SANDOZ #Circulatory_system #Hypertension #HEALTH_CARE
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 into 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 the release of aldosterone, ramiprilat helps to reduce the secretion of aldosterone. The response to monotherapy with ACE inhibitors was, on average, less pronounced in patients of the Negroid race (Afro-Caribbean origin) with hypertension (a population characterized by low renin levels in hypertension) than in representatives of other races.
The administration of ramipril causes a significant decrease in peripheral arterial resistance. In general, the preparation does not significantly alter renal blood flow and glomerular filtration rate.
Prescribing ramipril to patients with hypertension leads to a decrease in blood pressure in the supine and standing positions without a compensatory increase in heart rate.
In most patients, the antihypertensive effect manifests itself within 1–2 hours after using the preparation, reaches a maximum after 3–6 hours and lasts for 24 hours. The maximum therapeutic effect is usually achieved after constant use after 3–4 weeks. It was found that the antihypertensive effect persists with prolonged therapy for 2 years. Sudden discontinuation of ramipril does not cause a rapid and sharp increase in blood pressure.
In addition to conventional diuretic therapy and, if necessary, cardiac glycosides, ramipril is effective in patients with NYHA functional class (FC) II – IV. The preparation exhibits beneficial effects on cardiac hemodynamics (decreased filling pressure of the left and right ventricles, systemic vascular resistance, increased cardiac output and improved cardiac index). It also reduces neuroendocrine activation.
Pharmacokinetics. Absorption. After oral administration, ramipril is rapidly absorbed in the gastrointestinal tract: its Cmax in blood plasma is reached within 1 hour. The degree of absorption is 56%, this indicator does not depend on the presence of food in the gastrointestinal tract. Cmax of ramiprilat, the only active metabolite of ramipril, is reached in blood plasma 2–4 hours after taking the preparation. In the case of using the usual dose (1 time per day), the equilibrium concentration of ramiprilat in the blood plasma is achieved on the 4th day of treatment.
Distribution. The binding of ramipril to blood plasma proteins is about 73%, and ramiprilat is 56%.
Metabolism. Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazic acid, and the glucuronides of ramipril and ramiprilat.
Excretion. Excretion of metabolites is predominantly renal. The decrease in the concentration of ramiprilat in the blood plasma occurs in several phases. Given the strong saturated binding to ACE and slow dissociation with the enzyme, ramiprilat is characterized by a prolonged terminal elimination phase at very low plasma concentrations.
After repeated administration of ramipril, its T1 / 2 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 saturating ability of the enzyme to bind ramiprilat.
When taking a single dose, ramipril and its metabolite were not detected in breast milk. 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 the reduced activity of hepatic esterases, the level of ramipril in the blood plasma of these patients was increased. However, the Cmax of ramiprilat in these patients did not differ from that in patients with normal liver function.
Indications
Treatment of ag. prevention of cardiovascular disease: reducing cardiovascular morbidity and mortality in patients with:
- severe cardiovascular diseases of atherothrombotic genesis (history of ischemic heart disease or stroke, or peripheral vascular disease);
- diabetes mellitus, which have at least one cardiovascular risk factor (see PHARMACOLOGICAL PROPERTIES).
Treatment for 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 nondiabetic nephropathy, as evidenced by the presence of macroproteinuria ≥3 g / day (see PHARMACOLOGICAL PROPERTIES).
Treatment of congestive heart failure. Secondary prevention after acute myocardial infarction: a decrease in mortality during the acute stage of myocardial infarction in patients with clinical signs of heart failure when starting treatment more than 48 hours after the onset of acute myocardial infarction.
Application
The preparation is for oral administration.
Rami Sandoz is recommended to be taken at the same time every day. The preparation can be taken before, during and after meals, since food intake does not affect the bioavailability of the preparation. Rami Sandoz tablets should be swallowed whole with water. They must not be chewed or crushed.
Adults. Rami Sandoz can cause arterial hypotension, the development of which is more likely in patients who are simultaneously receiving diuretics. In such cases, it is recommended to exercise caution, since these patients may have a decrease in BCC and / or electrolytes. It is advisable to stop using the diuretic 2-3 days before starting treatment with Rami Sandoz, if possible (see SPECIAL INSTRUCTIONS).
In hypertensive patients for whom the diuretic cannot be withdrawn, Rami Sandoz should be started with a dose of 1.25 mg. Renal function and blood potassium levels should be closely monitored. The further dose of Rami Sandoz should be adjusted depending on the target blood pressure.
AG. The dose should be selected individually, depending on the patient's condition (see SPECIAL INSTRUCTIONS) and the results of control measurements of blood pressure. Rami Sandoz can be used as monotherapy or in combination with other classes of antihypertensive preparations.
Initial dose. Treatment with Rami Sandoz should be started gradually, starting with the recommended starting dose of 2.5 mg / day.
In patients with significant activation of the renin-angiotensin-aldosterone system after taking the initial dose, a significant decrease in blood pressure may occur. For such patients, the recommended dose is 1.25 mg, and their treatment should be started under supervision (see SPECIAL INSTRUCTIONS).
Dose titration and maintenance dose. The dose can be doubled every 2–4 weeks until the target BP is reached; the maximum dose of Rami Sandoz is 10 mg / day. As a rule, the preparation is taken once a day.
Prevention of cardiovascular diseases. Initial dose. The recommended starting dose of Rami Sandoz is 2.5 mg once a day.
Dose titration and maintenance dose. Depending on the individual tolerance of the preparation, the dose should be gradually increased. It is recommended to double the dose after 1-2 weeks of treatment, and then after 2-3 weeks increase it to the target maintenance dose of 10 mg once a day. Also see the information above regarding dosing for patients receiving diuretics.
Treating kidney disease. In patients with diabetes and microalbuminuria. Initial dose. The recommended starting dose of Rami Sandoz is 1.25 mg once a day.
Dose titration and maintenance dose. Depending on the individual tolerance of the preparation, the dose is increased during further treatment. After 2 weeks of treatment, a single dose is recommended to be doubled to 2.5 mg, and then to 5 mg after 2 weeks of treatment.
In patients with diabetes mellitus and at least one cardiovascular risk factor
Initial dose. The recommended starting dose of Rami Sandoz is 2.5 mg once a day.
Dose titration and maintenance dose. Depending on the individual tolerance of the preparation, the dose is increased during further treatment. After 1-2 weeks of treatment, the dose of Rami Sandoz is recommended to be doubled to 5 mg, and then to 10 mg after 2-3 weeks of treatment. The target daily dose is 10 mg.
In patients with nondiabetic nephropathy, as evidenced by the presence of macroproteinuria ≥3 g / day. Initial dose. The recommended starting dose of Rami Sandoz is 1.25 mg once a day.
Dose titration and maintenance dose. Depending on the individual patient's tolerance of the preparation, the dose is increased during further treatment. After 2 weeks of treatment, a single dose is recommended to be doubled 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 diuretic treatment, the recommended starting 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 cannot be increased to 2.5 mg 2 times a day, treatment should be canceled. See the above information regarding dosage of the preparation for patients receiving diuretics.
Dose titration and maintenance dose. In the future, the daily dose is increased by doubling it with an interval of 1-3 days until the target maintenance dose of 5 mg is reached 2 times a day. Whenever possible, the maintenance dose is divided into 2 doses.
If the dose cannot be increased to 2.5 mg 2 times a day, treatment should be canceled. The experience of treating patients with severe (IV FC according to NYHA classification) heart failure immediately after myocardial infarction is still insufficient. If a decision is made to treat such patients with this preparation, it is recommended to start therapy with a dose of 1.25 mg 1 time per day and any increase should be carried out with extreme caution.
Special categories of patients
Patients with impaired renal function. The daily dose for patients with impaired renal function depends on the creatinine clearance rate (see PHARMACOLOGICAL PROPERTIES):
- if creatinine clearance is ≥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: during hemodialysis, ramipril is excreted slightly; the initial dose is 1.25 mg, and the maximum daily dose is 5 mg; the preparation should be taken several hours after the hemodialysis session.
Patients with impaired liver function (see. PHARMACOLOGICAL PROPERTIES). Treatment with Rami Sandoz in patients with impaired liver function should be started 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 further titration of the dose should be carried out more gradually, given the high likelihood of side effects, especially in patients with asthenic age and those with asthenia. In such cases, a minimum initial dose of 1.25 mg of ramipril is prescribed.
Contraindications
Hypersensitivity to the active substance, any other component of the preparation or other APF inhibitors; a history of angioedema (hereditary, idiopathic, or associated with the use of APF inhibitors); renal artery stenosis (bilateral or single kidney artery stenosis); severe renal failure; primary hyperaldosteronism. ramie sandoz is not used in patients with arterial hypotension or hemodynamically unstable conditions.
Pregnancy period (see. Application during pregnancy and lactation).
It should not be used in conjunction with preparations containing aliskiren in patients with diabetes mellitus or moderate or severe renal impairment (glomerular filtration rate 60 ml / min).
It is necessary to avoid the simultaneous use of ACE inhibitors and extracorporeal treatments that lead to blood contact with negatively charged surfaces, since such use can cause severe anaphylactic reactions. Such extracorporeal therapies include dialysis or hemofiltration using certain membranes with high fluid permeability (eg polyacrylonitrile) and LDL apheresis using dextran sulfate.
Side effects
Adverse reactions are classified by frequency of occurrence: very often (≥1 / 10), often (≥1 / 100, 1/10), infrequently (≥1 / 1000, 1/100), rarely (≥1 / 10,000, 1 / 1000), very rare (1/10 000), unidentified (impossible to establish from the available data).
From the side of the immune system: unidentified - anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.
From the side of the cardiovascular system: often - arterial hypotension, orthostatic decrease in blood pressure, syncope; infrequently - myocardial ischemia, including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema, redness, hot flashes; rarely - vascular stenosis, hypoperfusion, vasculitis; very rarely - short-term ischemic attack, ischemic stroke; unidentified - 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 levels, a decrease in the number of platelets; unidentified - bone marrow failure, pancytopenia, hemolytic anemia.
From the nervous system: often - headache, dizziness; infrequently - vertigo, paresthesia, ageusia, dysgeusia; rarely - tremor, imbalance; unidentified - cerebral ischemia, including ischemic stroke and transient ischemic attack, impaired psychomotor functions, heartburn, parosmia.
Mental disorders: infrequently - mood changes, anxiety, nervousness, restlessness, sleep disturbance, including somnolence; rarely - a state of confusion; unidentified - violation of attention.
From the side of the organ of vision: infrequently - visual impairment, including blurred vision; rarely - conjunctivitis.
From the side of the organ of hearing: rarely - hearing impairment, ringing in the ears.
From the respiratory system: often - unproductive cough, bronchitis, sinusitis; infrequently - bronchospasm, including exacerbation of asthma, nasal congestion; rarely - dyspnea.
From the digestive system: often - inflammation in the mouth and digestive tract, indigestion, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; infrequently - pancreatitis (in isolated cases, it was reported about death with the use of ACE inhibitors), increased levels of pancreatic enzymes, angioedema of the small intestine, pain in the upper abdomen, including gastritis, constipation, dry mouth; rarely - glossitis, abdominal discomfort, stomach pain; unidentified - aphthous stomatitis.
Impaired perception of smell and taste (for example, metallic taste), sometimes a complete loss of taste.
Metabolic disorders: often - an increase in the level of potassium in the blood; infrequently - anorexia, decreased appetite; unidentified - a decrease in the level of sodium in the blood.
Hepatobiliary disorders: infrequently - increased levels of hepatic enzymes and / or bilirubin conjugates; rarely - cholestatic jaundice, liver cell damage; unidentified - acute liver failure, cholestatic or cytolytic hepatitis (in exceptional cases - with a fatal outcome).
From the urinary system: infrequently - impaired renal function, including acute renal failure, an increase in the amount of urine, worsening background proteinuria, an increase in the level of urea in the blood and creatinine.
Reproductive system disorders: infrequently - transient erectile impotence, decreased libido; unidentified - gynecomastia.
From the side of the skin: often - rash, in particular maculopapular, itching, urticaria; infrequently - angioedema, in exceptional cases - impaired airway patency due to angioedema, which can be fatal; hyperhidrosis; rarely - exfoliative dermatitis, urticaria, onycholysis; very rarely - photosensitivity reaction; unidentified - pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.
From the side of the musculoskeletal system: often - muscle spasms, myalgia; infrequently - arthralgia.
General disorders: often - chest pain, asthenia; infrequently - pyrexia; rarely - weakness, drowsiness, fatigue.
Endocrine disorders: unidentified - syndrome of inappropriate secretion of antidiuretic hormone.
Special instructions
Special categories of patients. double blockade of the renin-angiotensin-aldosterone system with preparations containing aliskiren.
Double blockade of the renin-angiotensin-aldosterone system by the combined use of Rami Sandoz and aliskiren is not recommended, since 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 CONTRAINDICATIONS).
Patients with a special risk of arterial hypotension. Patients with pronounced activation of the renin-angiotensin-aldosterone system. The risk of a sudden noticeable decrease in blood pressure with deterioration of renal function due to inhibition of ACE increases in patients with pronounced activation of the renin-angiotensin-aldosterone system, especially if an ACE inhibitor or a concomitant diuretic is prescribed for the first time or at the first dose increase.
Significant activation of the renin-angiotensin-aldosterone system, which requires monitoring of blood pressure, can be expected, for example, in the following conditions:
- severe hypertension;
- decompensated congestive heart failure;
- a hemodynamically significant obstruction to the inflow or outflow of blood from the left ventricle (for example, stenosis of the aortic or mitral valve);
- unilateral renal artery stenosis with a second functioning kidney;
- loss of fluid or electrolytes (including in patients receiving diuretics);
- cirrhosis of the liver and / or ascites;
- when performing major surgical interventions or during anesthesia with preparations that cause arterial hypotension.
It is generally recommended to correct dehydration, hypovolemia, or electrolyte deficiency before starting treatment (however, in patients with heart failure, such corrective action should be carefully weighed against the risk of volume overload).
In patients with impaired liver function, the response to treatment with Rami Sandoz can be either increased or decreased. In addition, in patients with severe liver cirrhosis, which is accompanied by edema and / or ascites, the activity of the renin-angiotensin system may be significantly increased; therefore, special care must be taken during the treatment of these patients.
Treatment of persistent heart failure after myocardial infarction
Patients at risk of cardiac or cerebral ischemia in case of acute arterial hypotension. The initial stage of treatment requires special medical supervision.
Surgical interventions. It is recommended that treatment with ACE inhibitors such as ramipril be discontinued, if possible, 1 day before surgery.
Elderly patients. In the elderly, the reaction to ACE inhibitors may be more pronounced. At the beginning of their treatment, it is recommended to assess renal function.
Control of kidney function. Renal function should be assessed before and during treatment and the dose should be constantly adjusted, especially in the first weeks of therapy. In the presence of kidney damage, especially careful monitoring is necessary. There is a risk of worsening kidney function, especially in patients with congestive heart failure or after kidney transplantation.
Angioedema. The possibility of angioedema has been reported in patients treated with ACE inhibitors, including ramipril. In case of angioedema, the preparation should be discontinued. Immediately initiate emergency therapy. Patients should be under the supervision of a physician for at least 12-24 hours until the symptoms disappear completely.
In patients who were treated with ACE inhibitors, cases of angioedema of the intestine were noted. Patients complained of abdominal pain (with or without nausea / vomiting); in some cases, angioedema of the face also occurred. The symptoms of angioedema of the intestine disappeared after discontinuation of the ACE inhibitor.
Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens increases with ACE inhibitors. Temporarily discontinuing ramipril should be considered prior to desensitization.
Hyperkalemia. Hyperkalemia has been reported in some patients receiving ACE inhibitors, including ramipril. The risk of hyperkalemia is higher for patients with renal failure, over the age of 70, for patients with uncontrolled diabetes mellitus, for those receiving potassium salts, potassium-sparing diuretics, and other active substances that increase potassium, or for conditions such as dehydration , acute cardiac decompensation, metabolic acidosis. If the combined use of these preparations is advisable, then continuous monitoring of the level of potassium in the blood plasma is recommended.
Ethnic differences. ACE inhibitors are more likely to cause angioedema in black patients than in Caucasians. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients. This may be due to the fact that in patients of the Negroid race with hypertension, hypertension with low renin activity develops more often.
Neutropenia / agranulocytosis. Cases of neutropenia / agranulocytosis, as well as thrombocytopenia and anemia were rare. There have been reports of the possibility of bone marrow suppression. It is recommended to monitor the number of white cells in the blood to detect possible leukopenia. Monitoring should be carried out more frequently at the initial stage of treatment and in patients with impaired renal function, with concomitant collagenosis (systemic lupus erythematosus or scleroderma), or if patients are taking other preparations that can cause changes in the blood picture.
Cough. With the use of ACE inhibitors, cases of unproductive persistent cough that disappear after discontinuation of therapy have been reported. The possibility of cough caused by ACE inhibitors should be considered in the differential diagnosis of cough.
Use during pregnancy and lactation. Pregnancy. Rami Sandoz is contraindicated during pregnancy (see CONTRAINDICATIONS). Therefore, it is necessary to exclude pregnancy before starting treatment. Pregnancy should be avoided if treatment with ACE inhibitors is required. If the patient plans to become pregnant, it is necessary to stop treatment with ACE inhibitors, that is, replace them with another type of treatment.
If the patient becomes pregnant during treatment, the use of Rami Sandoz should be replaced with therapy without ACE inhibitors as soon as possible.
Lactation. Due to the lack of information on the use of ramipril during breastfeeding (see PHARMACOLOGICAL PROPERTIES), it is not recommended to prescribe this preparation to women who are breastfeeding, and it is advisable to give preference to other preparations, the use of which during lactation is safer, especially when breastfeeding newborns or premature babies.
Children. Rami Sandoz is not recommended for use in children (under the age of 18), as there is insufficient data on the efficacy and safety of this preparation for such patients.
The ability to influence the reaction rate when driving or working with other mechanisms. Some side effects (for example, symptoms of a decrease in blood pressure, such as dizziness) can interfere with the patient's ability to concentrate and reduce the speed of his reaction, which is risky in situations where these qualities are especially important (for example, when driving or operating other mechanisms ).
This is usually possible at the beginning of treatment or when switching from therapy with other preparations to treatment with Rami Sandoz. After taking the first dose or further increasing the dose, it is undesirable to drive a vehicle or operate machinery for several hours.
Interactions
Contraindicated combinations. extracorporeal therapies that bring blood into contact with negatively charged surfaces, such as dialysis or hemofiltration with certain high-flow membranes (such as polyacrylonitrile membranes) and LPNP apheresis with dextran sulfate, due to an 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 preparations.
Combinations not recommended. Potassium salts, heparin, potassium-sparing diuretics and other preparations that increase the level of potassium in the blood plasma (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporin): hyperkalemia may occur, therefore, the level of potassium in the blood plasma should be carefully monitored.
Use with caution. Antihypertensive preparations (for example diuretics) and other preparations that can lower blood pressure (for example, nitrates, tricyclic antidepressants, anesthetics, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): an increase in the hypotensive effect can be expected.
Vasopressor sympathomimetics and other substances (for example, isoproterenol, dobutamine, dopamine, epinephrine) that can reduce the severity of the antihypertensive effect of ramipril: blood pressure control is recommended.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that can change the number of cells in the blood: an increased likelihood of hematological reactions.
Lithium salts: ACE inhibitors reduce the excretion of lithium, so the likelihood of lithium toxicity may be increased. It is recommended to monitor the lithium level.
Antidiabetic preparations, including insulin: hypoglycemic reactions are possible. Plasma glucose control is recommended.
NSAIDs and acetylsalicylic acid: A decrease in the antihypertensive effect of ramipril can be expected. In addition, the combined use of ACE inhibitors and NSAIDs may be accompanied by an increased risk of impaired renal function and increased plasma potassium levels.
Food does not significantly affect the absorption of the preparation.
Salt. Increased salt intake can reduce the severity of the antihypertensive effect of ramipril.
Specific hyposensitization. Due to the inhibition of ACE, the likelihood of occurrence and the severity of anaphylactic and anaphylactoid reactions to insect venom increases. It is believed that this effect can also develop with respect to other allergens.
Overdose
Symptoms of an overdose with APF inhibitors may include excessive peripheral vasodilation (with severe arterial 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, prescription of sorbents) and agents to restore hemodynamic stability, including α1-adrenergic receptor agonists or angiotensin II (angiotensinamide). ramiprilat, the active metabolite of ramipril, is poorly excreted from the body by hemodialysis.
Storage conditions
At temperatures up to 25 ° C in original packaging.
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