Prilar® (Prilar®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAmlodipine + RamiprilAmlodipine + Ramipril
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  • Prilar®
    capsules inwards 
    Sandoz d.     Slovenia
  • Egipres®
    capsules inwards 
    Egis Pharmaceutical Plant OJSC     Hungary
    • Dosage form: & nbspcapsules
    Composition:

    1 capsule 5 mg + 2.5 mg contains:

    Active substances: Amlodipine besylate - 6,934 mg (in terms of amlodipine - 5,000 mg), ramipril - 2,500 mg;

    Excipients: cellulose microcrystalline - 95.466 mg, calcium hydrophosphate anhydrous - 37,000 mg, corn starch, pregelatinized - 46,000 mg, corn starch, pregelatinized, with a low moisture content of 20,000 mg, sodium starch glycolate (type A) -2,000 mg, sodium stearyl fumarate - 3,100 mg;

    Shell: auxiliary substances of the shell of the capsule: titanium dioxide (E 171) - 0.9120 mg, gelatin - q.s.;

    capsule caps accessories: iron dye oxide red (E 172) - 0.0261 mg, titanium dioxide (E 171) - 0.9120 mg, gelatin - q.s.

    1 capsule 5 mg + 5 mg contains:

    Active substances: Amlodipine besylate - 6,934 mg (in terms of amlodipine - 5,000 mg), ramipril - 5,000 mg;

    Excipients: cellulose microcrystalline - 95.466 mg, calcium hydrophosphate anhydrous - 37,000 mg, corn starch, pregelatinized - 46,000 mg, corn starch, pregelatinized, with a low moisture content of 20,000 mg, sodium starch glycolate (type A) -2,000 mg, sodium stearyl fumarate - 3,100 mg;

    Shell: auxiliary substances of the shell of the capsule: titanium dioxide (E 171) - 0.9120 mg, gelatin - q.s.;

    capsule caps accessories: iron dye oxide red (E 172) 0.0608 mg, titanium dioxide (E 171) 0.4560 mg, gelatin - q.s.

    1 capsule 5 mg of 4-10 mg contains:

    Active substances: Amlodipine besylate - 6,934 mg (in terms of amlodipine - 5,000 mg), ramipril - 10,000 mg;

    Excipients: cellulose microcrystalline - 95.466 mg, calcium hydrophosphate anhydrous - 37,000 mg, corn starch, pregelatinized - 46,000 mg, corn starch, pregelatinized, with a low moisture content of 20,000 mg, sodium starch glycolate (type A) -2,000 mg, sodium stearyl fumarate - 3,100 mg;

    Shell: auxiliary substances of the shell of the capsule: titanium dioxide (E 171) - 0.9120 mg, gelatin - q.s.;

    capsule caps accessories: ferric oxide red (E 172) 0.1871 mg, titanium dioxide (E 171) 0.6080 mg, gelatin - q.s.

    1 capsule 10 mg + 5 mg contains:

    Active substances: Amlodipine besylate - 13.868 mg (in terms of amlodipine - 10,000 mg), ramipril - 5,000 mg;

    Excipients: cellulose microcrystalline - 88,532 mg, calcium hydrophosphate anhydrous - 37,000 mg, corn starch, pregelatinized - 46,000 mg, corn starch, pregelatinized, with a low moisture content of 20,000 mg, sodium starch glycolate (type A) -2,000 mg, sodium stearyl fumarate - 3,100 mg;

    Shell: auxiliary substances of the shell of the capsule: titanium dioxide (E 171) - 0.9120 mg, gelatin - q.s.;

    capsule caps accessories: dye iron oxide red (E 172) - 0.4560 mg titanium dioxide (E 171) - 0.1520 mg, gelatin - q.s.

    1 capsule 10 mg + 10 mg contains:

    Active substances: amlodipine besylate - 13.868 mg (in terms of amlodipine - 10,000 mg), ramipril - 10,000 mg;

    Excipients: cellulose microcrystalline - 88,532 mg, calcium hydrophosphate anhydrous - 37,000 mg, corn starch, pregelatinized - 46,000 mg, corn starch, pregelatinized, with a low moisture content of 20,000 mg, sodium starch glycolate (type A) -2,000 mg, sodium stearyl fumarate - 3,100 mg;

    Shell: auxiliary substances of the shell of the capsule: titanium dioxide (E 171) - 0.9120 mg, gelatin - q.s.;

    capsule caps accessories: iron oxide yellow dye (E 172) - 0.0608 mg iron oxide black dye (E 172) - 0.0851 mg, colorant ferric oxide red (E 172) - 0.2584 mg titanium dioxide (E 171) - 0 , 2026 mg, gelatin - q.s.

    Description:

    Dosage 5 mg + 2.5 mg:

    Capsule shell: solid opaque gelatin capsules of size 1, with a white body and a lid of light pink color.

    Contents of capsules: white or almost white powder.

    Dosage of 5 mg + 5 mg:

    Capsule shell: solid opaque gelatin capsule size 1, with a white body and a pink lid.

    Contents of capsules: white or almost white powder.

    Dosage of 5 mg + 10 mg:

    Capsule shell: solid opaque gelatin capsule size 1, with a white body and a lid of a dark pink color.

    Contents of capsules: white or almost white powder.

    Dosage of 10 mg + 5 mg:

    Capsule shell: Solid opaque gelatin capsule size № 1, with a housing and a lid of white red-brown.

    Contents of capsules: white or almost white powder.

    Dosage of 10 mg + 10 mg:

    Capsule shell: solid opaque gelatin capsule size 1, with a white body and a brown lid.

    Contents of capsules: white or almost white powder.

    Pharmacotherapeutic group:Antihypertensive combined (blocker "slow" calcium channel inhibitor + ACE)
    ATX: & nbsp

    C.09.B.B   ACE inhibitors in combination with calcium channel blockers

    Pharmacodynamics:

    Amlodipine

    Amlodipine - a derivative of dihydropyridine, a blocker of "slow" calcium channels (BCCI), has an antianginal and hypotensive effect.Linking with dihydropyridine receptors, blocks calcium channels, reduces the transmembrane transition of calcium ions into the cell (mostly in smooth muscle cells of blood vessels, rather than in cardiomyocytes). Antianginal effect is due to the expansion of coronary and peripheral arteries and arterioles: with angina decreases the severity of myocardial ischemia; expanding peripheral arterioles, reduces the overall peripheral vascular resistance (OPSS), reduces preload on the heart, reduces the need for myocardium in oxygen. Expanding the main coronary arteries and arterioles in unchanged and ischemic zones of the myocardium, increases the flow of oxygen into the myocardium (especially with vasospastic angina); prevents the development of constriction of the coronary arteries (including caused by smoking). In patients with angina, a single daily dose increases the time of exercise, slows the development of angina pectoris and the "ischemic" depression of the segment ST, reduces the incidence of angina attacks and consumption of nitroglycerin. Has a long-term dose-dependent hypotensive effect.The hypotensive effect is due to a direct vasodilating effect on smooth muscle vessels. With arterial hypertension, a single dose provides a clinically significant decrease in blood pressure (BP) for 24 hours (in the patient's position "lying" and "standing"). Orthostatic hypotension with amlodipine is rare. Amlodipine does not cause a decrease in exercise tolerance, the ejection fraction of the left ventricle. Reduces the degree of myocardial hypertrophy of the left ventricle, has antiatherosclerotic and cardioprotective effect in coronary heart disease. Does not affect the contractility and conductance of the myocardium, does not cause a reflex increase in the heart rate, inhibits platelet aggregation, increases the rate of glomerular filtration, has a weak natriuretic effect. When diabetic nephropathy does not increase the severity of microalbuminuria. It does not adversely affect the metabolism and concentration of plasma lipids. The time of onset of the effect is 2-4 hours, the duration of the effect is 24 hours.

    Ramipril

    Ramipril is a prodrug, rapidly absorbed in the gastrointestinal tract (GIT), undergoes hydrolysis in the liver with the formation of an active metabolite of ramiprilate. Ramiprilat is a long-acting inhibitor of the angiotensin-converting enzyme (ACE), an enzyme that catalyzes the conversion of angiotensin I into angiotensin II. Ramipril causes a decrease in angiotensin II in the blood plasma, an increase in renin activity and a decrease in aldosterone release. Suppresses the level of kinase II, prevents the disintegration of bradykinin, enhances the synthesis of prostaglandins. When taking ramipril, the formation of angiotensin II decreases and the accumulation of bradykinin occurs, which leads to vasodilation and a decrease in blood pressure.

    Arterial hypertension

    Has hypotensive effect in the patient's position "lying" and "standing". Reduces OPSS (afterload), wedging pressure in the pulmonary capillaries without a compensatory increase in the heart rate. Strengthens coronary and renal blood flow, without affecting the rate of glomerular filtration.

    The onset of hypotensive action develops 1-2 hours after ingestion, the maximum effect is 3-6 hours after ingestion. The action lasts no less than 24 hours.

    Chronic heart failure and heart failure due to acute myocardial infarction

    Ramipril reduces OPSS and, ultimately, blood pressure. Increases the minute volume of the heart and tolerance to physical activity. With prolonged use, it contributes to the reverse development of myocardial hypertrophy in patients with cardiac insufficiency of I and II functional class according to the classification NYHA, improves the blood supply of the ischemic myocardium.

    Ramipril increases the survival of patients with symptoms of acute or chronic heart failure after myocardial infarction. Has cardioprotective effect, prevents coronary ischemic episodes, reduces the likelihood of developing myocardial infarction and reduces the duration of hospitalization.

    Diabetic and nondiabetic nephropathy

    In patients with diabetic and nondiabetic nephropathy, ramipril slows the rate of progression of renal failure and the time at which the terminal stage of renal failure occurs and, as a result, reduces the need for hemodialysis or kidney transplantation procedures.At the initial (preclinical) stages of diabetic or nondiabetic nephropathy ramipril reduces the severity of albuminuria.

    Patients with a high risk of cardiovascular disease

    Due to vascular lesions (diagnosed ischemic heart disease, obliterating peripheral arterial disease or stroke in history), diabetes mellitus with at least one additional risk factor (microalbuminuria, hypertension, increased plasma concentrations of total cholesterol (OX), decreased plasma concentrations of high-density lipoprotein cholesterol (HDL-C), smoking) addition of ramipril to standard therapy significantly reduces the incidence of myocardial infarction, stroke and from cardiovascular reasons.

    Pharmacokinetics:

    Amlodipine

    After oral administration amlodipine is slowly absorbed from the digestive tract by almost 100%. Maximum concentration in the blood (FROMmOh) is achieved 6-12 hours after ingestion. The average absolute bioavailability is about 64-80%. The volume of distribution is approximately 21 liters / kg, indicating that most of the drug is in the tissues, and relatively less in the blood. The connection with plasma proteins is approximately 97.5%.Eating food does not affect the bioavailability of amlodipine. The half-life (T1 / 2) of amlodipine from the blood plasma is about 35-50 hours. Amlodipine is subjected to a slow but extensive metabolism (90%) in the liver with the formation of inactive metabolites, has the effect of a "primary" passage through the liver. Metabolites do not have significant pharmacological activity, with 10% of the dose taken unchanged, 60% excreted by the kidneys in the form of metabolites, and 20-25 % - through the intestines. The total clearance of amlodipine is 7 ml / min / kg (in patients with a body weight of 60 kg - 25 l / h, in elderly patients - 19 l / h). Excretion with breast milk is unknown.

    Patients with impaired renal function

    In patients with renal insufficiency no significant changes in the pharmacokinetics of amlodipine are observed, dose adjustment is not required.

    Patients with impaired hepatic function

    Data on the use of amlodipine in patients with impaired liver function are limited. In patients with impaired hepatic function, amlodipine clearance decreases, which leads to an increase in T1 / 2 to about 60 hours and an increase AUC (the area under the concentration-time curve) is approximately 40-60%.

    Patients elderly (over 70 years)

    Time to reach CmAmlodipine in blood plasma is similar in elderly and younger patients. In elderly patients, amlodipine clearance decreases because of increased AUC and T1 / 2 (T1 / 2 65 h compared with younger patients, but this difference does not have a clinical values). Increase AUC and T1 / 2 in patients with chronic heart failure corresponds to the expected value for this age group.

    Ramipril

    After oral administration ramipril fast absorbed from the digestive tract. After absorption ramipril quickly and almost completely transformed into an active metabolite ramiprilat under the action of the liver esterase enzyme. FROMmOh ramipril in blood plasma is reached within 1 hour after ingestion, its main metabolite is ramiprilata - within 2-4 hours after taking the drug. The bioavailability of ramipril is 60%, ramiprilata is 45%. Absorption does not depend on food intake.

    Binding to plasma proteins reaches 73% for ramipril and 56% for ramiprilate.

    Ramipril is almost completely is metabolized to ramiprilata and to pharmacologically inactive metabolites: a diketopiperazine ester, diketopiperazic acid and ramipril glucuronides. Ramiprilat approximately 6 times more inhibits ACE than ramipril.

    Excretion metabolites occurs mainly by the kidneys. T1 / 2 ramiprilata prolonged use of ramipril in doses of 5-10 mg once daily is 13-17 h. Upon receiving 5 mg ramipril renal clearance of 10-55 ml / min, extrarenal clearance reaches 750 ml / min. For ramiprilate, these values ​​are 70-120 ml / min and about 140 ml / min, respectively. Ramipril and ramiprilate are mainly excreted by the kidneys (40-60%).

    Patients with impaired renal function

    Excretion ramiprilata reduced in patients with impaired renal function, renal clearance ramiprilata proportional to the creatinine clearance. This leads to an increase in the concentration of the latter in blood plasma, which decreases more slowly than in patients with unchanged function kidney.

    Patients with impaired hepatic function

    In patients with impaired liver function transformation ramipril ramiprilat slows down due to the relatively short period of esterases, so ramipril concentration in blood plasma increased in these patients.Nevertheless, CmRamiprilata in these patients does not differ from that in patients with unchanged liver function.

    Indications:

    Arterial hypertension (patients who are shown combined therapy with ramipril and amlodipine in the same doses).

    Contraindications:

    - Hypersensitivity to amlodipine, dihydropyridine derivative, ramipril, other ACE inhibitors or to any of the drug components;

    - hereditary or idiopathic angioedema Quincke (including the taking of ACE inhibitors in the anamnesis);

    - severe arterial hypotension (systolic blood pressure less than 90 mm Hg) or a condition with unstable hemodynamics;

    - Decompensated chronic heart failure (CHF);

    - hemodynamically unstable heart failure after acute myocardial infarction;

    - cardiogenic shock;

    - obstruction of the left ventricular outflow tract (eg clinically significant aortic stenosis), hemodynamically significant aortic or mitral stenosis (risk of excessive blood pressure lowering with subsequent renal impairment (creatinine clearance more than 20 ml / min)), hypertrophic obstructive cardiomyopathy;

    - hemodynamically significant stenosis of the renal arteries (bilateral or unilateral in the case of a single kidney);

    - primary hyperaldosteronism;

    - Nephropathy, which is treated with glucocorticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs), immunomodulators and / or other cytotoxic drugs (clinical experience is insufficient)

    - severe renal failure (CC less than 20 ml / min); hemodialysis (experience of clinical use is insufficient); hemodialysis or hemofiltration using some membranes with a negatively charged surface (high-flux membranes from polyacrylonitrile (the risk of developing reactions of hypersensitivity));

    - apheresis of low density lipoproteins (LDL) using dextran sulfate (the risk of developing hypersensitivity reactions);

    - desensitizing therapy in reactions of hypersensitivity to poisons of insects, such as bees, wasps; simultaneous use with angiotensin II receptor antagonists in patients with diabetic nephropathy;

    - simultaneous use with preparations containing aliskiren, in patients with diabetes mellitus or renal insufficiency (CC less than 60 ml / min);

    - pregnancy and the period of breastfeeding;

    - age to 18 years (efficacy and safety of use not established);

    - contraindications when using the drug in the acute stage of myocardial infarction:

    - severe heart failure (IV functional class by classification NYHA);

    - unstable angina;

    - life-threatening ventricular arrhythmias;

    - "pulmonary" heart.

    Carefully:

    - Simultaneous use with preparations containing aliskiren, or with angiotensin II receptor antagonists, leading to a double blockade of the renin-angiotensin-aldosterone system (RAAS);

    - Hyperkalemia, hyponatremia (including against a background of diuretics and a diet with restriction of consumption of table salt);

    - diabetes mellitus (the risk of hyperkalemia);

    - Acute myocardial infarction (and within 1 month after it);

    - CHF, especially severe or about which other drugs with antihypertensive action are taken; severe lesions of the coronary and cerebral arteries (the risk of a decrease in blood flow with excessive decrease in blood pressure);

    - hemodynamically significant unilateral stenosis of the renal artery (in the presence of both kidneys);

    - conditions accompanied by a decrease in the volume of circulating blood (including diarrhea, vomiting);

    - simultaneous use of lithium drugs, immunosuppressants, saluretics, dantrolene intravenously, inhibitors and inducers of isoenzyme CYP3A4;

    - connective tissue diseases (including systemic lupus erythematosus, scleroderma - increased risk of developing neutropenia or agranulocytosis);

    - elderly age (over 70 years) (increased risk of concurrent liver and / or kidney and heart failure);

    - condition after kidney transplantation, liver failure;

    - CHF of non-ischemic etiology III-IV functional class by classification NYHA,

    - aortic stenosis;

    - syndrome of weakness of the sinus node;

    - mitral stenosis;

    - arterial hypotension;

    - severe, especially malignant hypertension;

    - renal dysfunction (KK 20-60 ml / min) because of the risk of hyperkalemia and leukopenia;

    - the only functioning kidney, renovascular hypertension;

    surgery / general anesthesia.

    Pregnancy and lactation:

    Pregnancy. The use of Prilar® during pregnancy is contraindicated, becausethe use of ramipril can adversely affect the fetus: impaired fetal kidney development, fetal and neonatal fetal pressure, renal dysfunction, hyperkalemia, hypoplasia of the skull bones, and lung hypoplasia. Prilar® is not recommended for women planning pregnancy. In case of pregnancy, during treatment with Prilar®, stop taking the drug as early as possible and monitor the development of the fetus.

    Women with childbearing potential who are receiving ACE inhibitor therapy should use effective contraception. If women with childbearing potential with arterial hypertension take ACE inhibitors, then it is necessary to remember the necessity in case of pregnancy of the transfer of the patient to taking an antihypertensive drug from another group. In all cases, careful medical supervision is necessary.

    Breastfeeding period. There is no information as to whether the amlodipine or ramipril in breast milk. Studies in animals have shown that ramipril excreted in breast milk of rats.The use of Prilar® during breastfeeding is contraindicated. If it is necessary to prescribe Prilar®, a breastfeeding mother should decide whether to stop breastfeeding.

    Fertility. In some patients who took BCCI, reversible changes in the heads of spermatozoa were noted. Clinical studies on the potential effects of amlodipine on fertility is not enough.

    Dosing and Administration:

    Inside, 1 capsule 1 time per day, at the same time, regardless of food intake. Capsules should be swallowed whole, not chewing and not breaking, squeezed with a sufficient amount of liquid (for example, water).

    The dose of Prilar® is selected individually after previous titration of the doses of each component of the drug: amlodipine and ramipril. Prilar® should not be used for the initial treatment of hypertension. If it is necessary to correct the dose of Prilar® it is necessary to carry out individual selection of doses of components in monotherapy. Only after this, the use of Prilar® with fixed doses of components in the following combinations is possible:

    - 5 mg of amlodipine + 2.5 mg of ramipril;

    - 5 mg of amlodipine + 5 mg of ramipril;

    - 5 mg of amlodipine + 10 mg of ramipril;

    - 10 mg of amlodipine + 5 mg of ramipril;

    - 10 mg of amlodipine + 10 mg of ramipril.

    The maximum daily dose of amlodipine is 10 mg, the maximum daily dose of ramipril is 10 mg.

    Dosages of 10 mg of amlodipine + 10 mg of ramipril (for amlodipine and ramipril), 10 mg of amlodipine + 5 mg of ramipril (for amlodipine) and 5 mg of amlodipine + 10 mg of ramipril (for ramipril) are the maximum daily doses.

    Adults

    Caution should be exercised in patients taking diuretics, because of the possible development of a risk of disturbance of the water-electrolyte balance. It is necessary to monitor the kidney function and the content of potassium in the blood serum.

    Patients with impaired hepatic function

    Prilar® is recommended only for patients receiving 2.5 mg of ramipril as the optimal maintenance dose established during the titration of a dose of ramipril.

    Patients with impaired renal function

    In patients with impaired renal function, dosage adjustment of amlodipine is not required. Amlodipine Do not undergo dialysis. In patients on hemodialysis, amlodipine should be used with extreme caution.

    The daily dose of ramipril in patients with impaired renal function should be selected with regard to the CC:

    - at CC ≥60 ml / min dose adjustment is not required (initial dose of 2.5 mg / day), maximum daily dose of 10 mg;

    - with KK 20-60 ml / min the maximum daily dose should be 5 mg;

    - with CC less than 20 ml / min, the use of ramipril is contraindicated.

    It is necessary to monitor the function of the kidneys and the concentration of potassium in the blood serum during therapy with amlodipine / ramipril. If the kidney function worsens, Prilar® should be discontinued.

    Elderly patients

    Older patients are advised to take usual doses, with a dose increase to be carried out with caution, dose titration should be gradual, since there is a risk of developing unwanted reactions, especially in very elderly and weakened patients.

    Children and teens

    Prilar® is not recommended for children under 18 due to the lack of clinical data on the efficacy and safety of ramipril and amlodipine in both monotherapy and combination therapy.
    Side effects:

    According to the World Health Organization (WHO), unwanted effects are classified according to their frequency of development as follows: very often (≥1 / 10),often (from ≥1 / 100 to <1/10), infrequently (from ≥1 / 1,000 to <1/100), rarely (from ≥1 / 10,000 to <1 / 1,000), very rarely (<1 / 10,000) ; frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.

    Class of organ systems

    Frequency of occurrence

    Amlodipine

    Ramipril

    Violations of the blood and lymphatic system

    Infrequently

    Eosinophilia

    Rarely

    Leukopenia (including neutropenia and agranulocytosis), a decrease in the number of erythrocytes, thrombocytopenia, a decrease in the concentration of hemoglobin

    Rarely

    Leukopenia, thrombocytopenia, thrombocytopenic purpura

    Frequency unknown

    Inhibition of bone marrow hematopoiesis, pancytopenia, hemolytic anemia

    Immune system disorders

    Rarely

    Allergic reactions, angioedema, erythema multiforme, urticaria

    Frequency unknown

    Anaphylactic or anaphylactoid reactions, an increase in the titer of antinuclear antibodies

    Disorders from metabolism and nutrition and laboratory data

    Often

    Increase in the concentration of potassium in the blood plasma

    Infrequently

    Increase / decrease in body weight

    Anorexia, decreased appetite

    Rarely

    Hyperglycaemia

    Frequency unknown

    Reduction of the concentration of sodium in blood plasma, syndrome of inadequate secretion of antidiuretic hormone

    Disorders of the psyche

    Infrequently

    Insomnia, mood lability (including anxiety), depression, unusual dreams

    Depression, anxiety, nervousness, motor excitement, sleep disorders, including insomnia

    Rarely

    Confusion of consciousness

    Confusion of consciousness

    Frequency unknown

    Disturbance of concentration

    Disturbances from the nervous system

    Often

    Headache, dizziness, drowsiness (especially at the beginning of therapy)

    Headache, dizziness

    Infrequently

    Tremor, dysgeusia. fainting, hypoesthesia, paresthesia, asthenia

    Vertigo, paresthesia (spontaneous sensation of numbness, tingling), agevzia (loss of taste sensitivity), dysgeusia (a violation of taste sensitivity)

    Rarely

    Convulsions, apathy, migraine

    Tremor, imbalance

    Rarely

    Ataxia, amnesia, peripheral neuropathy, hypertonia

    Frequency unknown

    Extrapyramidal disorders

    Ischemia of the brain, including ischemic stroke and transient disorders of cerebral circulation, psychomotor disorders,parosmia (impaired perception of odors), burning sensation

    Disturbances on the part of the organ of sight

    Infrequently

    Visual disorders, including diplopia, accommodation disorder, xerophthalmia, conjunctivitis, eye pain

    Visual disorders, including blurred vision

    Rarely

    Conjunctivitis

    Hearing and balance disorders

    Infrequently

    Noise in ears

    Rarely

    Hearing impairment, tinnitus

    Heart Disease

    Often

    Heart palpitations

    Infrequently

    Myocardial ischemia, including angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema

    Rarely

    Development or aggravation of chronic heart failure

    Rarely

    Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation), arterial hypertension

    Vascular disorders

    Often

    Hyperemia of the skin (sensation of heat and "tides" of blood to the skin of the face), peripheral swelling (ankles and feet)

    Excessive reduction in blood pressure, violation of orthostatic regulation of vascular tone (orthostatic hypotension), fainting

    Infrequently

    Excessive reduction in blood pressure, orthostatic hypotension

    Hyperemia ("tides" of blood to the skin of the face)

    Rarely

    Stenosis of blood vessels, reduction of blood circulation, vasculitis

    Rarely

    Vasculitis

    Frequency unknown

    Raynaud's syndrome

    Disturbances from the respiratory system, chest and mediastinal organs

    Often

    "Dry" cough (worse at night and lying down), bronchitis, sinusitis, dyspnoea (dyspnea)

    Infrequently

    Dyspnea (dyspnea), rhinitis (runny nose)

    Bronchospasm, including weighting of the course of bronchial asthma, nasal congestion

    Rarely

    Cough

    Disorders from the gastrointestinal tract

    Often

    Nausea, abdominal pain

    Inflammatory processes in the gastrointestinal tract, digestive disorders, abdominal pain, dyspepsia, diarrhea, nausea, vomiting

    Infrequently

    Vomiting, indigestion, changes in the rhythm of defecation (including diarrhea and constipation), dryness of the oral mucosa, flatulence, anorexia, thirst

    Pancreatitis (cases of death were observed extremely rarely with ACE inhibitors), increased activity of pancreatic enzymes, intestinal angioedema, pain in the upper abdomen, gastritis, constipation, dryness of the oral mucosa

    Rarely

    Increased appetite

    Glossitis

    Rarely

    Pancreatitis, gastritis, gingival hyperplasia

    Frequency unknown

    Aphthous stomatitis

    Disturbances from the liver and bile ducts

    Infrequently

    Increased activity of "liver" enzymes and / or concentration of conjugated bilirubin

    Rarely

    Cholestatic jaundice, hepatocellular disorders

    Rarely

    Hepatitis, jaundice, increased activity of "liver" enzymes

    Frequency unknown

    Acute liver failure, cholestatic or cytolytic hepatitis (cases of death were very rare)

    Disturbances from the skin and subcutaneous tissues

    Often

    Skin rash, mainly maculopapular

    Infrequently

    Alopecia, hemorrhagic rash, skin discoloration, hyperhidrosis (increased sweating), itchy skin, skin rash, exanthema

    Angioedema, including fatal outcome (laryngeal edema can cause airway obstruction with fatal outcome); skin itching, hyperhidrosis (increased sweating)

    Rarely

    Exfoliative dermatitis, urticaria, onycholysis (exfoliation of the nail from the soft tissues of the finger)

    Rarely

    Exfoliative dermatitis, Stevens-Johnson syndrome, Quincke's edema, photosensitivity reactions, xeroderma, "cold sweat," a violation of skin pigmentation

    Photosensitivity reactions

    Frequency unknown

    Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus (blistering rash), weight gain of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid exanthema, alopecia

    Disturbances from the musculoskeletal system and connective tissue

    Often

    Puffiness in the ankle

    Muscle cramps, myalgia

    Infrequently

    Arthralgia, myalgia, muscle cramps, back pain, arthrosis

    Arthralgia

    Rarely

    Myasthenia gravis

    Disorders from the kidneys and urinary tract

    Infrequently

    Painful urination, nocturia, frequent urination

    Violation of kidney function, including the development of acute renal failure, increased diuresis, worsening of existing proteinuria, an increase in the concentration of urea and creatinine in the blood plasma

    Violations of the genitals and mammary glands

    Infrequently

    Impotence, gynecomastia

    Transient erectile dysfunction, decreased libido

    Frequency unknown

    Gynecomastia

    Systemic disorders and complications at the site of administration

    Often

    Increased fatigue

    Pain in the chest, increased fatigue

    Infrequently

    Chest pain, chills

    Fever

    Rarely

    Asthenia
    Overdose:

    Cases of overdose with a combination of amlodipine / ramipril are unknown. The data on overdose of amlodipine and ramipril received separately.

    Amlodipine

    Symptoms: marked decrease in blood pressure with the possible development of reflex tachycardia and excessive peripheral vasodilation (there is a possibility of a pronounced and persistent arterial hypotension, including with the development of shock and death).

    Treatment: gastric lavage, activated charcoal intake (in healthy volunteers, taking activated charcoal for 2 hours after taking 10 mg of amlodipine reduced the rate of absorption of amlodipine), elevating limbs, monitoring the function of the cardiovascular and respiratory systems, monitoring the volume of circulating blood and diuresis. To restore the tone of blood vessels and blood pressure, it is possible to use vasoconstrictors in the absence of contraindications to their use.To neutralize the effect of BCCI - intravenous calcium gluconate. Hemodialysis is ineffective.

    Ramipril

    Symptoms: excessive peripheral vasodilation (with pronounced decrease in blood pressure and development of shock), bradycardia, disturbances of water electrolyte balance, acute renal failure, stupor.

    Treatment: gastric lavage, intake of adsorbents, sodium sulfate (preferably within the first 30 minutes after administration). With severe arterial hypotension should be given an elevated position to the limbs, to therapy to replenish the volume of circulating blood and restore electrolyte balance, the introduction of α-adrenergic agonists (norepinephrine, dopamine) and angiotensin-II (angiotensinamil). In the case of bradycardia, the appointment of atropine or the installation of a temporary artificial pacemaker is recommended. It is necessary to carefully monitor blood pressure, kidney function and the concentration of electrolytes in the blood serum. Ramiprilate, an active metabolite of ramipril, is poorly excreted from the systemic circulation by hemodialysis.

    Interaction:

    Amlodipine

    The simultaneous use of amlodipine with powerful or moderate inhibitors of isoenzyme CYP3A4 (HIV protease inhibitors, azole antifungal agents (itraconazole and ketoconazole), macrolides, (for example, erythromycin or clarithromycin, verapamil and diltiazem) can lead to a significant increase in the concentration of amlodipine in the serum. Clinical manifestations of these pharmacokinetic variations may be more pronounced in elderly patients. In particular, in patients taking both clarithromycin and amlodipine, increased risk of lowering blood pressure. A thorough clinical observation and, if necessary, dose adjustment are recommended.

    Use with caution inducers of isoenzyme CYP3A4 (eg, rifampicin, St. John's wort pitted), since it is possible to reduce the concentration of amlodipine in the blood plasma.

    It is not recommended to apply amlodipine simultaneously with grapefruit or grapefruit juice in connection with the possible increase in the bioavailability of amlodipine, which contributes to the intensification of the hypotensive effect of the drug. Because of the possible development of hyperkalemia, BCCC should not be used, incl. amlodipine, from dantrolene intravenously in patients predisposed to malignant hyperthermia, as well as in the treatment of malignant hyperthermia.

    With the repeated use of amlodipine in a dose of 10 mg and simvastatin in a dose of 80 mg, an increase in the exposure of simvastatin by 77% compared with simvastatin monotherapy. When used simultaneously with Amlodipine, the maximum daily dose of simvastatin should not exceed 20 mg.

    With the simultaneous use of amlodipine and tacrolimus may increase tacrolimus concentration in the blood serum. In order to prevent the development of tacrolimus toxicity, it is required to regularly monitor the dose of tacrolimus in the blood serum during treatment and, if necessary, adjust its dose.

    Studies of simultaneous use of amlodipine and cyclosporine in healthy volunteers and all patient groups, except for patients after kidney transplantation, were not performed. Various studies of amlodipine with cyclosporine in patients after kidney transplantation show that the use of this combination may not lead to any effect or increase the minimum concentration of cyclosporine to varying degrees to 40%.These data should be taken into account and the concentration of cyclosporine in this group of patients should be monitored while cyclosporine and amlodipine are used simultaneously.

    With simultaneous application amlodipine can increase the system exposure tasononemine in the blood plasma. In such cases, regular monitoring of the tasononemine in the blood and a dose adjustment if necessary.

    Corticosteroids can help reduce the antihypertensive effect of amlodipine and cause a delay in the fluid and sodium ions in the body as a result of their action.

    Baclofen intensifies the antihypertensive effect, you should carefully monitor the level of blood pressure and, if necessary, adjust the dose of antihypertensive drugs.

    Amifostine can enhance the antihypertensive effect of amlodipine.

    Ritonavir increases plasma concentrations of BCCC, including amlodipine.

    When combined with some tricyclic antidepressants may increase the antihypertensive effect of the drug.

    Shown, that amlodipine does not cause clinically significant changes in pharmacokinetics atorvastatin, digoxin, warfarin, cimetidine, non-steroidal anti-inflammatory drugs (NSAIDs), special indomethacin.

    Ethanol (alcoholic beverages): at a single and repeated application in a dose of 10 mg amlodipine has no significant effect on the pharmacokinetics of ethanol.

    A single dose of 100 mg sildenafil in patients with essential hypertension does not affect the pharmacokinetic parameters of amlodipine.

    When used with thiazide and "looped" diuretics, verapamil, ACE inhibitors, beta-blockers and nitrates it is possible to increase the anti-anginal and hypotensive effect of BCCI, as well as enhance their hypotensive effect when combined with alpha 1-adrenoblockers, isoflurane, and antipsychotics.

    Combined application of BCCI and beta-adrenoreceptor blockers in patients with myocardial infarction can lead to its re-emergence and the development of severe heart failure.

    With the simultaneous use of amlodipine with antiarrhythmic drugs that cause lengthening of the interval QT (eg, amiodarone, quinidine), it is possible to intensify the negative negative inotropic effect.

    When combined with lithium preparations may increase the manifestation of symptoms of neurotoxicity (nausea, vomiting, diarrhea, ataxia, tremor, tinnitus).

    Calcium preparations reduce the effect of BCCI.

    Ramipril

    Contraindicated combinations

    The use of some high-strength membranes with a negatively charged surface (for example, polyacrylonitrile membranes) during hemodialysis or hemofiltration, the use of dextran sulfate in the apoplexy of LDL can lead to the development of severe anaphylactic reactions; if the patient requires these procedures, other types of membranes should be used (in the case of plasmapheresis and haemofiltration) or transfer the patient to other antihypertensive drugs.

    As with other ACE inhibitors, joint use of ramipril with aliskiren and aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or moderate or severe renal insufficiency (CC less than 60 ml / min).

    Simultaneous application with other means acting on the renin-angiotensin-aldosterone system (RA AS) increases the risk of developing arterial hypotension, renal failure (including acute renal failure), hyperkalemia. It is recommended to regularly measure blood pressure, monitor kidney function and electrolyte levels in patients taking ramipril, as well as other drugs that affect the RAAS.

    Simultaneous use of the drug and angiotensin II receptor antagonists in patients with diabetic nephropathy is contraindicated and is not recommended in other patients.

    Combinations, which should be used with caution

    Simultaneous application with potassium salts, potassium-sparing diuretics (for example, amiloride, triamterene, spironolactone), and drugs that increase the level of potassium in the blood serum (including co-trimoxazole, tacrolimus, ciclosporin, angiotensin II receptor antagonists), can lead to an increase in potassium in the blood serum (regular monitoring of potassium in the blood serum is required).

    Hypotensive drugs (alfuzosin, doxazosin, prazozin, tamsulosin, terazosin), baclofen, diuretics, nitrates, tricyclic antidepressants, antipsychotics, sleeping pills, narcotic analgesics, means for general and local anesthesia, ethanol reinforce antihypertensive action of ramipril.

    Vasopressornye sympathomimetics and other drugs that cause antihypertensive effects (for example, isoproterenol, dobutamine, dopamine, epinephrine) reduce the antihypertensive effect of ramipril, while regular monitoring of blood pressure is required.

    Simultaneous application with allopurinol, procainamide, cytostatics, immunosuppressants, corticosteroids (glucocorticosteroids and mineralocorticosteroids) and other means that can affect hematologic indices, increases the risk of developing leukopenia. The simultaneous use of ramipril with corticosteroids is not recommended. Inhibitors of RAAS may reduce excretion lithium salts. Simultaneous use with lithium salts leads to an increase in the concentration of lithium in the blood serum and an increase in the cardio- and neurotoxic effects of lithium. It is recommended to monitor the concentration of lithium in the blood serum. Ramipril increases hypoglycemic effect hypoglycemic agents (insulin, hypoglycemic agents for oral administration (derivatives of sulfonylureas)) up to the development of hypoglycemia. It is necessary to control the concentration of glucose.

    Dipeptidyl peptidase type IV inhibitors-IV) (glyptins), eg, sitagliptin, saxagliptin, vildagliptin, linogliptin, can lead to an increased incidence of angioedema.

    The simultaneous use of ramipril with inhibitors mTOR (mammalian Target of Rapamycin - The target of rapamycin in mammalian cells), for example, with sirolimus, tamsyrolimus, everolimus may lead to an increased risk of angioedema.

    With simultaneous use of ACE inhibitors and neutral endopeptidase (NEP) inhibitors, such as racecadotril, reported increased risk of angioedema.

    Other interactions

    Non-steroidal anti-inflammatory drugs (NSAIDs) (eg, acetylsalicylic acid (more than 3 g / day), inhibitors of cyclooxygenase-2 (COX2)) can weaken the antihypertensive effect of ramipril, as well as cause renal dysfunction, sometimes leading to the development of renal failure.

    Heparin can increase the potassium content in the serum.

    Sodium chloride can weaken the effect of ramipril.

    Do not use ethanol during treatment with ramipril (increased inhibitory effect of ethanol on the central nervous system (CNS)).

    Estrogens weaken the antihypertensive effect (fluid retention). Interaction estramustine may increase the risk of developing angioedema.

    Desensitizing therapy with hypersensitivity to insect venoms. ACE inhibitors, including ramipril, increase the likelihood of developing severe anaphylactic or anaphylactoid reactions to insect venoms. It is assumed that this effect can occur when other allergens are used.

    Special instructions:

    Amlodipine does not adversely affect the metabolism and lipids of blood plasma, so it can be used in patients with bronchial asthma, diabetes mellitus and gout, as well as in cases when the patient is predisposed to vasospasm / vasoconstriction.

    Patients with low body weight, low growth patients and patients with severe liver dysfunction may need a smaller dose.During treatment, it is necessary to control body weight and monitor the dentist (to prevent soreness, bleeding and gingival hyperplasia).

    Double blockade of RAAS

    Simultaneous use with drugs containing aliskiren, or with angiotensin II receptor antagonists, resulting in a double blockade of RAAS, is not recommended due to the risk of excessive BP reduction, the development of hyperkalemia, and impaired renal function compared to monotherapy.

    As with other ACE inhibitors, the combined use of ramipril with aliskiren and aliskiren-containing drugs in patients with diabetes mellitus or moderate or severe renal failure (CC less than 60 ml / min) is contraindicated (see section "Contraindications"). Simultaneous use with angiotensin II receptor antagonists in patients with diabetic nephropathy is contraindicated (see section "Contraindications ").

    Patients with severe RAAS activation have an increased risk of developing arterial hypotension and worsening kidney function when RAAS activity is suppressed, especially with the first appointment or increase in the dose of ACE inhibitors and / or diuretics.The pronounced activation of RAAS is most likely in the following categories of patients:

    - patients with severe arterial hypertension;

    - patients with decompensated CHF;

    - patients with aortic or mitral stenosis or other diseases that interfere with the inflow or outflow of blood from the left ventricle;

    - patients with unilateral stenosis of the renal artery in the presence of a normally functioning contralateral kidney;

    - patients with the available or expected development of dehydration or sodium deficiency (including patients receiving diuretics);

    - patients with cirrhosis of the liver and / or ascites);

    - patients who are scheduled for extensive surgery or general anesthesia.

    Start treatment

    Before starting treatment with Prilar®, it is necessary to eliminate hyponatremia and hypovolemia. In patients who have been taking diuretics, it is necessary to cancel them or reduce their dose 2-3 days before the start of Prilar®. Nevertheless, the condition of patients with CHF should be closely monitored in connection with the possibility of developing decompensation in them against the background of an increase in the volume of circulating blood and weigh the benefits of such correction with respect to potential risks.

    After taking the first dose, as well as increasing the dose of the diuretic and / or Prilar®, patients should stay for 8 hours under medical supervision in view of the possibility of developing orthostatic hypotension.

    Arterial hypotension

    Transient arterial hypotension is not a contraindication for the continuation of treatment with Prilar®, since when recovering the volume of circulating blood and normalizing blood pressure, taking the following doses of the drug usually does not cause symptomatic arterial hypotension. In the case of repeated occurrence of severe arterial hypotension, the dose should be reduced or the drug should be withdrawn.

    Patients with malignant hypertension or concomitant heart failure, especially in the acute stage of myocardial infarction, should begin treatment only in a hospital.

    Care should also be taken with physical activity and / or hot weather due to the risk of increased sweating and dehydration with the development of arterial hypotension due to a decrease in the volume of circulating blood and a decrease in the sodium content in the blood.

    CHF

    In patients with CHF (III and IV functional class by classification NYHA) there was a higher incidence of pulmonary edema. It is necessary to use BCCC with caution, incl. amlodipine, in patients with CHF because of the possible risk of complications from the cardiovascular system until death.

    In patients with CHF, taking Prilar® can lead to a marked decrease in blood pressure, which in some cases is accompanied by oliguria or azotemia and rarely with acute renal failure.

    Hypertensive crisis

    The safety and efficacy of the drug Prilar® and its individual components in hypertensive crisis have not been established.

    Surgical interventions

    The use of ACE inhibitors, including ramipril, in patients undergoing surgery with general anesthesia, can lead to the development of arterial hypotension. It is recommended to stop taking Prilar® one day before surgery.

    Elderly patients

    When using the drug in elderly patients, increasing the dose should be done with caution.

    Renal impairment

    Prior to initiation of therapy and during treatment with Prilar®, the kidney function (creatinine, urea), the content of potassium in the blood plasma, a general blood test, hemoglobin, functional tests of the liver. Especially carefully monitor the condition of patients with renal insufficiency. In patients with renal insufficiency amlodipine may be given in normal doses. The concentration of amlodipine in the blood plasma does not correlate with the severity of renal failure. Amlodipine not excreted by hemodialysis. There is a risk of developing a kidney deficiency in the background of the use of ramipril, especially in patients with CHF or who underwent kidney transplantation.

    Dysfunction of the liver

    In patients with impaired liver function AUC and T1 / 2 amlodipine increases. Reception of amlodipine should be started with low doses, increasing the dose gradually, regular monitoring of the patient's condition is necessary. With the development of cholestatic jaundice or a marked increase in the activity of "liver" transaminases, the use of ACE inhibitors should be stopped.

    Hyperkalemia

    The risk group for hyperkalemia is elderly patients (over 70 years), patients with renal insufficiency, decompensated diabetes mellitus,potassium-sparing diuretics, potassium preparations or potassium-containing substitutes for edible salt and preparations that increase potassium levels in the blood serum (eg heparin) or patients with conditions such as dehydration, acute decompensation of heart failure, metabolic acidosis. Regular monitoring of serum potassium concentration is recommended.

    Neutropenia / agranulocytosis

    The development of neutropenia / agranulocytosis, thrombocytopenia and anemia as board of myelosuppression was reported in the background of ramipril. It is recommended to monitor the peripheral blood parameters for the development of leukopenia. In patients with an increased risk of developing neutropenia (with impaired renal function, systemic connective tissue diseases, such as systemic lupus erythematosus or scleroderma, and other drugs that can cause changes in the pattern of peripheral blood), when Prilar® is prescribed The control of the general or common analysis of a blood of 1 time a month during the first 3-6 months of therapy, and also at the first signs of an infection is necessary.If neutropenia is detected (the number of neutrophils is less than 2000 / μL) therapy with ACE inhibitors should be discontinued.

    Angioedema

    In rare cases with angiotensin-converting enzyme inhibitors, including ramipril, angioedema of the face, extremities, lips, tongue, throat and / or pharynx is noted. If there is swelling that can develop suddenly in any period of treatment, stop taking the medication immediately, take emergency medical care and ensure that the patient is carefully monitored until the symptom is completely and permanently disappeared. Observation should be conducted for at least 12-24 hours.

    In patients receiving ACE inhibitors, there were cases of intestinal angioedema, which manifested itself with abdominal pain with or without nausea and vomiting, and in some cases angioedema was observed simultaneously. When a patient appears on the background of treatment with ACE inhibitors of the above-described symptoms, it is necessary to consider the possibility of developing an intestinal angioedema in the course of a differential diagnosis.

    Anaphylactoid reactions in patients, hemodialysis patients, or with an aphthous LDL

    Some high-strength membranes with a negatively charged surface (for example, polyacrylonitrile membranes) should be avoided, for example, for urgent hemodialysis or hemofiltration in combination with ACE inhibitors (due to the possibility of anaphylactoid reactions in patients). In rare cases, with the apheresis of LDL with dextran sulfate and the simultaneous administration of ACE inhibitors, the development of anaphylactoid reactions is possible. Therefore, this method should not be used in patients receiving ACE inhibitors.

    Ethnic Features

    Among patients of the Negroid race receiving ACE inhibitor therapy, the incidence of angioedema is higher than among patients of other race. Patients with an angioneurotic edema in a history not associated with the use of ACE inhibitors have an increased risk of developing angioedema while taking any ACE inhibitor.

    Cough

    With the use of ACE inhibitors, it is possible to develop a dry cough. Coughing attacks are of a persistent nature, but quickly disappear after the drug is discontinued.This feature should be taken into account in the differential diagnosis of cough. If necessary, treatment can be continued.

    Interaction with medicinal products

    Amlodipine can be used in combination with thiazide diuretics, alpha and beta adrenoblockers, ACE inhibitors, prolonged-action nitrates, nitroglycerin for oral administration, NSAIDs, antibiotics, oral hypoglycemic agents.

    Desensitizing therapy

    Desensitizing therapy with increased susceptibility to insect venoms and simultaneous administration of ACE inhibitors, including ramipril, can initiate anaphylactic and anaphylactoid reactions (eg, lowering blood pressure, dyspnea, vomiting, allergic skin reactions) that can be life threatening. With the use of ACE inhibitors, hypersensitivity reactions to insect venom (bees, wasps) develop faster and take more severe course. If it is necessary to conduct desensitization to insect venom, it is recommended to replace the ACE inhibitor with a drug of another group.

    Hyperaldosteronism

    Hypotensive agents that inhibit RAAS,usually are not effective in the treatment of patients with primary hyperaldosteronism, therefore, the use of ramipril in such cases is not recommended.

    Effect on the ability to drive transp. cf. and fur:

    Amlodipine and ramipril can have little or moderate impact on the ability to manage vehicles, mechanisms. When there is dizziness (especially at the beginning of therapy), headache, visual disorders, it is recommended to refrain from driving and other potentially dangerous activities that require increased concentration and speed of psychomotor reactions.

    Form release / dosage:

    Capsules, 5 mg + 2.5 mg, 5 mg + 5 mg, 5 mg + 10 mg, 10 mg + 5 mg, 10 mg + 10 mg.

    Packaging:7 capsules per blister of combined material (polyamide / aluminum / polyvinyl chloride), sealed with aluminum foil. For 4 blisters per pack of cardboard along with instructions for use.
    Storage conditions:

    In the original packaging in a dark place at a temperature of no higher than 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    2 years.

    Do not use the drug after the expiry date printed on the package.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-004630
    Date of registration:15.01.2018
    Expiration Date:15.01.2023
    The owner of the registration certificate:Sandoz d.Sandoz d. Slovenia
    Manufacturer: & nbsp
    Representation: & nbspSANDOZ SANDOZ Switzerland
    Information update date: & nbsp20.02.2018
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