Amprilan, tablets 2,5mg 30 pcs

Pharmacotherapeutic group:

Angiotensin-converting enzyme (ACE) inhibitor

ATX code: C09AA05

Pharmacological properties

Pharmacodynamics

The active metabolite of ramipril formed by “hepatic” enzymes, ramiprilate, is a long-acting ACE inhibitor (synonyms ACE: kininase II, dipeptidylcarboxydipeptidase I). ACE in blood plasma and tissues catalyzes the conversion of angiotensin I into angiotensin II, which has a vasoconstrictor effect, and the breakdown of bradykinin, which has a vasodilator effect.

Therefore, when ramipril is taken orally, angiotensin II formation is reduced and bradykinin accumulates, resulting in vasodilatation and a decrease in blood pressure (BP).

The increase of activity of kallikrein-kinin system in plasma and tissues with activation of prostaglandin system and increase of synthesis of prostaglandins that stimulate formation of nitric oxide (N0) in endotheliocytes cause its cardioprotective action.

Angiotensin II stimulates production of aldosterone; therefore, taking ramipril results in decreased secretion of aldosterone and increased serum potassium.

When plasma concentrations of angiotensin II are reduced, its negative feedback inhibitory effect on renin secretion is eliminated, resulting in increased plasma renin activity.

It is assumed that the development of some adverse reactions (in particular, “dry” cough) is associated with increased bradykinin activity.

In patients with arterial hypertension, ramipril administration leads to a decrease in BP in the supine and standing position without a compensatory increase in heart rate (HR).

Ramipril significantly reduces total peripheral vascular resistance (TPR) with little or no change in renal blood flow and glomerular filtration rate. Antihypertensive effect begins to appear 1 to 2 hours after oral administration of a single dose of the drug, reaching the greatest value after 3-6 hours, and lasts for 24 hours.

When taking Amprilan as a course, the antihypertensive effect may increase gradually, stabilizing usually by 3-4 weeks of regular use and then persisting for a long time. Sudden discontinuation of the drug does not lead to a rapid and significant increase in BP (no “withdrawal” syndrome).

In patients with arterial hypertension, ramipril slows the development and progression of myocardial and vascular wall hypertrophy.

In patients with chronic heart failure (CHF), ramipril decreases PEEP (decreases afterload on the heart), increases venous capacity and decreases left ventricular (LV) filling pressure, which consequently leads to a decrease in cardiac preload. In these patients, ramipril administration has increased cardiac output, LV ejection fraction (LVEF) and improved exercise tolerance.

In diabetic and nondiabetic nephropathy, taking ramipril slows the rate of progression of renal failure and time to end-stage renal failure and thus reduces the need for hemodialysis or renal transplantation.

In the initial stages of diabetic or nondiabetic nephropathy, ramipril reduces the incidence of albuminuria.

. In patients at high risk of cardiovascular disease due to vascular lesions (diagnosed coronary heart disease, history of peripheral arterial obliterative disease, history of stroke) or diabetes with at least one additional risk factor (microalbuminuria, arterial hypertension, increased concentration of total cholesterol (TC), decreased concentration of high-density lipoprotein cholesterol (HDL-C), smoking) the addition of ramipril to standard therapy reduces the incidence of myocardial infarction, stroke and mortality from cardiovascular causes.

In addition, ramipril reduces overall mortality and the need for revascularization procedures and slows the onset or progression of CHF.

. In patients with heart failure with clinical manifestations that developed during the first days of acute myocardial infarction (days 2-9), ramipril administration started from day 3 to day 10 of acute myocardial infarction reduced mortality (by 27%), risk of sudden death (by 30%), risk of progression of heart failure to severe (NYHA functional class III-IV)/resistant to therapy (by 23%), the likelihood of subsequent hospitalization due to the development of heart failure (by 26%).

In the general patient population, as well as in patients with diabetes mellitus, both with arterial hypertension and with normal BP, ramipril reduces the risk of nephropathy and microalbuminuria.

Pharmacokinetics

After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract (50 – 60%). Food intake slows its absorption but does not affect the completeness of absorption.

Ramipril undergoes intensive presystemic metabolism/activation (mainly in the liver by hydrolysis) resulting in the formation of its only active metabolite, ramiprilate, which has approximately 6 times greater activity with respect to ACE inhibition than ramipril.

In addition, metabolism of ramipril produces diketopiperazine, which has no pharmacological activity and then undergoes conjugation with glucuronic acid; ramiprilat is also glucuronized and metabolized to diketopiperazine acid.

The bioavailability of ramipril after oral administration ranges from 15% (for 2.5 mg dose) to 28% (for 5 mg dose). The bioavailability of the active metabolite, ramiprilate, after oral administration of 2.5 mg and 5 mg ramipril is approximately 45% (compared to its bioavailability after intravenous administration in the same doses).

After oral administration of ramipril, maximum plasma concentrations of ramipril and ramiprilate are reached after 1 and 2 to 4 hours, respectively.

The decrease in plasma concentrations of ramiprilat occurs in several phases: a distribution and excretion phase with a half-life (T1/2) of ramiprilat of approximately 3 hours, then an intermediate phase with a T1/2 of ramiprilat of approximately 15 hours, and an end phase with a very low plasma concentration of ramiprilat and a T1/2 of ramiprilat of approximately 4-5 days.

This end phase is due to the slow release of ramiprilat from strong binding to ACE receptors. Despite the prolonged end phase when ramipril is taken once daily at a dose of 2.5 mg or more, equilibrium plasma concentrations of ramiprilat are reached after approximately 4 days of treatment.

When administered as a regimen, the “effective” TT/2 is 13 to 17 hours, depending on the dose.

The binding to plasma proteins is approximately 73% for ramipril and 56% for ramiprilat.

After intravenous administration, the volume of distribution of ramipril and ramiprilat is approximately 90 L and approximately 500 L, respectively.

After intravenous administration of radioactive isotope-labeled ramipril (10 mg), 39% of the radioactivity is excreted through the intestine and about 60% through the kidneys. After intravenous administration of ramipril, 50-60% of the dose is detected in the urine as ramipril and its metabolites.

After intravenous administration of ramiprilat, about 70% of the dose is detected in the urine as ramiprilat and its metabolites; in other words, when ramipril and ramiprilat are administered intravenously, a significant portion of the dose is eliminated through the intestine with the bile, bypassing the kidneys (50% and 30%, respectively).

After oral administration of 5 mg of ramipril in patients with bile duct drainage, almost equal amounts of ramipril and its metabolites are excreted by the kidneys and through the intestine during the first 24 hours after administration.

Approximately 80 to 90% of metabolites in urine and bile have been indentified as ramipril and ramiprilate metabolites. Ramipril glucuronide and ramipril diketopiperazine account for approximately 10-20% of the total, and the urinary content of unmetabolized ramipril is approximately 2%. In animal studies, ramipril has been shown to be excreted in maternal milk.

In impaired renal function with a creatinine clearance (CK) of less than 60 ml/min, excretion of ramiprilat and its metabolites by the kidneys is delayed. This leads to increased plasma concentration of ramiprilat, which decreases more slowly than in patients with normal renal function.

When taking ramipril at high doses (10 mg), impaired liver function leads to slower presystemic metabolism of ramipril to active ramiprilate and slower excretion of ramiprilate.

In healthy volunteers and in patients with arterial hypertension after two weeks of treatment with ramipril at a daily dose of 5 mg, there is no clinically significant accumulation of ramipril and ramiprilat. In patients with CHF after two weeks of treatment with ramipril at a daily dose of 5 mg there was a 1.5-1.8-fold increase in plasma concentrations of ramiprilat and area under the “concentration-time curve” (AUC).

In healthy elderly volunteers (65 to 75 years of age), the pharmacokinetics of ramipril and ramiprilat are not significantly different from those of younger healthy volunteers.

Indications

Active ingredient

Composition

Active ingredient:

ramipril – 2.5 mg./ 1 tablet

Excipients:

sodium bicarbonate,

lactose monohydrate,

croscarmellose sodium,

Pregelatinized starch,

sodium stearyl fumarate.

How to take, the dosage

The tablet should be taken orally regardless of the time of eating (i.e., tablets can be taken either before, during, or after a meal) and washed down with a sufficient amount (1/2 cup) of water. The tablets should not be chewed or crushed before being taken.

The dose is adjusted according to the therapeutic effect and patient tolerance.

The treatment with Amprilan is usually long, and its duration is determined by the physician in each case.

If not otherwise prescribed, the following dosing regimens are recommended when renal and hepatic function is normal.

In arterial hypertension

The usual starting dose is 2.5 mg once daily in the morning. If Amprilan® at this dose for 3 weeks or more fails to normalize BP, the dose may be increased to 5 mg daily. If the 5 mg dose is not effective enough, after 2 to 3 weeks it may be doubled further to the maximum recommended daily dose of 10 mg.

As an alternative to increasing the dose to 10 mg daily if the daily dose of 5 mg is not sufficiently antihypertensive, other hypotensive agents such as diuretics or slow calcium channel blockers may be added to the treatment.

In chronic heart failure

The recommended starting dose is 1.25 mg once daily. The dose can be increased depending on the patient’s response to the therapy.

It is recommended that the dose be doubled at 1-2 week intervals. If a daily dose of 2.5 mg or more is required, it can be taken either once daily or divided into two doses.

The maximum recommended daily dose is 10 mg.

In diabetic or nondiabetic nephropathy

The recommended starting dose is 1.25 mg once daily.

The dose may be increased to 5 mg once daily. For these conditions, doses higher than 5 mg once daily have not been sufficiently studied in controlled clinical trials.

To reduce the risk of myocardial infarction, stroke, or cardiovascular mortality in patients at high cardiovascular risk

The recommended starting dose is 2.5 mg once daily.

The dose may be gradually increased depending on the patient’s tolerance to Amprilan.

It is recommended that the dose be doubled after 1 week of treatment, and over the next 3 weeks of treatment increase it to the usual maintenance dose of 10 mg once daily. The use of a dose greater than 10 mg daily has not been sufficiently studied in controlled clinical trials.

The use of the drug in patients with CKD less than 0.6 ml/sec has not been studied sufficiently.

In heart failure with clinical manifestations developed within the first few days (2nd to 9th day) after acute myocardial infarction

The recommended initial dose is 5 mg per day divided into two single doses of 2.5 mg, which are taken one in the morning and the other in the evening. If the patient cannot tolerate this initial dose (excessive BP reduction is observed), it is recommended that he or she take 1.25 mg twice daily for two days. Then, depending on the patient’s response, the dose may be increased.

It is recommended that the dose be doubled at 1-3 day intervals as it is increased. Then the total daily dose, which was initially divided into two doses, can be used once. The maximum recommended dose is 10 mg.

The experience in treatment of patients with severe heart failure (functional class III – IV according to NYHA classification), which occurred immediately after acute myocardial infarction, is currently insufficient.

If the decision is made to treat these patients with Amprilan, it is recommended that treatment is started with the lowest possible dose of 1.25 mg once daily, and great care must be taken with each increasing dose.

The use of Amprilan in selected patient groups

Patients with impaired renal function

In patients with a CKR of 50 to 20 ml/min per 1.73 m of body surface area, the initial daily dose is usually 1.25 mg. The maximum tolerated daily dose is 5 mg.

Patients with incompletely corrected fluid and electrolyte loss, patients with severe arterial hypertension, and patients for whom excessive BP reduction poses some risk (e.g., in severe atherosclerotic lesions of the coronary and cerebral arteries)

The starting dose is reduced to 1.25 mg/day.

Patients with prior diuretic therapy

If possible, diuretics should be stopped 2-3 days (depending on the duration of diuretic action) before starting Amprilan® treatment or at least the dose of diuretics taken should be reduced. Treatment of these patients should be started with the lowest dose of 1.25 mg of Amprilan®, taken once daily, in the morning.

After the first dose and whenever the dose of Amprilan® and/or loop diuretics is increased, patients should be under medical supervision for at least 8 hours to avoid uncontrolled hypotensive reaction.

Patients of advanced age (over 65 years) The starting dose is reduced to 1.25 mg per day.

Patients with hepatic impairment

The BP response to Amprilan may both increase (due to delayed excretion of ramiprilate) and decrease (due to delayed conversion of low-active ramipril to active ramiprilate). Therefore, careful medical monitoring is required at the beginning of treatment.

The maximum permitted daily dose is 2.5 mg.

Interaction

Vasopressor sympathomimetics (epinephrine, norepinephrine) may decrease the hypotensive effect of ramipril. BP levels should be carefully monitored when these drugs are used concomitantly.

ACE inhibitors increase the CNS depressant effect of ethanol.

Lithium drugs: Concomitant use of lithium drugs and ACE inhibitors has reported cases of reversible increase in lithium concentration in blood serum. Concomitant use with thiazide diuretics may increase the concentration of lithium and the risk of its toxic effects against the ACE inhibitor.

NSAIDs: Combination of ACE inhibitors with NSAIDs (non-selective COX-1 and COX-2 inhibitors from the group of NSAIDs, such as acetylsalicylic acid in doses that have anti-inflammatory effects): decreases the hypotensive effect of ACE inhibitors; increases the risk of renal dysfunction, up to the development of acute renal failure; increases serum potassium in patients with pre-existing renal dysfunction.

Tricyclic antidepressants, antipsychotics (neuroleptics): increase the hypotensive effect and increase the risk of orthostatic hypotension (additive effect).

GCS, tetracosactide: decrease hypotensive effect (fluid retention).

Potassium-saving diuretics (spironolactone, triamterene, amiloride, eplerenone) and potassium preparations: Combined use of ramipril and potassium-saving diuretics as well as potassium preparations and potassium containing food salt substitutes is not recommended.

Perhaps caution should be exercised and plasma potassium and ECG parameters should be monitored regularly.

Hypoglycemic oral agents (sulfonylurea derivatives) and insulin: use of ACE inhibitors may increase the hypoglycemic effect of oral hypoglycemic agents and insulin in patients with diabetes; their combined use may increase glucose tolerance, which may require adjustment of doses of oral hypoglycemic agents and insulin.

Allopurinol, cytostatic drugs, immunosuppressants, GCS (when used systemically) and procainamide: Concomitant use of these drugs with ACE inhibitors may increase the risk of leukopenia.

General anesthetic agents: ACE inhibitors may increase the hypotensive effect of some general anesthetic agents.

Gold preparations: Nitrate-like reactions (nausea, vomiting, marked BP reduction, facial hyperemia) have been noted when ACE inhibitors, including ramipril, are administered to patients receiving gold preparations (sodium aurothiomalate) by IV.

Special Instructions

Renal function should be assessed at the start of treatment. Renal function should be carefully monitored in patients with impaired renal function, heart failure, bilateral renal artery stenosis or artery stenosis of the single kidney, as well as in patients after renal transplantation.

Hepatic failure

In rare cases with ACE inhibitors cholestatic jaundice occurs with progression of which fulminant liver necrosis develops, sometimes with fatal outcome. If jaundice or significant increase in liver transaminase activity occurs with ACE inhibitors, the use of Amprilan® should be discontinued.

In patients with uncomplicated arterial hypertension after the first dose of the drug, symptomatic arterial hypotension is rare. The risk of developing arterial hypotension is increased in the following patients:

Aortic/mitral stenosis/GCMP

ACE inhibitors should be used with caution in patients with left ventricular outflow tract obstruction and with aortic and/or mitral stenosis.

Neutropenia/agranulocytosis

In patients taking ACE inhibitors there may be cases of neutropenia/agranulocytosis, thrombocytopenia and anemia. In patients with normal renal function in the absence of other complications neutropenia is rare and resolves on its own after ACE inhibitors withdrawal.

Ramipril should be used with great caution in patients with connective tissue disease concomitantly receiving immunosuppressive therapy, allopurinol or procainamide, especially in existing renal impairment. Such patients may develop severe infections that do not respond to intensive antibiotic therapy. If ramipril is used, it is recommended to periodically monitor the number of white blood cells in the blood. The patient should be warned that in case of any signs of infectious disease (sore throat, fever) it is necessary to immediately consult a physician.

Hyperkalemia

May develop during treatment with ACE inhibitors, including ramipril. Risk factors of hyperkalemia include renal insufficiency, elderly age, diabetes mellitus, some concomitant conditions (decreased BOD, decompensated acute heart failure, metabolic acidosis), concomitant use of potassium-saving diuretics (such as spironolactone, eplerenone, triamterene, amiloride), as well as potassium preparations or potassium-containing salt substitutes and other drugs that increase plasma potassium content (e.g. heparin). Hyperkalemia can lead to serious cardiac rhythm disturbances, sometimes fatal.

Potassium-saving diuretics and potassium preparations

The combined use of Amprilan® and potassium-saving diuretics as well as potassium preparations and potassium-containing salt substitutes is not recommended.

Surgical interventions/general anesthesia

The use of ACE inhibitors in patients undergoing surgery with general anesthesia may result in a significant decrease in BP, especially with the use of general anesthetics with hypotensive effect.

The use of ACE inhibitors, including ramipril, should be discontinued 12 hours before surgery and the anesthesiologist should be informed about the use of ACE inhibitors.

Cough

Dry cough may occur with ACE inhibitor therapy, which disappears after discontinuation of the drugs of this group. If you have a dry cough, you should be aware of the possible association of this symptom with ACE inhibitor therapy.

Anaphylactoid reactions during desensitization procedures

There have been isolated reports of long-term, life-threatening anaphylactoid reactions in patients receiving ACE inhibitors during desensitization therapy with venom of hymenopteran insects (bees, wasps). ACE inhibitors should be used with caution in patients prone to allergic reactions undergoing desensitization procedures. Administration of ACE inhibitor should be avoided in patients receiving immunotherapy with venom of hymenopterous insects. However, the development of anaphylactoid reactions can be avoided by temporarily withdrawing the ACE inhibitor at least 24 hours before the desensitization procedure.

Anaphylactoid reactions during LDL apheresis

In rare cases, patients receiving ACE inhibitors may develop life-threatening anaphylactoid reactions during LDL apheresis with dextran sulfate. To prevent anaphylactoid reactions, therapy with an ACE inhibitor should be discontinued before each LDL apheresis procedure using high-flow membranes.

Hemodialysis

In patients receiving ACE inhibitors, anaphylactoid reactions have been noted during hemodialysis using high-flow membranes (e.g., AN69®). Therefore, it is advisable to use a different type of membrane or to use a hypotensive drug from a different pharmacotherapeutic group.

Impact on ability to drive or perform work requiring increased speed of physical and mental reactions

At the time of treatment, caution must be exercised during potentially hazardous activities requiring increased concentration and rapid psychomotor reactions, as dizziness, drowsiness, confusion and other side effects are possible.

Contraindications

Side effects

World Health Organization (WHO) recommended frequency of side effects:

Cardiac disorders:

infrequent: myocardial ischemia, including the development of an attack of angina or myocardial infarction, tachycardia, arrhythmias (occurrence or increase), palpitations, peripheral edema.

Vascular disorders:

often: excessive BP decrease, impaired orthostatic regulation of vascular tone (orthostatic hypotension), syncopal states; infrequently: “flushes” of blood to the skin of the face; rare: occurrence or aggravation of circulatory disorders against stenotic vascular lesions, vasculitis; frequency unknown: Raynaud’s syndrome.

Nervous system disorders:

often: headache, dizziness (feeling of “lightness” in the head);

infrequent: vertigo, paresthesia, agueusia (loss of taste sensitivity), dysgeusia (impaired taste sensitivity); rarely: tremor, balance disorder; frequency unknown: cerebral ischemia, including ischemic stroke and transient cerebral circulation disorder, psychomotor reaction disorder (decreased responsiveness), burning sensation, parosmia (disturbance of smell perception).

Visual impairment:

infrequent: visual disturbances, including blurred vision; rare: conjunctivitis.

Hearing disorders:

rarely: hearing loss, tinnitus.

Mental disorders:

infrequent: depressed mood, anxiety, nervousness, motor restlessness, sleep disturbance, including drowsiness; rare: confusion; frequency unknown: impaired attention.

Disorders of the respiratory system, thorax and mediastinum:

often: “dry” cough (worsening at night and when lying down), bronchitis, sinusitis, shortness of breath;

infrequently: bronchospasm, including aggravation of the course of bronchial asthma, nasal congestion.

Disorders of the digestive system:

often: inflammatory reactions in the stomach and intestines, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting; infrequent: fatal pancreatitis (cases of fatal pancreatitis while taking ACE inhibitors have been observed very rarely), increased pancreatic enzyme activity in blood plasma, angioedema of the small intestine, upper abdominal pain, including that associated with gastritis, constipation, dry oral mucosa; rare:glossitis; frequency unknown: aphthous stomatitis (inflammatory reaction of the oral mucosa).

Hepatic and biliary tract disorders:

infrequent: increased activity of “hepatic” enzymes and concentration of conjugated bilirubin in plasma; rare: cholestatic jaundice, hepatocellular lesions; frequency unknown: acute liver failure, cholestatic or cytolytic hepatitis (lethal outcome was observed very rarely).

Renal and urinary tract disorders:

infrequent: impairment of renal function, including development of acute renal failure, increased urine excretion, increased pre-existing proteinuria, increased concentration of urea and creatinine in plasma.

Genital and mammary disorders:

infrequent: transient impotence due to erectile dysfunction, decreased libido; frequency unknown: gynecomastia.

Disorders of the blood and lymphatic system:

infrequent: eosinophilia; rare: leukopenia, including neutropenia and agranulocytosis, decreased number of red blood cells in peripheral blood, decreased hemoglobin, thrombocytopenia; frequency unknown: inhibition of medullary hematopoiesis, pancytopenia, hemolytic anemia.

Skin and subcutaneous tissue disorders:

often: skin rash, particularly maculopapular; infrequent: Angioneurotic edema, including fatal (laryngeal edema can cause fatal airway obstruction), skin itching, hyperhidrosis (increased sweating); rare: exfoliative dermatitis, urticaria, onycholysis; very rare: photosensitization reactions; frequency unknown: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, worsening the course of psoriasis, psoriasis-like dermatitis, pemphigoid or lichenoid (licheniform) exanthema or enanthema, alopecia.

Muscular and connective tissue disorders:

often: muscle cramps, myalgia; infrequent: arthralgia.

Endocrine system disorders:

frequency unknown: syndrome of inadequate secretion of antidiuretic hormone (SNS ADH).

Disorders of metabolism and nutrition:

often: increased plasma potassium; infrequent: anorexia, decreased appetite; frequency unknown: decreased plasma sodium.

Disorders of the immune system:

incidence unknown: anaphylactic or anaphylactoid reactions (ACE inhibition increases anaphylactic or anaphylactoid reactions to insect venoms), increased antinuclear antibody titer.

General disorders and disorders at the site of administration:

often: chest pain, increased fatigue; infrequent: increased body temperature; rare: asthenia (weakness).

Overdose

Symptoms: marked BP decrease, bradycardia, shock, impaired water-electrolyte balance, acute renal failure, stupor.

Treatment: in mild cases of overdose – gastric lavage, prescription of adsorbents and sodium picosulfate (preferably within 30 minutes after ingestion).

In case of marked BP decrease – IV administration of catecholamines, alpha1-adrenergic agonists (norepinephrine, dopamine), angiotensin II (angiotensinamide), the patient should be laid on his back on a surface with a low headboard, if necessary BOD can be replenished by infusion of 0.9% sodium chloride solution; In bradycardia, a temporary artificial pacemaker may be used.

Pressure, renal function and serum potassium should be monitored closely. The effectiveness of hemodialysis has not been established.

Pregnancy use

The drug Amprilan is contraindicated in pregnancy since it may have adverse effects on the fetus: impaired fetal renal development, decreased fetal and neonatal BP, impaired renal function, hyperkalemia, hypoplasia of the skull bones, hypoplasia of the lungs.

Therefore, pregnancy should be excluded before starting the drug in women of childbearing age.

If a woman plans to become pregnant, treatment with an ACE inhibitor should be discontinued.

If a woman becomes pregnant during treatment with Amprilan, the drug should be discontinued as soon as possible and the patient should be switched to another drug with the lowest risk to the baby.

If treatment with Amprilan is needed while breastfeeding, breastfeeding should be stopped.

Similarities