Polapril
Ukraine
Table of Contents
INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT POLAPRIL (POLAPRIL)
Composition:
Active substance: ramipril;
1 capsule contains 2.5 mg or 5 mg or 10 mg of ramipril;
Excipients: pregelatinized starch, gelatin, purified water, titanium dioxide (E 171), black iron oxide (E 172), indigo carmine (E 132), yellow iron oxide (E 172).
Pharmaceutical form. Hard capsules.
Main physicochemical characteristics:
For the 2.5 mg dose: hard gelatin capsule size № 4, with a light-grey body marked with "2.5" and a light-green cap marked with "R". The capsule contains a white or almost white powder;
For the 5 mg dose: hard gelatin capsule size № 4, with a light-grey body marked with "5" and a green cap marked with "R". The capsule contains a white or almost white powder;
For the 10 mg dose: hard gelatin capsule size № 4, with a light-grey body marked with "10" and a dark-green cap marked with "R". The capsule contains a white or almost white powder.
Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors.
ATC code C09A A05.
Pharmacological properties.
Pharmacodynamics.
Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme; 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. Reduction in angiotensin II formation and inhibition of bradykinin degradation lead to vasodilation.
Since angiotensin II also stimulates the release of aldosterone, ramiprilat reduces aldosterone secretion. Increased bradykinin activity likely contributes to cardioprotective and endothelioprotective effects. However, it has not yet been established to what extent this influences the development of certain adverse effects (e.g., non-productive cough).
ACE inhibitors are effective even in patients with arterial hypertension who have low plasma renin concentrations. The average response to monotherapy with an ACE inhibitor in patients of African descent (typically in populations with arterial hypertension and low renin levels) has been lower compared to individuals of other races.
Administration of ramipril causes a significant reduction in peripheral arterial resistance. Overall, renal plasma flow and glomerular filtration rate do not change significantly.
Use of ramipril in patients with arterial hypertension leads to a reduction in arterial blood pressure in both supine and standing positions, without compensatory increase in heart rate.
In most patients, the antihypertensive effect after a single oral dose becomes apparent within 1–2 hours. The maximum effect of a single dose is usually achieved within 3–6 hours and typically lasts for 24 hours.
The maximum antihypertensive effect during long-term ramipril therapy is generally observed after 3–4 weeks. It has been shown that this effect is maintained for up to 2 years during prolonged therapy.
Abrupt discontinuation of ramipril does not result in a rapid or pronounced increase in arterial blood pressure.
In patients with clinical manifestations of heart failure, treatment initiated 3–10 days after acute myocardial infarction, ramipril reduced mortality risk by 27% compared to placebo.
In patients with overt non-diabetic or diabetic nephropathy, ramipril reduces the rate of progression of renal failure and the onset of end-stage renal disease, thereby reducing the need for dialysis or kidney transplantation. In patients with early non-diabetic or diabetic nephropathy, ramipril reduces albumin excretion.
Ramipril significantly reduces, with high statistical significance, the incidence of myocardial infarction, stroke, or cardiovascular death. Additionally, ramipril reduces overall mortality and the need for revascularization procedures, and delays the onset and progression of congestive heart failure. Ramipril also reduces the risk of developing nephropathy in the general population and in patients with diabetes mellitus. Ramipril significantly reduces the incidence of microalbuminuria. These effects were observed in patients both with arterial hypertension and with normotension.
Pharmacokinetics. In the liver, ramipril undergoes hydrolysis to form a single active metabolite – ramiprilat.
The bioavailability of ramiprilat after oral administration of 2.5 and 5 mg of ramipril is approximately 45% compared to its availability after intravenous administration of the same doses.
After oral administration of 10 mg of ramipril, approximately 40% is excreted in feces and 60% in urine.
Approximately 80–90% of metabolites in urine and bile are ramiprilat or metabolites of ramiprilat.
Animal studies have shown that ramipril passes into breast milk.
Ramipril is rapidly absorbed after oral administration. The absorption of ramipril is at least 56%. Co-administration with food does not significantly affect absorption.
Peak plasma concentration of ramipril is reached within 1 hour after oral administration. The elimination half-life of ramipril is approximately 1 hour. Peak plasma concentration of ramiprilat occurs between 2 and 4 hours after oral administration of ramipril.
The decline in ramiprilat plasma concentration occurs in several phases. The half-life of the initial distribution and elimination phase is approximately 3 hours. This is followed by a transitional phase (half-life approximately 15 hours), and then a terminal phase (half-life approximately 4–5 days).
The presence of the terminal phase is due to the slow dissociation of ramiprilat from a tight but saturable binding to ACE.
After a single dose of ramipril of 2.5 mg or higher, a steady state—where plasma concentrations of ramiprilat remain constant—is reached within approximately 4 days. After multiple dosing, the effective half-life, depending on the dose, ranges from 13 to 17 hours.
Protein binding of ramipril and ramiprilat to plasma proteins is approximately 73% and 56%, respectively.
In healthy subjects aged 65 to 76 years, the kinetics of ramipril and ramiprilat are similar to those observed in younger healthy individuals.
In renal impairment, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat decreases proportionally to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline significantly more slowly than in individuals with normal renal function.
When high doses (10 mg) are administered in patients with impaired liver function, the conversion of ramipril to ramiprilat occurs later, plasma concentrations of ramipril increase, and elimination of ramiprilat is delayed.
In both healthy individuals and patients with arterial hypertension after oral administration of 5 mg ramipril once daily for 2 weeks, no significant accumulation of ramipril and ramiprilat was observed in patients with congestive heart failure.
Clinical characteristics.
Indications.
Treatment of arterial hypertension.
Prevention of cardiovascular diseases: reduction of cardiovascular morbidity and mortality in patients with:
- established atherosclerotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
- diabetes mellitus and at least one cardiovascular risk factor (see section "Pharmacological properties").
Treatment of kidney disease:
- early diabetic nephropathy, indicated by the presence of microalbuminuria;
- overt diabetic nephropathy, indicated by the presence of macroproteinuria, in patients with at least one cardiovascular risk factor (see section "Pharmacological properties");
- overt non-diabetic glomerular nephropathy, indicated by the presence of macroproteinuria ≥ 3 g/24 hours (see section "Pharmacological properties").
Treatment of heart failure with clinical manifestations.
Secondary prevention following acute myocardial infarction: reduction of mortality during the acute phase of myocardial infarction in patients with clinical signs of heart failure, provided that treatment is initiated more than 48 hours after the onset of acute myocardial infarction.
Contraindications.
Hypersensitivity to the active substance or to any of the excipients of the medicinal product, or to other angiotensin-converting enzyme (ACE) inhibitors (see section "Composition").
History of angioedema (hereditary, idiopathic, or previously induced by ACE inhibitors or angiotensin II receptor antagonists).
Concomitant use with sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
Significant bilateral renal artery stenosis or stenosis of the artery to a solitary functioning kidney.
Should not be used in pregnant women or women planning pregnancy (see section "Use during pregnancy and lactation").
Ramipril should not be used in patients with arterial hypotension or hemodynamically unstable conditions.
Should not be used concomitantly with aliskiren-containing products in patients with diabetes mellitus or moderate to severe renal impairment (glomerular filtration rate (GFR) < 60 mL/min) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").
Concomitant use of ACE inhibitors and extracorporeal treatment methods that involve blood contact with negatively charged surfaces should be avoided, as such use may cause severe anaphylactoid reactions. Extracorporeal treatment methods include dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate.
Primary hyperaldosteronism.
Interaction with other medicinal products and other forms of interaction.
Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with an increased incidence of adverse events such as arterial hypotension, hyperkalemia, and worsening renal function (including acute renal failure), compared to use of a single RAAS-acting agent (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").
Contraindicated combinations.
Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Ramipril therapy should be initiated only 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan therapy should be initiated only 36 hours after the last dose of ramipril.
Concomitant use of ACE inhibitors with extracorporeal treatment methods involving blood contact with negatively charged surfaces, such as dialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, is contraindicated due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using an alternative dialysis membrane or another class of antihypertensive agents.
Concomitant use of Polapril with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or moderate to severe renal impairment and is not recommended in other patient populations (see sections "Contraindications" and "Special precautions for use").
Combinations requiring precautions.
Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, fixed-dose combinations of trimethoprim with sulfamethoxazole, tacrolimus, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be closely monitored.
Antihypertensive medicinal products (e.g., diuretics) and other substances capable of lowering blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). Increased risk of arterial hypotension should be anticipated (see section "Special precautions for use" regarding diuretics).
Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of Polapril. Blood pressure should be closely monitored.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may cause hematological changes. Increased risk of hematological reactions (see section "Special precautions for use").
Lithium salts. ACE inhibitors may reduce lithium excretion, potentially leading to increased lithium toxicity. Lithium levels should be closely monitored.
Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Blood glucose levels should be closely monitored.
Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. Reduced antihypertensive effect of Polapril is expected. Additionally, concomitant use of ACE inhibitors and NSAIDs may be associated with increased risk of worsening renal function and elevated blood potassium levels.
Salt. Excessive salt intake may reduce the antihypertensive effect of the drug.
Specific allergen immunotherapy. Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom are increased. This effect may also occur with other allergens.
mTOR (mammalian target of rapamycin) inhibitors or vildagliptin. Increased risk of angioedema may occur in patients receiving concomitant therapy with mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Such therapy should be initiated cautiously (see section "Special precautions for use").
Racecadotril. Increased risk of angioedema has been reported with concomitant use of ACE inhibitors and neutral endopeptidase (NEP) inhibitors such as racecadotril (see section "Special precautions for use").
Neprilysin inhibitors. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema.
Special precautions for use.
Special patient categories.
Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated during pregnancy. Except in cases where continued treatment with an ACE inhibitor / angiotensin II receptor antagonist is absolutely necessary, women planning pregnancy should be switched to another antihypertensive agent considered safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors / angiotensin II receptor antagonists should be discontinued immediately and, if necessary, replaced with another suitable medication (see sections "Contraindications" and "Use during pregnancy or breastfeeding").
Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with medicinal products containing aliskiren.
Dual blockade of the renin-angiotensin-aldosterone system by combining the medicinal product Polapril with aliskiren is not recommended, as this increases the risk of developing arterial hypotension, hyperkalaemia, and renal function impairment (including acute kidney injury).
If such dual blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision and with frequent, careful monitoring of renal function, electrolyte levels, and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists must not be used concomitantly in patients with diabetic nephropathy.
Combination of the medicinal product Polapril with aliskiren is contraindicated in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min) (see section "Contraindications").
Patients at particular risk of arterial hypotension.
Patients with markedly increased renin-angiotensin-aldosterone system activity. In patients with markedly increased renin-angiotensin-aldosterone system activity, there is a risk of sudden and significant reduction in blood pressure and worsening of renal function due to ACE inhibition, particularly when the ACE inhibitor or a concomitant diuretic is initiated or its dose is increased for the first time. Markedly increased renin-angiotensin-aldosterone system activity requiring medical supervision, including continuous blood pressure monitoring, may be expected, for example, in patients:
- with severe arterial hypertension;
- with decompensated congestive heart failure;
- with hemodynamically significant obstruction to inflow or outflow of blood from the left ventricle (e.g., aortic or mitral valve stenosis);
- with unilateral renal artery stenosis and a functioning contralateral kidney;
- who have or may develop fluid or electrolyte depletion (including those receiving diuretics);
- with liver cirrhosis and/or ascites;
- undergoing major surgery or receiving anaesthesia with agents that induce arterial hypotension.
Generally, correction of dehydration, hypovolaemia, or electrolyte deficiency is recommended prior to starting treatment (however, for patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).
In patients with hepatic impairment, the response to Polapril may be either enhanced or diminished. Furthermore, in patients with severe liver cirrhosis associated with oedema and/or ascites, renin-angiotensin system activity may be markedly increased; therefore, particular caution is required when treating these patients.
Transient or persistent heart failure after myocardial infarction.
Patients at risk of cardiac or cerebral ischaemia in case of acute arterial hypotension. Special medical supervision is required during the initial phase of treatment.
Elderly patients. See section "Dosage and administration".
Surgery. If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day prior to surgery.
Monitoring of renal function. Renal function should be assessed before and during treatment, and dosage adjusted accordingly, especially during the first weeks of therapy. Particular vigilance is required in patients with impaired renal function (see section "Dosage and administration"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation.
Angioedema. Angioedema has been reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). The risk of angioedema is increased in patients concurrently receiving medicinal products such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), vildagliptin, or neprilysin inhibitors (such as racecadotril).
The combination of ramipril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").
If angioedema occurs, administration of the medicinal product Polapril must be discontinued. Immediate emergency treatment should be initiated. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.
Cases of intestinal angioedema have been reported in patients receiving ACE inhibitors, including Polapril (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).
Anaphylactic reactions during desensitisation. The use of ACE inhibitors increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens. Polapril should be temporarily discontinued prior to desensitisation procedures.
Monitoring of electrolyte balance. Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including Polapril. Patients at risk of hyperkalaemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, and patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of the above-mentioned agents is considered necessary, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Monitoring of electrolyte balance. Hyponatraemia. The syndrome of inappropriate antidiuretic hormone secretion (SIADH), leading to hyponatraemia, has been observed in some patients receiving ramipril. Regular monitoring of serum sodium levels is recommended, particularly in elderly patients and other patients at risk of hyponatraemia.
Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leucopenia, monitoring of white blood cell count is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those receiving other medicinal products that may cause blood count abnormalities (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").
Ethnic differences. ACE inhibitors are more frequently associated with angioedema in black patients than in those of other ethnicities. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients compared to other ethnic groups. This may be due to the higher prevalence of low-renin hypertension in black patients with arterial hypertension.
Cough. Cough has been reported with the use of ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. When performing differential diagnosis of cough, the possibility of ACE inhibitor-induced cough should be considered.
Use during pregnancy or breastfeeding.
Pregnancy. The medicinal product is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is diagnosed during treatment, the drug should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during pregnancy (see section "Contraindications").
Breastfeeding. Due to lack of information on the use of ramipril during breastfeeding (see section "Pharmacological properties"), this medicinal product is not recommended for breastfeeding women. Alternative medicinal products with a more favourable safety profile during lactation should be preferred, especially when breastfeeding newborns or preterm infants.
Ability to affect reaction speed when driving or operating machinery.
Some adverse effects (e.g., decreased blood pressure, drowsiness, visual disturbances, dizziness) may impair a patient's attention and reaction speed. If such reactions occur, patients should refrain from driving or operating machinery.
This may occur particularly at the beginning of treatment or when switching from other medications. Driving or operating machinery is not recommended for several hours after the first dose or any subsequent dose increase.
Administration and Dosage
The medicinal product is intended for oral administration.
Polapril is recommended to be taken daily at the same time. It can be taken before, during, or after meals, as food intake does not affect the bioavailability of the drug. Polapril tablets should be swallowed whole with water. They must not be chewed or crushed.
Adults.
Patients receiving diuretics. Arterial hypotension may occur at the beginning of Polapril therapy, and this is more likely in patients concurrently receiving diuretics. Caution is advised in such cases, as these patients may have reduced circulating blood volume (CBV) and/or electrolyte levels.
It is advisable to discontinue diuretic therapy 2–3 days before initiating Polapril treatment, if possible (see section "Special precautions for use").
In patients with arterial hypertension who cannot discontinue diuretics, Polapril therapy should be initiated at a dose of 1.25 mg (administered in the appropriate dosage form). Renal function and serum potassium levels should be closely monitored. Subsequent dosing of Polapril should be adjusted according to the target blood pressure level.
Arterial hypertension.
The dose should be individually adjusted based on patient-specific factors (see section "Special precautions for use") and blood pressure monitoring results. Polapril can be used as monotherapy or in combination with other classes of antihypertensive medicinal products.
Initial dose. Polapril therapy should be initiated gradually with the recommended initial dose of 2.5 mg once daily.
In patients with significant activation of the renin-angiotensin-aldosterone system, marked reduction in blood pressure may occur after the initial dose. For such patients, the recommended initial dose is 1.25 mg (administered in the appropriate dosage form), and treatment should be initiated under medical supervision (see section "Special precautions for use").
Dose titration and maintenance dose. The dose may be doubled every 2–4 weeks until the target blood pressure level is achieved; the maximum daily dose of Polapril is 10 mg. The drug is generally taken once daily.
Prevention of cardiovascular diseases.
Initial dose. The recommended initial dose of Polapril is 2.5 mg once daily.
Dose titration and maintenance dose. Depending on individual tolerance, the dose should be gradually increased. The dose should be doubled after 1–2 weeks of treatment, and then further increased to the target maintenance dose of 10 mg once daily after another 2–3 weeks.
See also the information above regarding dosing in patients receiving diuretics.
Treatment of kidney disease.
In patients with diabetes and microalbuminuria.
Initial dose. The recommended initial dose of Polapril is 1.25 mg (administered in the appropriate dosage form) once daily.
Dose titration and maintenance dose. Depending on individual tolerance during continued treatment, the dose should be increased. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.
In patients with diabetes and at least one cardiovascular risk factor.
Initial dose. The recommended initial dose of Polapril is 2.5 mg once daily.
Dose titration and maintenance dose. Depending on individual tolerance during continued treatment, the dose should be increased. After 1–2 weeks of treatment, the daily dose of Polapril should be doubled to 5 mg, and then to 10 mg after another 2–3 weeks of treatment. The target daily dose is 10 mg.
In patients with non-diabetic nephropathy, indicated by macroproteinuria ≥ 3 g/day.
Initial dose. The recommended initial dose of Polapril is 1.25 mg (administered in the appropriate dosage form) once daily.
Dose titration and maintenance dose. Depending on individual patient tolerance during continued treatment, the dose should be increased. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.
Heart failure with clinical manifestations.
Initial dose. For patients whose condition has been stabilized following diuretic therapy, the recommended initial dose is 1.25 mg (administered in the appropriate dosage form) once daily.
Dose titration and maintenance dose. The dose of Polapril should be titrated by doubling every 1–2 weeks until the maximum daily dose of 10 mg is reached. The dose should preferably be divided into two administrations.
Secondary prevention following 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 should be given an initial dose of 2.5 mg twice daily for 3 days. If the initial dose of 2.5 mg is poorly tolerated, a dose of 1.25 mg (administered in the appropriate dosage form) twice daily should be used for 2 days, followed by escalation to 2.5 mg and then 5 mg twice daily. If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued.
See also the information above regarding dosing in patients receiving diuretics.
Dose titration and maintenance dose. Subsequently, the daily dose should be increased by doubling every 1–3 days until the target maintenance dose of 5 mg twice daily is reached.
When possible, the maintenance daily dose should be divided into two administrations.
If the dose cannot be increased to 2.5 mg twice daily, treatment should be discontinued. Experience with treating patients with severe [NYHA Class IV (New York Heart Association)] heart failure immediately after myocardial infarction is still limited. If treatment of such patients with this medicinal product is nevertheless decided upon, therapy should be initiated at a dose of 1.25 mg (administered in the appropriate dosage form) once daily, and any dose increase should be performed with extreme caution.
Special patient categories.
Patients with impaired renal function. The daily dose for patients with impaired renal function depends on creatinine clearance (see section "Pharmacological properties"):
- if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose (2.5 mg/day) is required, and the maximum daily dose is 10 mg;
- if creatinine clearance is 30–60 mL/min, no adjustment of the initial dose (2.5 mg/day) is required, and the maximum daily dose is 5 mg;
- if creatinine clearance is 10–30 mL/min, the initial daily dose is 1.25 mg/day (administered in the appropriate dosage form), and the maximum daily dose is 5 mg;
- patients with arterial hypertension undergoing hemodialysis: ramipril is only minimally removed during hemodialysis; the initial dose is 1.25 mg (administered in the appropriate dosage form), and the maximum daily dose is 5 mg; the drug should be taken several hours after a hemodialysis session.
Patients with impaired hepatic function (see section "Pharmacological properties"). Polapril therapy in patients with impaired liver function should be initiated under strict medical supervision, and the maximum daily dose in such cases should not exceed 2.5 mg.
Elderly patients. The initial dose should be lower, and subsequent dose titration should be performed more gradually due to the higher likelihood of adverse effects, especially in very elderly and frail patients. In such cases, a lower initial dose of 1.25 mg (administered in the appropriate dosage form) of ramipril should be prescribed.
See also the information above regarding dosing in patients receiving diuretics.
Children.
Polapril is not recommended for use in children (under 18 years of age), as there is insufficient data on the efficacy and safety of this medicinal product in such patients.
Overdose.
Symptoms associated with ACE inhibitor overdose may include excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte imbalance, and renal failure. Close monitoring of the patient is required, along with symptomatic and supportive therapy. Recommended therapeutic measures include primary detoxification (gastric lavage, administration of adsorbents) and interventions aimed at restoring stable hemodynamics, including administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from systemic circulation by hemodialysis.
Adverse Reactions
The safety profile of the drug Polapril includes data on persistent cough and reactions caused by arterial hypotension. Serious adverse reactions include angioedema, hyperkalemia, liver or kidney function disorders, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.
The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (from ≥ 1/100 to < 1/10); uncommon (from ≥ 1/1000 to < 1/100); rare (from ≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be estimated from available data). Within each group, adverse events are listed in order of decreasing severity.
Cardiac system
Uncommon: Myocardial ischemia, including angina pectoris or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema.
Blood and lymphatic system
Uncommon: Eosinophilia.
Rare: Decreased leukocyte count (including neutropenia or agranulocytosis), decreased erythrocyte count, decreased hemoglobin levels, decreased platelet count.
Frequency not known: Bone marrow failure, pancytopenia, hemolytic anemia.
Nervous system
Common: Headache, dizziness.
Uncommon: Vertigo, paresthesia, ageusia, dysgeusia.
Rare: Tremor, impaired balance.
Frequency not known: Cerebral ischemia, including ischemic stroke and transient ischemic attack, psychomotor disturbances, burning sensation, parosmia.
Eye disorders
Uncommon: Visual disturbances, including blurred vision.
Rare: Conjunctivitis.
Ear and labyrinth disorders
Rare: Hearing disturbances, tinnitus.
Respiratory, thoracic and mediastinal system
Common: Non-productive irritating cough, bronchitis, sinusitis, dyspnea.
Uncommon: Bronchospasm, including asthma exacerbation; nasal congestion.
Gastrointestinal system
Common: Inflammatory gastrointestinal events, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting.
Uncommon: Pancreatitis (in isolated cases fatal outcomes have been reported with ACE inhibitors), increased pancreatic enzyme levels, angioedema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth.
Rare: Glossitis.
Frequency not known: Aphthous stomatitis.
Renal and urinary system
Uncommon: Renal function disorders, including acute renal failure, increased urine output, worsening of background proteinuria, increased blood urea levels, increased serum creatinine levels.
Skin and subcutaneous tissue
Common: Rash, particularly maculopapular.
Uncommon: Angioedema; in very rare cases – airway obstruction due to angioedema, which may be fatal; pruritus, hyperhidrosis.
Rare: Exfoliative dermatitis, urticaria, onycholysis.
Very rare: Photosensitivity reactions.
Frequency not known: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthem or enanthem, alopecia.
Musculoskeletal and connective tissue system
Common: Muscle spasms, myalgia.
Uncommon: Arthralgia.
Endocrine system
Frequency not known: Syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Nutritional and metabolic disorders
Common: Increased blood potassium levels.
Uncommon: Anorexia, decreased appetite.
Frequency not known: Decreased blood sodium levels.
Vascular system
Common: Arterial hypotension, orthostatic hypotension, syncope.
Uncommon: Flushing sensation.
Rare: Vascular stenosis, hypoperfusion, vasculitis.
Frequency not known: Raynaud's phenomenon.
General disorders
Common: Chest pain, increased fatigue.
Uncommon: Pyrexia.
Rare: Asthenia.
Immune system
Frequency not known: Anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.
Hepatobiliary system
Uncommon: Increased levels of liver enzymes and/or conjugated bilirubin.
Rare: Cholestatic jaundice, hepatocellular injury.
Frequency not known: Acute liver failure, cholestatic or cytolytic hepatitis (in very rare cases with fatal outcome).
Reproductive system and breast
Uncommon: Transient erectile dysfunction, decreased libido.
Frequency not known: Gynecomastia.
Psychiatric disorders
Uncommon: Depressed mood, anxiety, nervousness, restlessness, sleep disturbances, including somnolence.
Rare: Confusion.
Frequency not known: Attention disturbances.
Pediatric population. The safety of ramipril has been evaluated in 325 children and adolescents aged 2–16 years in two clinical trials. According to the results, the nature and severity of adverse reactions in children were similar to those observed in adults, but the frequency of some reactions was higher in children than in adults, specifically:
Tachycardia, nasal congestion, and rhinitis: common in the pediatric population and uncommon in the adult population.
Conjunctivitis: common in the pediatric population and rare in the adult population.
Tremor and urticaria: uncommon in the pediatric population and rare in the adult population.
The overall safety profile of ramipril in adults and children does not differ significantly.
Shelf life. 2 years.
Storage conditions.
Keep out of reach and sight of children.
Store in the original packaging at a temperature not exceeding 25 °C.
Packaging.
14 capsules in a blister, 1 or 2 blisters per cardboard box.
Prescription status. Prescription only.
Manufacturer.
Pharmaceutical Works “Polpharma” S.A., Poland.
Manufacturer’s address.
19 Pelplinska Street, 83-200 Starogard Gdanski, Poland.