10 mg hard gelatin capsules without label, they themselves are closed, with an opaque, light pink color body and an opaque maroon cap, filled with a mixture of granules and powder, free of mechanical impurities, white or almost white, without or almost odorless

capsules of 10 mg / 5 mg
hard gelatin capsules without labeling, they themselves are closed, with an opaque, light pink color body and an opaque light-burgundy lid, filled with a mixture of granules and powder, free of mechanical impurities, white or almost white, without or almost odorless

capsules of 10 mg / 10 mg
hard gelatin capsules without labeling, they themselves are closed, with an opaque, dark-burgundy body and an opaque maroon lid filled with a mixture of granules and powder that does not contain mechanical impurities, white or almost white, without or almost no smell.

Shelf life

3 years.

Storage conditions

Store at a temperature not exceeding 30 ° C in a place inaccessible to children.

Packaging

7 capsules in a blister, 4 blisters or 8 blisters in a cardboard package;
or 10 capsules in a blister, 3 or 9 blisters each in a cardboard box.

Category of leave

On prescription.