Pharmacological properties
Pharmacodynamics. Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: APF, kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. A decrease in the amount of angiotensin II and inhibition of the breakdown of bradykinin lead to vasodilation.
Since angiotensin II also stimulates aldosterone release, ramiprilat contributes to the reduction of aldosterone secretion. The response to monotherapy with ACE inhibitors was on average less pronounced in black (Afro-Caribbean) hypertensive patients (a population characterized by low-renin states in hypertension) than in non-black patients.
Administration of ramipril causes a significant decrease in peripheral arterial resistance. In general, the drug does not significantly change renal blood flow and glomerular filtration rate.
Administration of ramipril to patients with hypertension results in a decrease in supine and standing blood pressure without a compensatory increase in heart rate.
In most patients, the antihypertensive effect is manifested 1-2 hours after administration of the drug, reaches a maximum after 3-6 hours and lasts for 24 hours. The maximum therapeutic effect is usually achieved after continuous use after 3-4 weeks. It has been established that the antihypertensive effect is maintained with long-term therapy for 2 years. Abrupt discontinuation of ramipril does not cause a rapid and sharp increase in blood pressure.
In addition to conventional therapy with diuretics and, if necessary, cardiac glycosides, ramipril is effective in patients with NYHA functional class (FC) II-IV. The drug exhibits beneficial effects on cardiac hemodynamics (reduction of left and right ventricular filling pressures, OPSS, increase in cardiac output and improvement of cardiac index). It also reduces neuroendocrine activation.
Pharmacokinetics. Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract: its C max in plasma is reached within 1 hour. The extent of absorption is 56%, this indicator does not depend on the presence of food in the gastrointestinal tract. C max of ramiprilat, the only active metabolite of ramipril, is reached in plasma 2-4 hours after taking the drug. In the case of using the usual dose (1 time per day), the equilibrium concentration of ramiprilat in plasma is reached on the 4th day of treatment.
Distribution: The plasma protein binding of ramipril is approximately 73% and that of ramiprilat is approximately 56%.
Metabolism: Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazine acid, and the glucuronides of ramipril and ramiprilat.
Elimination. Excretion of metabolites is mainly renal. The decrease in plasma ramiprilat concentration occurs in several phases. Due to the strong saturable binding to ACE and slow dissociation from the enzyme, ramiprilat is characterized by a prolonged terminal elimination phase at very low plasma concentrations.
After multiple doses of ramipril, its T½ was 13-17 hours for doses of 5-10 mg and slightly longer for doses of 1.25-2.5 mg. This difference is due to the saturable ability of the enzyme to bind ramiprilat.
Ramipril and its metabolite are not detected in breast milk after a single dose. However, the effect of multiple doses is unknown.
Renal excretion of ramiprilat is reduced in patients with impaired renal function. In patients with liver damage, the metabolism of ramipril is slowed down, which is due to reduced activity of hepatic esterases, the level of ramipril in the blood plasma of these patients was increased. However, C max of ramiprilat in such patients did not differ from that in patients with normal liver function.
Indication
Treatment and prevention of cardiovascular diseases: reduction of cardiovascular morbidity and mortality in patients with:
severe cardiovascular diseases of atherothrombotic genesis (history of coronary heart disease or stroke, or peripheral vascular disease); diabetes mellitus, who have at least one cardiovascular risk factor (see Pharmacological properties).
Treatment of kidney disease:
initial glomerular diabetic nephropathy, as evidenced by the presence of microalbuminuria; severe glomerular diabetic nephropathy, as evidenced by the presence of macroproteinuria, in patients with at least one cardiovascular risk factor (see Pharmacological properties); severe glomerular non-diabetic nephropathy, as evidenced by the presence of macroproteinuria ≥3 g/day (see Pharmacological properties).
Treatment of heart failure accompanied by clinical manifestations. Secondary prevention after acute myocardial infarction: reduction of mortality during the acute phase of myocardial infarction in patients with clinical signs of heart failure when treatment is started more than 48 hours after the onset of acute myocardial infarction.
Application
Drug for oral use.
Adults. Rami Sandoz may cause hypotension, the development of which is more likely in patients who are simultaneously receiving diuretics. In such cases, caution is recommended, since these patients may experience a decrease in BCC and / or electrolytes. It is advisable to stop the use of diuretics 2-3 days before starting treatment with Rami Sandoz, if possible (see Features of use).
In patients with hypertension who cannot discontinue the diuretic, Rami Sandoz should be initiated at a dose of 1.25 mg. Renal function and blood potassium levels should be closely monitored. The subsequent dose of Rami Sandoz should be adjusted according to the target blood pressure.
Hypertension. The dose should be selected individually, depending on the patient's condition (see Features of use) and the results of control measurements of blood pressure. Rami SANDOZ can be used as monotherapy or in combination with antihypertensive drugs of other classes.
Initial dose: Treatment with Rami Sandoz should be initiated gradually, starting with the recommended starting dose of 2.5 mg/day.
In patients with a strongly activated renin-angiotensin-aldosterone system, a significant decrease in blood pressure may occur after the initial dose. For such patients, the recommended dose is 1.25 mg and their treatment should be initiated under supervision (see Precautions).
Dose titration and maintenance dose. The dose can be doubled every 2-4 weeks until the target blood pressure is reached; the maximum dose of Rami Sandoz is 10 mg/day. The drug is usually taken once a day.
Prevention of cardiovascular diseases. Initial dose. The recommended initial dose of Rami Sandoz is 2.5 mg once a day.
Dose titration and maintenance dose. Depending on individual tolerability, the dose should be increased gradually. It is recommended to double the dose after 1-2 weeks of treatment, and then increase it after 2-3 weeks to the target maintenance dose of 10 mg 1 time per day. Also see the above information on dosing for patients receiving diuretics.
Treatment of kidney disease. In patients with diabetes and microalbuminuria. Initial dose. The recommended initial dose of Rami Sandoz is 1.25 mg once daily.
Dose titration and maintenance dose. Depending on individual tolerability of the drug, the dose is increased during further treatment. After 2 weeks of treatment, it is recommended to double the single dose to 2.5 mg, and then to 5 mg after 2 weeks of treatment.
In patients with diabetes and at least one cardiovascular risk factor
Initial dose. The recommended initial dose of Rami Sandoz is 2.5 mg once daily.
Dose titration and maintenance dose. Depending on individual tolerability of the drug, the dose is increased during further treatment. After 1-2 weeks of treatment, it is recommended to double the dose of Rami Sandoz to 5 mg, and then to 10 mg after 2-3 weeks of treatment. The target daily dose is 10 mg.
In patients with non-diabetic nephropathy, as evidenced by macroproteinuria ≥3 g/day. Initial dose. The recommended initial dose of Rami Sandoz is 1.25 mg once daily.
Dose titration and maintenance dose. Depending on the individual patient's tolerance of the drug, the dose is increased during further treatment. After 2 weeks of treatment, it is recommended to double the single dose to 2.5 mg, and then to 5 mg after 2 weeks of treatment.
Heart failure with clinical manifestations. Initial dose. For patients whose condition has stabilized after treatment with diuretics, the recommended initial dose is 1.25 mg/day.
Dose titration and maintenance dose. The dose of Rami Sandoz is titrated by doubling it every 1-2 weeks until a maximum daily dose of 10 mg is reached. It is advisable to divide the dose into 2 doses.
Secondary prevention after acute myocardial infarction in the presence of heart failure. Initial dose. 48 hours after the onset of myocardial infarction, patients whose condition is clinically and hemodynamically stable are prescribed an initial dose of 2.5 mg 2 times a day for 3 days. If the initial dose of 2.5 mg is poorly tolerated, then a dose of 1.25 mg 2 times a day for 2 days should be used, followed by an increase to 2.5 and 5 mg 2 times a day. If the dose can be increased to 2.5 mg 2 times a day, treatment should be discontinued. See above for information on the dosage of the drug for patients receiving diuretics.
Dose titration and maintenance dose. The daily dose is then increased by doubling it at 1-3 day intervals until the target maintenance dose of 5 mg twice daily is reached. Whenever possible, the maintenance dose is divided into 2 doses.
If the dose can be increased to 2.5 mg twice daily, treatment should be discontinued. Experience in treating patients with severe (NYHA class IV) heart failure immediately after myocardial infarction is still insufficient. If a decision is made to treat such patients with this drug, it is recommended to start therapy with a dose of 1.25 mg once daily and any increase should be carried out with extreme caution.
Patients with renal impairment. The daily dose for patients with renal impairment depends on the creatinine clearance (see Pharmacological properties):
if creatinine clearance ≥60 ml/min, there is no need to adjust the initial dose (2.5 mg/day), and the maximum daily dose is 10 mg; if creatinine clearance is 30-60 ml/min, there is no need to adjust the initial dose (2.5 mg/day), and the maximum daily dose is 5 mg; if creatinine clearance is 10-30 ml/min, the initial dose is 1.25 mg/day, and the maximum daily dose is 5 mg; patients with hypertension on hemodialysis: ramipril is excreted insignificantly during hemodialysis; the initial dose is 1.25 mg, and the maximum daily dose is 5 mg; the drug should be taken a few hours after the hemodialysis session.
Patients with hepatic impairment (see Pharmacological properties). Treatment with Rami Sandoz in patients with hepatic impairment should be initiated under close supervision, and the maximum daily dose in such cases should be 2.5 mg.
Elderly patients. The initial dose should be lower, and subsequent dose titration should be carried out more gradually, given the high likelihood of side effects, especially in elderly patients and those with asthenia. In such cases, a lower initial dose of 1.25 mg ramipril should be prescribed.
Contraindication
Hypersensitivity to the active substance, any other component of the drug or to other ACE inhibitors; history of angioedema (hereditary, idiopathic or associated with the use of ACE inhibitors); renal artery stenosis (bilateral or stenosis of the artery to a single kidney); severe renal failure; primary hyperaldosteronism. Rami Sandoz is not used in patients with arterial hypotension or hemodynamically unstable conditions.
Pregnancy (see Use during pregnancy and breastfeeding).
Should not be used with aliskiren-containing products in patients with diabetes mellitus or moderate or severe renal impairment (glomerular filtration rate 60 ml/min).
The concomitant use of ACE inhibitors and extracorporeal treatments that result in contact of blood with negatively charged surfaces should be avoided, as such use may cause severe anaphylactoid reactions. Such extracorporeal treatments include dialysis or hemofiltration using certain membranes with high hydraulic permeability (e.g. polyacrylonitrile) and LDL apheresis using dextran sulfate.
Side effects
Adverse reactions are classified according to frequency of occurrence: very common (≥1/10), common (≥1/100, 1/10), uncommon (≥1/1000, 1/100), rare (≥1/10,000, 1/1000), very rare (1/10,000), not established (cannot be established based on available data).
On the part of the immune system: unknown - anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.
From the cardiovascular system: often - arterial hypotension, orthostatic decrease in blood pressure, syncope; infrequently - myocardial ischemia, including angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema, flushing, feeling of hot flashes; rarely - vascular stenosis, hypoperfusion, vasculitis; very rarely - transient ischemic attack, ischemic stroke; unknown - Raynaud's syndrome.
From the hematopoietic system: infrequently - eosinophilia; rarely - a decrease in the number of white cells (including neutropenia and agranulocytosis), a decrease in the number of red cells, a decrease in hemoglobin level, a decrease in the number of platelets; not established - bone marrow failure, pancytopenia, hemolytic anemia.
From the nervous system: often - headache, dizziness; infrequently - vertigo, paresthesia, ageusia, dysgeusia; rarely - tremor, balance disorders; unknown - cerebral ischemia, including ischemic stroke and transient ischemic attack, impaired psychomotor functions, heartburn, parosmia.
Mental disorders: infrequently - mood changes, anxiety, nervousness, restlessness, sleep disorders, including somnolence; rarely - confusional state; not established - disturbance in attention.
On the part of the organ of vision: infrequently - visual disturbances, including blurred vision; rarely - conjunctivitis.
On the part of the organ of hearing: rarely - hearing impairment, tinnitus.
From the respiratory system: often - unproductive cough, bronchitis, sinusitis; infrequently - bronchospasm, including exacerbation of asthma, nasal congestion; rarely - dyspnea.
On the part of the digestive system: often - inflammation in the oral cavity and digestive tract, indigestion, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; infrequently - pancreatitis (in isolated cases, fatal outcome was reported when using ACE inhibitors), increased levels of pancreatic enzymes, angioedema of the small intestine, pain in the upper abdomen, including gastritis, constipation, dry mouth; rarely - glossitis, feeling of discomfort in the abdominal cavity, stomach pain; unknown - aphthous stomatitis.
Disturbances in the perception of smell and taste (for example, a metallic taste), sometimes complete loss of taste.
Hepatobiliary disorders: infrequently - increased levels of liver enzymes and / or bilirubin conjugates; rarely - cholestatic jaundice, liver cell damage; unknown - acute liver failure, cholestatic or cytolytic hepatitis (in exceptional cases - with a fatal outcome).
On the part of the urinary system: infrequently - impaired renal function, including acute renal failure, increased urine output, worsening of background proteinuria, increased blood urea and creatinine levels.
From the reproductive system: infrequently - transient erectile impotence, decreased libido; unknown - gynecomastia.
Skin: often - rash, in particular maculopapular, itching, urticaria; infrequently - angioedema, in exceptional cases - airway obstruction due to angioedema, which can be fatal; hyperhidrosis; rarely - exfoliative dermatitis, urticaria, onycholysis; very rarely - photosensitivity reaction; unknown - pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid rash or enanthema, alopecia.
On the part of the musculoskeletal system: often - muscle spasms, myalgia; infrequently - arthralgia.
General disorders: often - chest pain, asthenia; infrequently - pyrexia; rarely - weakness, drowsiness, fatigue.
Endocrine disorders: unknown - syndrome of inappropriate antidiuretic hormone secretion.
Special instructions
Special patient categories: dual blockade of the renin-angiotensin-aldosterone system with aliskiren-containing medicinal products.
Dual blockade of the renin-angiotensin-aldosterone system by the combined use of Rami Sandoz and aliskiren is not recommended, as there is an increased risk of arterial hypotension, hyperkalemia and changes in renal function. In patients with diabetes mellitus or impaired renal function (glomerular filtration rate 60 ml/min), the combined use of Rami Sandoz and aliskiren is contraindicated (see Side effects).
Patients at particular risk of hypotension: Patients with strongly activated renin-angiotensin-aldosterone system: The risk of a sudden marked fall in blood pressure with worsening of renal function due to ACE inhibition is increased in patients with a strongly activated renin-angiotensin-aldosterone system, especially when an ACE inhibitor or a concomitant diuretic is given for the first time or at the first dose increase.
Significant activation of the renin-angiotensin-aldosterone system, requiring blood pressure monitoring, can be expected, for example, in the following conditions:
severe hypertension; decompensated congestive heart failure; significant obstruction to the inflow or outflow of blood from the left ventricle (for example, aortic or mitral valve stenosis); unilateral renal artery stenosis with a second functioning kidney; fluid or electrolyte loss (including patients receiving diuretics); cirrhosis of the liver and / or ascites; when performing major surgical interventions or during anesthesia with agents that cause hypotension.
It is generally recommended to correct dehydration, hypovolemia, or electrolyte depletion before initiating treatment (however, in patients with heart failure, such corrective actions should be carefully weighed against the risk of developing volume overload).
In patients with impaired liver function, the response to treatment with Rami Sandoz may be either increased or decreased. In addition, in patients with severe cirrhosis of the liver, accompanied by edema and / or ascites, the activity of the renin-angiotensin system may be significantly increased; therefore, special caution should be exercised when treating these patients.
Treatment of persistent heart failure after myocardial infarction
Patients at risk of cardiac or cerebral ischemia in the event of acute hypotension. The initial stage of treatment requires special medical supervision.
Surgery: It is recommended to discontinue treatment with ACE inhibitors such as ramipril, if possible, 1 day before surgery.
Elderly patients: Elderly patients may respond more to ACE inhibitors. It is recommended that renal function be assessed at the start of treatment.
Monitoring of renal function. Renal function should be assessed before and during treatment and the dose should be adjusted regularly, especially in the first weeks of therapy. In the presence of renal impairment, particularly close monitoring is necessary. There is a risk of deterioration of renal function, especially in patients with congestive heart failure or after renal transplantation.
Angioedema. Angioedema has been reported in patients treated with ACE inhibitors, including ramipril. If angioedema occurs, the drug should be discontinued. Emergency treatment should be initiated immediately. Patients should be monitored for at least 12-24 hours until symptoms resolve.
Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased when taking ACE inhibitors. Temporary discontinuation of ramipril should be considered before desensitization.
Hyperkalemia. Hyperkalemia has been reported in some patients receiving ACE inhibitors, including ramipril. The risk of hyperkalemia is higher in patients with renal insufficiency, in patients over 70 years of age, in patients with uncontrolled diabetes mellitus, in patients receiving potassium salts, potassium-sparing diuretics, as well as other active substances that increase potassium levels, or in conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If concomitant use of these drugs is appropriate, continuous monitoring of potassium levels in the blood plasma is recommended.
Ethnic differences. ACE inhibitors are more likely to cause angioedema in black patients than in whites. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients. This may be because black patients with hypertension are more likely to develop low-renin hypertension.
Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia have been reported rarely. There have been reports of possible bone marrow suppression. It is recommended to monitor the number of white blood cells in the blood to detect possible leukopenia. More frequent monitoring should be carried out at the initial stage of treatment and in patients with impaired renal function, with concomitant collagen disease (systemic lupus erythematosus or scleroderma) or if patients are taking other drugs that can cause changes in the blood picture.
Cough: Cases of nonproductive persistent cough, which resolves after discontinuation of therapy, have been reported with ACE inhibitors. The possibility of cough caused by ACE inhibitors should be considered in the differential diagnosis of cough.
Use during pregnancy and breastfeeding. Pregnancy. Rami Sandoz is contraindicated during pregnancy (see Side effects). Therefore, pregnancy should be excluded before starting treatment. Pregnancy should be avoided if treatment with ACE inhibitors is necessary. If the patient plans to become pregnant, treatment with ACE inhibitors should be discontinued, i.e. replaced with another type of treatment.
If the patient becomes pregnant during treatment, Rami Sandoz should be replaced with non-ACE inhibitor therapy as soon as possible.
Breastfeeding. Due to the lack of information regarding the use of ramipril during breastfeeding (see Pharmacological properties), this drug is not recommended for use in breastfeeding women and alternative treatments with better established safety profiles during lactation are preferable, especially while breastfeeding a newborn or preterm infant.
Children: Rami Sandoz is not recommended for use in children (under 18 years of age) as there is insufficient data on the efficacy and safety of this medicine in these patients.
Ability to influence the speed of reaction when driving vehicles or operating other mechanisms. Some side effects (for example, symptoms of low blood pressure, such as dizziness) may impair the patient's ability to concentrate and reduce the speed of his reaction, which is risky in situations where these qualities are particularly important (for example, when driving vehicles or operating other mechanisms).
This is usually possible at the beginning of treatment or when switching from other drugs to Rami Sandoz. After taking the first dose or a subsequent increase in dose, it is undesirable to drive a vehicle or operate machinery for several hours.
Interactions
Combinations are contraindicated. Extracorporeal therapy procedures that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and LDL apheresis using dextran sulfate, due to the increased risk of severe anaphylactoid reactions. If such treatment is necessary, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive drugs.
Not recommended combinations: Potassium salts, heparin, potassium-sparing diuretics and other drugs that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): hyperkalemia may occur, therefore, careful monitoring of plasma potassium levels is necessary.
Use with caution. Antihypertensive drugs (e.g. diuretics) and other agents that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anesthetics, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): increased hypotensive effect is expected.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that can change the number of cells in the blood: increased likelihood of hematological reactions.
Lithium salts: ACE inhibitors reduce lithium excretion, which may increase the risk of lithium toxicity. Monitoring of lithium levels is recommended.
Antidiabetic drugs, including insulin: hypoglycemic reactions are possible. Monitoring of blood glucose levels is recommended.
NSAIDs and acetylsalicylic acid: a reduction in the antihypertensive effect of ramipril can be expected. In addition, the simultaneous use of ACE inhibitors and NSAIDs may be associated with an increased risk of deterioration of renal function and an increase in plasma potassium levels.
Food does not significantly affect the absorption of the drug.
Salt: Increased salt intake may reduce the antihypertensive effect of ramipril.
Specific hyposensitization. ACE inhibition increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom. It is believed that this effect may also develop with respect to other allergens.
Overdose
Symptoms of overdose with ACE inhibitors may include excessive peripheral vasodilation (with pronounced hypotension, shock), bradycardia, electrolyte disturbances, renal failure. The patient's condition should be carefully monitored. Symptomatic and supportive therapy is prescribed: primary detoxification (gastric lavage, the appointment of sorbents) and means to restore hemodynamic stability, including α1-adrenoceptor agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from the body by hemodialysis.
Storage conditions
At a temperature not exceeding 25 °C in the original packaging.
1-01-REC-CIS-0919
