Instructions for Polapril A hard capsules 5 mg/5 mg No. 30
Composition
active ingredients: ramipril; amlodipine;
1 capsule contains
5 mg ramipril and 5 mg amlodipine (as amlodipine besylate) or
10 mg ramipril and 5 mg amlodipine (as amlodipine besylate), or
10 mg of ramipril and 10 mg of amlodipine (as amlodipine besylate);
excipients: microcrystalline cellulose, hypromellose, crospovidone (type B), glycerol dibehenate;
capsule shell: gelatin; titanium dioxide (E 171); indigo carmine (E 132).
Dosage form
The capsules are hard.
Main physicochemical properties:
5 mg + 5 mg capsules: hard gelatin capsules, size 3, blue, filled with white or almost white powder or slightly compacted agglomerate;
5 mg + 10 mg capsules: hard gelatin capsules size 1 with a white body and a blue cap, filled with white or almost white powder or slightly compacted agglomerate;
10 mg + 10 mg capsules: hard gelatin capsules, size 1, blue, filled with white or almost white powder or slightly compacted agglomerate.
Pharmacotherapeutic group
Agents affecting the cardiovascular system. Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme inhibitor and calcium channel blocker. ATC code C09B B07.
Pharmacological properties
Pharmacodynamics.
Ramipril
Mechanism of action. Ramiprilat, the active metabolite of the prodrug ramipril, inhibits the enzyme dipeptidylcarboxypeptidase I (synonyms: angiotensin-converting enzyme, kininase II). In plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the active vasoconstrictor angiotensin II, as well as the cleavage of the active vasodilator bradykinin. The reduction in the formation of angiotensin II and the inhibition of the cleavage of bradykinin lead to vasodilation.
Since angiotensin II also stimulates aldosterone release, ramiprilat reduces aldosterone secretion. The average response to ACE (angiotensin-converting enzyme) inhibitor monotherapy in hypertensive patients of African-Caribbean origin (usually a low-renin hypertensive population) was lower than in non-African-Americans.
Pharmacodynamic effects. Antihypertensive properties. The use of ramipril causes a pronounced decrease in peripheral arterial resistance. In general, renal plasma flow and glomerular filtration rate do not change significantly. The use of ramipril in patients with arterial 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 after oral administration of a single dose of the drug is manifested after 1-2 hours. The maximum effect after taking a single dose of the drug is usually achieved after 3-6 hours. The antihypertensive effect of a single dose of the drug usually lasts for 24 hours.
The maximum antihypertensive effect of long-term treatment with ramipril is generally observed after 3-4 weeks. It has been shown to be maintained for 2 years with long-term therapy. There is no rapid and excessive ("ricochet") increase in blood pressure in response to abrupt discontinuation of ramipril.
Amlodipine
Mechanism of action. Amlodipine is a dihydropyridine calcium ion flux inhibitor (slow channel blocker, or calcium ion antagonist) that slows the transmembrane flow of calcium ions in the smooth muscles of the heart and blood vessels.
The mechanism of antihypertensive action of amlodipine is due to a direct relaxing effect on vascular smooth muscle. The exact mechanism of action of amlodipine in angina is not fully established, but it is known that amlodipine reduces total myocardial ischemia in two ways:
- In patients with arterial hypertension, once-daily dosing provides clinically significant reductions in both supine and standing blood pressure over 24 hours. Due to its slow onset of action, amlodipine does not cause a rapid decrease in blood pressure.
- Amlodipine does not cause any adverse metabolic effects or changes in plasma lipid concentrations and is acceptable for use in patients with bronchial asthma, diabetes mellitus, and gout.
Pharmacokinetics.
Ramipril
Distribution: The serum protein binding of ramipril is approximately 73% and that of ramiprilat is approximately 56%.
Metabolism: Ramipril is almost completely metabolized to ramiprilat and diketopiperazine ester, diketopiperazine acid, as well as to the glucuronides of ramipril and ramiprilat.
Elimination. Metabolites are excreted mainly by the kidneys. The plasma concentration of ramiprilat decreases polyphasically. Due to the intensive saturable binding to ACE and the slow dissociation from the enzyme, ramiprilat has an inherent prolongation of the terminal elimination phase at very low plasma concentrations. After multiple once-daily administration of ramipril, the effective half-life of ramiprilat is 13-17 hours when the drug is used in a dose of 5-10 mg and is longer at lower doses of 1.25-2.5 mg. This difference is due to the saturable ability of the enzyme to bind ramiprilat. After a single oral dose, ramipril and its metabolites are not detected in breast milk. However, the effect of multiple doses of the drug is unknown.
Patients with renal impairment (see section 4.2). In patients with renal impairment, the renal excretion of ramiprilat is reduced and the renal clearance of ramiprilat is proportional to creatinine clearance. This results in increased plasma concentrations of ramiprilat, which decrease much more slowly than in patients with normal renal function.
Patients with impaired hepatic function (see section "Method of administration and dosage"). In patients with impaired hepatic function, the metabolism of ramipril to ramiprilat is slowed down due to reduced activity of hepatic esterases, and the concentration of ramipril in the blood plasma of such patients is increased. However, the maximum concentration of ramiprilat in patients with impaired hepatic function does not differ from that in patients with normal hepatic function.
Lactation: After a single oral dose of 10 mg ramipril, it is not detected in breast milk. However, the effect of multiple doses of the drug is unknown.
Amlodipine
Absorption, distribution, plasma protein binding. After oral administration in therapeutic doses, amlodipine is well absorbed, reaching maximum blood concentrations 6-12 hours after administration. Absolute bioavailability is estimated to be 64% to 80%. The volume of distribution is approximately 21 l/kg. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.
The bioavailability of amlodipine is not affected by food intake.
Biotransformation/Excretion: The terminal plasma half-life is approximately 35-50 hours and is consistent with once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites and excreted in the urine as unchanged compound (10%) and metabolites (60%).
Use in hepatic impairment: There are very limited clinical data on the use of amlodipine in patients with hepatic impairment. In patients with hepatic insufficiency, the clearance of amlodipine is reduced, resulting in a prolongation of the half-life and an increase in AUC of approximately 40-60%.
Use in the elderly. The time to reach maximum plasma concentrations of amlodipine is similar in elderly and younger patients. There is a tendency for amlodipine clearance to decrease in elderly patients, resulting in increased AUC and half-life. The increase in AUC and half-life in patients with congestive heart failure is consistent with what is expected for the age groups studied.
Use in renal impairment. Amlodipine is extensively biotransformed to inactive metabolites. 10% of amlodipine is excreted unchanged in the urine. Changes in plasma amlodipine concentrations do not correlate with the degree of renal impairment. Patients with renal impairment can be treated with normal doses of amlodipine. Amlodipine is not removed by dialysis.
Indication
POLAPRIL A is indicated for the treatment of hypertension in adult patients whose blood pressure is adequately controlled with ramipril and amlodipine when used concomitantly at the same dose as in the combination.
Contraindication
Related to the drug POLAPRYL A
- Hypersensitivity to ramipril, amlodipine, other ACE inhibitors, dihydropyridine derivatives or to any of the excipients.
Related to ramipril
- History of angioedema (hereditary, idiopathic or associated with ACE inhibitors or angiotensin II receptor antagonists).
- Extracorporeal therapy methods that result in blood coming into contact with negatively charged surfaces (see section "Interaction with other medicinal products and other types of interactions").
- Significant bilateral renal artery stenosis or renal artery stenosis of a single functioning kidney.
- Concomitant use of ramipril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) <2) (see sections 4.5 and 5.1). Concomitant use with sacubitril/valsartan therapy. Ramipril should not be administered earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections 4.4 and 5.1).
- Use is contraindicated in pregnant women and women planning to become pregnant (see section "Use during pregnancy and breastfeeding").
Related to amlodipine
- Severe arterial hypotension.
- Shock (including cardiogenic shock).
- Obstruction of the left ventricular outflow tract (e.g. severe aortic stenosis).
- Hemodynamically unstable heart failure after acute myocardial infarction.
- Childhood.
Interaction with other medicinal products and other types of interactions
Ramipril
Contraindicated combinations
Extracorporeal therapies that result in contact of blood with negatively charged surfaces, such as haemodialysis or haemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis using dextran sulphate, due to the increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is necessary, consideration should be given to using a different type of haemodialysis membrane or a different class of antihypertensive drug.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS): Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased incidence of adverse events such as hypotension, hyperkalaemia and worsening renal function (including acute renal failure) compared with the use of a single RAAS-acting agent (see sections 4.3, 4.4 and 5.1).
Drugs that increase the risk of angioedema: Concomitant use of ramipril with sacubitril/valsartan is contraindicated as it may increase the risk of angioedema.
Precautions for use
Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes. Although serum potassium is usually within normal limits, hyperkalaemia may occur in some patients treated with ramipril. Potassium-sparing diuretics (e.g. spironolactone, triamterene or amiloride), potassium supplements or potassium-containing salt substitutes may lead to significant increases in serum potassium. The concomitant use of ramipril with other medicinal products that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), is not recommended, as trimethoprim, like amiloride, is known to act as a potassium-sparing diuretic. An increased risk of hyperkalemia has been observed in patients receiving concomitant ACE inhibitors and trimethoprim or its fixed combination with co-trimoxazole (trimethoprim/sulfamethoxazole). If concomitant administration cannot be avoided, the drugs should be administered with caution and frequent monitoring of serum potassium is mandatory.
Cyclosporine: Concomitant use of ACE inhibitors with cyclosporine may cause hyperkalemia. Monitoring of plasma potassium levels is recommended.
Heparin: Concomitant use of ACE inhibitors with heparin may lead to hyperkalemia. Monitoring of serum potassium is recommended.
Potassium salts, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II receptor antagonists, trimethoprim, tacrolimus). Hyperkalemia may occur, therefore careful monitoring of serum potassium levels is necessary.
Antihypertensive agents (e.g. diuretics) and other substances that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, large amounts of alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). Potentiation of the effect with the risk of developing arterial hypotension is possible (see section "Method of administration and dosage").
Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, adrenaline) may reduce the antihypertensive effect of ramipril. Blood pressure monitoring is recommended.
Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may alter the parameters of the complete blood count. Increased likelihood of blood reactions (see section "Special warnings and precautions for use").
Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Blood glucose monitoring is recommended.
Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. The antihypertensive effect of ramipril may be reduced. In addition, the simultaneous use of ACE inhibitors and NSAIDs increases the risk of worsening of renal function and increased potassium levels in the blood.
mTOR inhibitors or vildagliptin: An increased incidence of angioedema has been observed in patients receiving concomitant ACE inhibitors and mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be exercised at the start of therapy.
Amlodipine
Effects of other drugs on amlodipine
CYP3A4 inhibitors: Concomitant use of amlodipine with strong or moderate CYP3A4 inhibitors (protease inhibitors, azole antifungals, macrolides such as erythromycin or clarithromycin, verapamil or diltiazem) may result in a significant increase in amlodipine exposure. These pharmacokinetic changes may be more pronounced in elderly patients. Clinical monitoring and dose adjustment may therefore be necessary.
CYP3A4 inducers. There are currently no data on the effect of CYP3A4 inducers on amlodipine. Concomitant use of CYP3A4 inducers (such as rifampicin, St. John's wort) may result in decreased plasma concentrations of amlodipine. Amlodipine should be used with caution in combination with CYP3A4 inducers.
Taking amlodipine with grapefruit or grapefruit juice is not recommended, as in some patients the bioavailability of the drug may increase, leading to increased antihypertensive effect.
Dantrolene (solution for infusion). Fatal ventricular fibrillation and cardiovascular collapse in association with hyperkalemia have been observed in animals following verapamil and intravenous administration of dantrolene. Due to the risk of hyperkalemia, it is recommended that concomitant use of calcium channel blockers such as amlodipine be avoided in patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.
Effect of amlodipine on other medicinal products. The hypotensive effect of amlodipine potentiates the hypotensive effects of other medicinal products with antihypertensive properties.
In clinical drug interaction studies, amlodipine did not alter the pharmacokinetics of atorvastatin, digoxin, warfarin, or cyclosporine.
Cyclosporine: No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other subjects, except in renal transplant patients, in whom variable increases in cyclosporine trough concentrations (mean 0-40%) were observed. Monitoring of cyclosporine levels should be considered in renal transplant patients receiving amlodipine; if necessary, a reduction in the cyclosporine dose should be considered.
Simvastatin: Co-administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.
Tacrolimus: There is a risk of increased blood levels of tacrolimus when co-administered with amlodipine, but the pharmacokinetic mechanism of this interaction is not fully established. To avoid tacrolimus toxicity, patients taking tacrolimus should have their blood levels monitored regularly and the tacrolimus dose adjusted if necessary when amlodipine is co-administered with amlodipine.
mTOR (mammalian target of rapamycin) inhibitors.
mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When amlodipine is used concomitantly with mTOR inhibitors, it may potentiate the effects of the latter.
Sildenafil. A single dose of 100 mg of sildenafil did not affect the pharmacokinetics of amlodipine in patients with essential hypertension. When amlodipine and sildenafil were used simultaneously as combination therapy, each drug exerted an independent hypotensive effect.
Other medicinal products: Clinical drug interaction studies have shown that amlodipine does not affect the pharmacokinetics of atorvastatin, digoxin or warfarin.
Ethanol (alcohol): Single and multiple doses of 10 mg amlodipine had no significant effect on the pharmacokinetics of ethanol.
Co-administration of amlodipine with cimetidine did not affect the pharmacokinetics of amlodipine.
Co-administration of aluminum/magnesium preparations (antacids) with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.
Laboratory tests: The effect on laboratory test results is unknown.
Application features
Caution is recommended in patients receiving concomitant diuretics, as excessive fluid and/or salt loss may occur. Monitoring of renal function and serum potassium is recommended.
Dual blockade of the renin-angiotensin-aldosterone system (RAAS). There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalaemia and worsening of renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections 4.5 and 5.1).
If such dual blockade therapy is considered absolutely necessary, it should only be used under specialist supervision and with frequent monitoring of renal function, electrolytes and blood pressure.
ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.
Special categories of patients
Pregnancy: Treatment with ACE inhibitors is contraindicated during pregnancy. When pregnancy is diagnosed, ACE inhibitors should be stopped immediately and, if necessary, alternative treatment should be started (see sections 4.3 and 4.4).
Patients at high risk of developing hypotension
Patients with a strongly activated renin-angiotensin-aldosterone system: Patients with a strongly activated renin-angiotensin-aldosterone system are at risk of a sudden, pronounced fall in blood pressure and deterioration in renal function due to ACE inhibition, particularly when an ACE inhibitor is used for the first time, either alone or in combination with a diuretic, or when the dose is increased for the first time.
Significant activation of the renin-angiotensin-aldosterone system is possible and medical supervision, including blood pressure monitoring, is necessary, for example, in the following cases:
- severe arterial hypertension;
- decompensated congestive heart failure;
- hemodynamically significant left ventricular pre- or afterload (e.g. aortic or mitral stenosis);
- unilateral renal artery stenosis with a functioning second kidney;
- liver cirrhosis and/or ascites;
- performing major surgery or anesthesia using drugs that induce arterial hypotension.
In general, it is recommended to correct dehydration, hypovolemia, or electrolyte deficiencies before starting treatment (however, in patients with heart failure, such correction should be carried out with caution, given the risk of volume overload).
- transient or persistent heart failure after myocardial infarction;
- risk of myocardial or cerebral ischemia in case of acute arterial hypotension.
In the initial phase of treatment, special medical supervision is necessary.
Elderly patients: See section "Method of administration and dosage".
Surgery: It is recommended, if possible, to discontinue treatment with angiotensin-converting enzyme inhibitors, such as ramipril, one day before surgery.
Monitoring of renal function. Renal function should be assessed before and during treatment and the dosage adjusted, especially in the first weeks of treatment. Particularly careful monitoring is required in patients with impaired renal function (see section 4.2). There is a risk of impaired renal function, especially in patients with congestive heart failure or after kidney transplantation.
Angioedema: Angioedema has been reported in patients receiving ACE inhibitors, including ramipril (see section 4.8). If angioedema occurs, ramipril should be discontinued.
Emergency treatment should be initiated immediately. The patient should be observed for at least 12-24 hours and may be discharged after complete resolution of symptoms.
Intestinal angioedema has been reported in patients taking ACE inhibitors, including ramipril (see section 4.8). These patients have experienced abdominal pain (with or without nausea or vomiting).
Concomitant use of ramipril with sacubitril/valsartan is contraindicated as it may increase the risk of angioedema. Sacubitril/valsartan should not be started earlier than 36 hours after the last dose of ramipril. If treatment with sacubitril/valsartan is discontinued, ramipril should not be started earlier than 36 hours after the last dose of sacubitril/valsartan.
Concomitant use of ACE inhibitors and racecadotril, MTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin may increase the risk of angioedema (e.g. swelling of the airways or tongue, with or without respiratory compromise).
Regarding patients already receiving an ACE inhibitor, caution should be exercised when prescribing racecadotril, mTOR inhibitors (e.g. sirolimus, everolimus, temsirolimus) and vildagliptin.
Anaphylactic reactions during desensitization. ACE inhibition increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens. Temporary discontinuation of ramipril should be considered before desensitization.
Hyperkalemia. Hyperkalemia has been observed in some patients taking ACE inhibitors, including ramipril. The risk of developing hyperkalemia exists in patients with renal insufficiency, patients over 70 years of age, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics and other active substances that increase plasma potassium levels, patients with conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If the use of the above agents is considered appropriate, monitoring of serum potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").
Hyponatremia: Syndrome of inappropriate antidiuretic hormone secretion with subsequent development of hyponatremia has been observed in some patients treated with ramipril. Regular monitoring of serum sodium levels is recommended in the elderly and in other patients at risk of hyponatremia.
Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been observed rarely, and bone marrow depression has also been reported. Monitoring of white blood cell counts is recommended to detect possible leukopenia. More frequent monitoring is recommended in patients in the initial phase of treatment, in patients with impaired renal function, in patients with concomitant systemic connective tissue disease (e.g. lupus erythematosus or scleroderma) and in all patients taking other drugs that may cause changes in complete blood counts (see sections “Interaction with other medicinal products and other forms of interaction” and “Adverse reactions”).
Race. ACE inhibitors cause angioedema more frequently in black patients than in non-blacks. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in blacks than in non-blacks, possibly because of a higher prevalence of low-renin states in the black hypertensive population.
Cough: Cough has been reported with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of the drug. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.
Amlodipine
The safety and efficacy of amlodipine in hypertensive crisis have not been evaluated.
Special categories of patients
Patients with heart failure. The drug should be used with caution in patients with heart failure. In a long-term placebo-controlled study in patients with severe heart failure (NYHA class III and IV), the reported incidence of pulmonary edema in the amlodipine group was higher than in the placebo group (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as these drugs may increase the risk of future cardiovascular events and mortality.
Patients with hepatic impairment. In patients with hepatic impairment, the half-life of amlodipine is prolonged and AUC values are higher; no dosage recommendations are available. Therefore, amlodipine should be started at the lower end of the dosing range and treatment and dose increases should be initiated with caution. Patients with severe hepatic impairment may require slow dose titration and close monitoring.
Elderly patients: For elderly patients, increasing the dose of the drug should be done with caution (see sections “Method of administration and dosage” and “Pharmacokinetics”).
Patients with renal insufficiency. Amlodipine can be used in patients with renal insufficiency at usual doses. Changes in plasma concentrations of amlodipine do not correlate with the degree of renal insufficiency. Amlodipine is not removed by dialysis.
Use during pregnancy or breastfeeding
Amlodipine is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is detected during therapy, the drug should be discontinued immediately and, if necessary, replaced by another drug approved for use in pregnancy (see section "Contraindications").
Ramipril is contraindicated during pregnancy. If a pregnant woman uses ACE inhibitors, it may cause illness and death of the fetus or newborn.
Use of ACE inhibitors during the second and third trimesters of pregnancy has been associated with fetal and neonatal harm, including hypotension, skull hypoplasia in the newborn, anuria, reversible or irreversible renal failure, and fatalities. Oligohydramnios has also been reported, presumably due to impaired fetal renal function; oligohydramnios in this setting has been associated with fetal limb contractures, craniofacial deformity, and hypoplastic lung development. Prematurity, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is unclear whether these are caused by ACE inhibitors. In addition, use of ACE inhibitors during the first trimester of pregnancy is associated with a potentially increased risk of congenital malformations.
If pregnancy is confirmed, ACE inhibitors should be discontinued as soon as possible and regular fetal monitoring should be performed. ACE inhibitors (including ramipril) should not be used in women planning pregnancy. Women of childbearing potential should be informed of the potential risk and ACE inhibitors (including ramipril) should only be prescribed after careful consultation and consideration of the individual risks and benefits.
Breastfeeding. Amlodipine is excreted in breast milk. The dose received by the newborn through breast milk is estimated in the interquartile range to be 3-7% of the maternal dose, with a maximum of 15%. The effect of amlodipine on infants is unknown.
A decision on whether to continue breast-feeding or to use amlodipine should be made taking into account the benefit of breast-feeding to the child and the benefit of the drug to the mother. Because no information is available regarding the use of ramipril during breast-feeding (see section 5.1), ramipril is not recommended for use in breast-feeding women and alternative treatments with better established safety profiles during lactation are preferable, especially while nursing a newborn or preterm infant.
Fertility: Reproductive toxicity has been observed in animal studies at high doses.
Reversible biochemical changes in the sperm head have been reported in some patients receiving calcium channel blockers. There is insufficient clinical information regarding the potential effect of amlodipine on fertility.
Ability to influence reaction speed when driving vehicles or other mechanisms
The drug POLAPRIL A may have minor or moderate influence on the ability to drive and use machines. Some side effects (in particular, symptoms that occur when blood pressure drops, such as dizziness, headache, increased fatigue) may impair the patient's ability to concentrate and reduce the speed of his reaction, which is risky in situations where these qualities are of particular importance (for example, when driving or using other mechanisms).
Such phenomena are more often observed at the beginning of treatment or when transferring the patient to this drug from other drugs. It is recommended to be careful, especially at the beginning of treatment.
Method of administration and doses
Dosage. The drug POLAPRIL A should not be used as initial therapy for arterial hypertension. The dosage of each component of the drug should be selected individually, according to the specific
