Polapril a

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT POLAPRIL A (POLAPRIL A)

Composition:

Active substances: ramipril; amlodipine;

1 capsule contains

5 mg of ramipril and 5 mg of amlodipine (as amlodipine besylate), or

5 mg of ramipril and 10 mg of 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).

Pharmaceutical form. Hard capsules.

Main physicochemical characteristics:

5 mg + 5 mg capsules: hard gelatin capsules, size 3, blue in color, filled with white or almost white powder or slightly compacted agglomerate;

5 mg + 10 mg capsules: hard gelatin capsules with white body and blue cap, size 1, filled with white or almost white powder or slightly compacted agglomerate;

10 mg + 10 mg capsules: hard gelatin capsules, size 1, blue in color, filled with white or almost white powder or slightly compacted agglomerate.

Pharmacotherapeutic group. Agents acting on 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 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 degradation of the active vasodilator bradykinin. The reduction in angiotensin II formation and inhibition of bradykinin breakdown lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat reduces aldosterone secretion. The average response to monotherapy with an ACE (angiotensin-converting enzyme) inhibitor in patients with arterial hypertension of African-Caribbean descent (who typically have low renin levels) is lower compared to that in individuals of other racial groups.

Pharmacodynamic effects. Antihypertensive properties. Administration of ramipril results in a pronounced reduction in peripheral arterial resistance. Overall, renal plasma flow and glomerular filtration rate do not change significantly. The use of ramipril in patients with arterial hypertension leads to a reduction in blood pressure in both supine and standing positions without a compensatory increase in heart rate. In most patients, the antihypertensive effect after a single oral dose appears within 1–2 hours. The maximum effect after a single dose is generally achieved within 3–6 hours. The antihypertensive effect of a single dose typically lasts for 24 hours.

The maximum antihypertensive effect during long-term ramipril therapy is generally observed within 3–4 weeks. It has been shown that this effect is maintained for up to 2 years with prolonged therapy. Abrupt discontinuation of ramipril does not result in a rapid or excessive ("rebound") increase in blood pressure.

Amlodipine

Mechanism of action. Amlodipine is a dihydropyridine group calcium ion influx inhibitor (a slow-channel blocker or calcium ion antagonist) that slows transmembrane calcium ion influx into cardiac and vascular smooth muscle.

The antihypertensive mechanism of amlodipine is due to its direct relaxant 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 myocardial ischemia through two pathways:

• In patients with arterial hypertension, once-daily dosing provides clinically significant reductions in blood pressure in both supine and standing positions over 24 hours. Due to its slow onset of action, amlodipine does not cause a sudden drop in blood pressure.
• Amlodipine does not cause any adverse metabolic effects or changes in plasma lipid concentrations and is suitable for use in patients with bronchial asthma, diabetes mellitus, and gout.

Pharmacokinetics

Ramipril

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract; maximum plasma concentration of ramipril is reached within one hour. Based on urinary excretion data, the extent of absorption is at least 56% and is not significantly affected by food intake. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at doses of 2.5 and 5 mg is 45%. Maximum plasma concentration of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after ramipril administration. Steady-state plasma concentrations of ramiprilat are achieved approximately on the fourth day of treatment with once-daily dosing of ramipril.

Distribution. Plasma protein binding of ramipril is approximately 73%, and that of ramiprilat is approximately 56%.

Metabolism. Ramipril is almost completely metabolized to ramiprilat, diketopiperazine ester, diketopiperazine acid, and glucuronides of ramipril and ramiprilat.

Elimination. Metabolites are primarily excreted by the kidneys. Plasma ramiprilat concentration declines in a polyphasic manner. Due to extensive saturable binding to ACE and slow dissociation from the enzyme, ramiprilat exhibits prolonged terminal elimination at very low plasma concentrations. After repeated once-daily administration of ramipril, the effective half-life of ramiprilat is 13–17 hours at doses of 5–10 mg and is longer at lower doses (1.25–2.5 mg). This difference is due to the saturable binding capacity of the enzyme for ramiprilat. After a single oral dose, ramipril and its metabolites are not detectable in breast milk. However, the effect of multiple doses is unknown.

Patients with renal impairment (see section "Dosage and Administration"). In patients with impaired renal function, renal elimination of ramiprilat is reduced, and the renal clearance of ramiprilat is proportional to creatinine clearance. As a result, plasma ramiprilat concentration is increased and declines much more slowly than in patients with normal renal function.

Patients with hepatic impairment (see section "Dosage and Administration"). In patients with impaired liver function, the metabolism of ramipril to ramiprilat is slowed due to reduced hepatic esterase activity, and plasma ramipril concentration is elevated. However, the maximum plasma concentration of ramiprilat in patients with hepatic impairment does not differ from that in patients with normal liver function.

Lactation. After a single oral dose of 10 mg ramipril, the drug is not detectable in breast milk. However, the effect of multiple doses is unknown.

Amlodipine

Absorption, distribution, plasma protein binding. After oral administration at therapeutic doses, amlodipine is well absorbed, reaching peak blood concentrations 6–12 hours after administration. Absolute bioavailability is estimated to be between 64% and 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.

Food intake does not affect the bioavailability of amlodipine.

Biological transformation/elimination. The terminal elimination half-life from plasma is approximately 35–50 hours and remains constant with once-daily dosing. Amlodipine is extensively metabolized in the liver to inactive metabolites and is excreted in urine as unchanged drug (10%) and metabolites (60%).

Use in patients with hepatic impairment. Clinical data on the use of amlodipine in patients with hepatic impairment are very limited. In patients with hepatic insufficiency, amlodipine clearance is reduced, resulting in prolonged elimination half-life and an increase in AUC by approximately 40–60%.

Use in elderly patients. Time to reach maximum plasma concentration of amlodipine is similar in elderly and younger patients. In elderly patients, there is a tendency toward reduced amlodipine clearance, resulting in increased AUC and prolonged elimination half-life. The increase in AUC and elimination half-life in patients with congestive heart failure corresponds to the expected values for the studied age groups.

Use in patients with renal impairment. Amlodipine is extensively biotransformed into inactive metabolites. Ten percent of amlodipine is excreted unchanged in urine. Changes in amlodipine plasma concentrations do not correlate with the degree of renal impairment. Standard doses of amlodipine can be used in patients with impaired renal function. Amlodipine is not removed by dialysis.

Clinical characteristics.

Indications.

POLAPRIL A is indicated for the treatment of arterial hypertension in adult patients whose blood pressure is adequately controlled with ramipril and amlodipine when used concomitantly at the same doses as in the combination.

Contraindications.

Related to the medicinal product POLAPRIL 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 due to ACE inhibitors or angiotensin II receptor antagonists).
• Extracorporeal therapies involving contact of blood with negatively charged surfaces (see section "Interaction with other medicinal products and other forms of interaction").
• Significant bilateral renal artery stenosis or stenosis of the artery of a solitary functioning kidney.
• Hypotensive or hemodynamically unstable conditions.
• Concomitant use of ramipril with aliskiren-containing products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics"). Concomitant use with sacubitril/valsartan therapy. Ramipril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Use is contraindicated in pregnancy and in women planning to become pregnant (see section "Use during pregnancy and breastfeeding").

Related to amlodipine

• Severe arterial hypotension.
• Shock (including cardiogenic shock).
• Left ventricular outflow tract obstruction (e.g., severe aortic stenosis).
• Hemodynamically unstable heart failure following acute myocardial infarction.
• Pediatric population.

Interaction with other medicinal products and other forms of interaction.

Ramipril

Contraindicated combinations

Extracorporeal therapies involving contact of blood with negatively charged surfaces, such as hemodialysis or hemofiltration using certain high-flux membranes (e.g., polyacrylonitrile membranes) and low-density lipoprotein apheresis using dextran sulfate, due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is required, consideration should be given to using a different type of hemodialysis membrane or switching to an antihypertensive agent from another class.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). 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 increased incidence of adverse events such as arterial hypotension, hyperkalemia, and worsening renal function (including development of acute renal failure), compared to treatment with a single agent acting on the RAAS (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

MEDICINAL PRODUCTS INCREASING 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-containing dietary supplements, or potassium-containing salt substitutes. Although serum potassium concentrations usually remain within normal limits, hyperkalemia may occur in some patients receiving ramipril. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Concomitant use of ramipril with other medicinal products that increase serum potassium levels, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), is not recommended, as trimethoprim, like amiloride, acts as a potassium-sparing diuretic. An increased risk of hyperkalemia has been observed in patients taking ACE inhibitors concomitantly with trimethoprim or its fixed combination with co-trimoxazole (trimethoprim/sulfamethoxazole). If concomitant use cannot be avoided, the products should be administered with caution, and frequent monitoring of serum potassium levels is mandatory.

Cyclosporine. Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of plasma potassium levels is recommended.

Heparin. Hyperkalemia may occur when ACE inhibitors are used concomitantly with heparin. Monitoring of serum potassium levels 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 reduce blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, large amounts of alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). Potentiation of effect with risk of developing arterial hypotension may occur (see section "Method of administration and dosage").

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, adrenaline) that may reduce the antihypertensive effect of ramipril.
Blood pressure should be monitored.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may alter blood count parameters. Increased risk of hematological reactions (see section "Special precautions for use").

Lithium salts. ACE inhibitors may reduce lithium excretion, thereby increasing its toxicity. Monitoring of lithium levels is required.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Blood glucose levels should be monitored.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. The antihypertensive effect of ramipril may be reduced. In addition, concomitant use of ACE inhibitors and NSAIDs increases the risk of worsening renal function and elevated blood potassium levels.

mTOR inhibitors or vildagliptin. Increased incidence of angioedema has been observed in patients taking ACE inhibitors concomitantly with mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Caution is advised at the beginning of therapy.

Amlodipine

Effect of other medicinal products 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 cause a significant increase in amlodipine exposure. Such pharmacokinetic changes may be more pronounced in elderly patients. Therefore, clinical monitoring and dose adjustment may be required.

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 lead to decreased plasma concentrations of amlodipine. Amlodipine should be used with caution when combined with CYP3A4 inducers.

Consumption of amlodipine with grapefruit or grapefruit juice is not recommended, as it may increase the bioavailability of the drug in some patients, thereby enhancing the antihypertensive effect.

Dantrolene (infusion solution). In animals, administration of verapamil followed by intravenous dantrolene has been associated with fatal ventricular fibrillation and cardiovascular collapse in combination with hyperkalemia. Due to the risk of hyperkalemia, concomitant use of calcium channel blockers such as amlodipine should be avoided in patients prone to malignant hyperthermia and during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products. The hypotensive effect of amlodipine may potentiate 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 populations except in kidney transplant patients, in whom an increase in cyclosporine trough concentrations (on average 0–40%) was observed. Monitoring of cyclosporine levels should be considered in kidney transplant patients receiving amlodipine; dose reduction of cyclosporine should be considered if necessary.

Simvastatin. Repeated concomitant administration of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. In 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 used concomitantly with amlodipine, although the pharmacokinetic mechanism of this interaction is not fully established. To avoid tacrolimus toxicity, regular monitoring of tacrolimus blood levels is recommended when amlodipine is used concomitantly, and dose adjustment of tacrolimus may be necessary.

mTOR inhibitors (mammalian target of rapamycin).

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When used concomitantly with mTOR inhibitors, amlodipine may enhance their effects.

Sildenafil. A single 100 mg dose of sildenafil did not affect the pharmacokinetics of amlodipine in patients with essential hypertension. When amlodipine and sildenafil are used concomitantly as combination therapy, each drug exerts its hypotensive effect independently of the other.

Other medicinal products. Clinical 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.

Concomitant use of amlodipine with cimetidine did not affect the pharmacokinetics of amlodipine.

Concomitant use of aluminum/magnesium-containing products (antacids) with a single dose of amlodipine had no significant effect on the pharmacokinetics of amlodipine.

Laboratory tests. The effect on laboratory test parameters is unknown.

Special precautions for use.

Caution is recommended in patients who are concurrently receiving diuretics, as excessive fluid and/or salt loss may occur in such patients. Renal function and serum potassium levels should be monitored.

Ramipril

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Evidence indicates that concomitant use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalaemia, and worsening renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is not recommended (see sections "Interaction with other medicinal products and other forms of interaction" and "Pharmacodynamics").

If such dual blockade therapy is considered absolutely necessary, it should be administered only under specialist supervision and with frequent monitoring of renal function, electrolyte levels, and blood pressure.

ACE inhibitors and angiotensin II receptor antagonists should not be used concomitantly in patients with diabetic nephropathy.

Special patient categories

Pregnancy. Treatment with ACE inhibitors is contraindicated during pregnancy. If pregnancy is diagnosed, ACE inhibitors should be discontinued immediately and alternative therapy initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Patients at high risk of developing arterial hypotension

Patients with marked activation of the renin-angiotensin-aldosterone system. Patients with marked activation of the RAAS are at risk of sudden, pronounced drop in blood pressure and reduced renal function following ACE inhibition, particularly when an ACE inhibitor is used for the first time alone or in combination with a diuretic, or when the dose is first increased.

Significant RAAS activation may occur, and medical supervision, including blood pressure monitoring, is required, for example, in the following cases:

• severe arterial hypertension;
• decompensated congestive heart failure;
• hemodynamically significant pre- or afterload of the left ventricle (e.g., aortic or mitral stenosis);
• unilateral renal artery stenosis with a functioning contralateral kidney;
• liver cirrhosis and/or ascites;
• major surgery or anaesthesia with agents inducing arterial hypotension.

In general, dehydration, hypovolaemia, or electrolyte deficiency should be corrected prior to initiating treatment (however, in patients with heart failure, such correction should be performed cautiously due to the risk of volume overload).

• transient or persistent heart failure after myocardial infarction;
• risk of myocardial 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. It is recommended, if possible, to discontinue treatment with ACE inhibitors such as ramipril one day prior to surgery.

Monitoring of renal function. Renal function should be assessed and dosage adjusted before and during treatment, especially during the first weeks of therapy. Close monitoring is particularly necessary 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. Cases of angioedema have been reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). Ramipril should be discontinued immediately if angioedema occurs.

Emergency treatment should be initiated immediately. The patient should be monitored 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 ramipril (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea or vomiting).

Concomitant use of ramipril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of ramipril. If treatment with sacubitril/valsartan is discontinued, ramipril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan.

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory distress). Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildaglptin may increase the risk of angioedema (e.g., airway or speech swelling, with or without respiratory impairment).

Concomitant use of ACE inhibitors and racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildaglitpin may increase the risk of angioedema (e.g., airway or speech swelling, with or without respiratory impairment).

Caution is required when prescribing racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildaglitpin to patients already receiving an ACE inhibitor.

Anaphylactic reactions during desensitization. Inhibition of ACE may increase the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens. Consider temporarily discontinuing ramipril before desensitization.

Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including ramipril. Risk factors for hyperkalaemia include renal impairment, age over 70 years, uncontrolled diabetes mellitus, concomitant use of potassium salts, potassium-sparing diuretics, or other agents that increase plasma potassium levels, and conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of these agents is considered necessary, monitoring of serum potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hyponatraemia. The syndrome of inappropriate antidiuretic hormone secretion with subsequent hyponatraemia has been observed in some patients receiving ramipril. Serum sodium levels should be monitored regularly, particularly in elderly patients and in other patients at risk of hyponatraemia.

Neutropenia/Agranulocytosis. Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been reported rarely, and bone marrow suppression has also been reported. Monitoring of white blood cell count to detect possible leukopenia is recommended. More frequent monitoring is advised during the initial phase of treatment, in patients with renal impairment, those with concomitant connective tissue diseases (e.g., systemic lupus erythematosus or scleroderma), and in all patients 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 origin. ACE inhibitors cause angioedema more frequently in black patients than in other racial groups. As with other ACE inhibitors, ramipril may be less effective in lowering blood pressure in black patients compared to other racial groups, possibly due to a higher prevalence of low plasma renin levels in this population.

Cough. Cough has been reported with the use of 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 patient categories

Patients with heart failure. Amlodipine should be used with caution in patients with heart failure. In a long-term placebo-controlled trial involving patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary oedema was higher in the amlodipine group than in the placebo group (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used cautiously in patients with congestive heart failure, as these agents may increase the future risk of cardiovascular events and mortality.

Patients with hepatic impairment. In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged and AUC values are higher; no specific dosage recommendations are available. Therefore, amlodipine should be initiated at the lower end of the dosing range, and initiation and dose escalation should be performed cautiously. Slow dose titration and careful monitoring may be required in patients with severe hepatic impairment.

Elderly patients. Dose escalation should be performed cautiously in elderly patients (see sections "Dosage and administration" and "Pharmacokinetics").

Patients with renal impairment. Amlodipine can be administered to patients with renal impairment at usual doses. Plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.

Use during pregnancy or breastfeeding.

Administration of POLAPRIL A is contraindicated during pregnancy and breastfeeding.

Amlodipine is contraindicated in pregnant women or women planning to become pregnant. If pregnancy is established during therapy, the drug should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use in pregnancy (see section "Contraindications").

Ramipril is contraindicated during pregnancy. Use of ACE inhibitors in pregnant women may cause fetal and neonatal morbidity and mortality.

Use of ACE inhibitors during the second and third trimesters of pregnancy is associated with fetal and neonatal adverse effects, including arterial hypotension, neonatal skull hypoplasia, anuria, reversible or irreversible renal failure, and fatal outcomes. Oligohydramnios, likely due to impaired fetal renal function, has also been reported; in such cases, oligohydramnios is associated with limb contractures, craniofacial deformities, and hypoplastic lung development. Preterm birth, intrauterine growth retardation, and patent ductus arteriosus have also been reported, although it is unclear whether these are caused by ACE inhibitors. Furthermore, use of ACE inhibitors during the first trimester of pregnancy is associated with a potentially increased risk of congenital malformations.

Upon confirmation of pregnancy, ACE inhibitors should be discontinued as soon as possible, and fetal development should be monitored regularly. Women planning pregnancy should not use ACE inhibitors (including ramipril). Women of reproductive age should be informed of the potential risks, and ACE inhibitors (including ramipril) should be prescribed only after careful consultation and individual assessment of risks and benefits.

Breastfeeding. Amlodipine is excreted in breast milk. The dose received by the infant via breast milk is estimated to be 3–7% of the maternal dose (up to 15% in the interquartile range). The effect of amlodipine on infants is unknown.

When deciding whether to continue breastfeeding or to use amlodipine, the benefits of breastfeeding for the child and the benefits of the drug for the mother should be weighed. Due to lack of information on the use of ramipril during breastfeeding (see section "Pharmacological properties"), this drug is not recommended for breastfeeding women, and preference should be given to other medicinal products with a more favourable safety profile during lactation, especially when breastfeeding newborns or preterm infants.

Fertility. Reproductive toxicity was observed in animal studies with high doses.

Reversible biochemical changes in sperm heads have been reported in some patients receiving calcium channel blockers. Clinical data on the potential effect of amlodipine on fertility are insufficient.

Ability to affect reaction speed when driving or operating machinery.

POLAPRIL A may have a minor or moderate effect on the ability to drive or operate machinery. Some adverse effects (particularly symptoms associated with reduced blood pressure, such as dizziness, headache, and increased fatigue) may impair a patient's concentration and reduce reaction speed, posing a risk in situations where these abilities are critical (e.g., driving vehicles or operating machinery).

Such effects are more commonly observed at the beginning of treatment or when switching to this medication from another drug. Caution is advised, particularly at the start of therapy.

Method of Administration and Dosage.

Dosage. POLAPRIL A should not be used as initial therapy for arterial hypertension. The dosage of each component of the drug should be individually adjusted according to patient characteristics and control of arterial pressure levels.

If dosage adjustment is required, the doses of ramipril and amlodipine should first be individually titrated; after determining the appropriate dosing regimen, these agents may be replaced with POLAPRIL A.

The recommended dose is one capsule once daily. The maximum daily dose is one capsule of 10 mg / 10 mg.

Patients Receiving Diuretics

Caution should be exercised in patients receiving diuretics due to the potential risk of dehydration and/or salt depletion. In such patients, renal function and serum potassium levels should be monitored.

Special Patient Categories

Renal Impairment. To determine the optimal initial and maintenance doses for patients with renal impairment, individual titration of each component (amlodipine and ramipril) should be performed separately.

Ramipril is only minimally removed during hemodialysis; therefore, the drug should be administered several hours after hemodialysis.

The daily dose of ramipril for patients with renal insufficiency should be based on creatinine clearance values:

• if creatinine clearance ≥ 60 mL/min, no adjustment of the initial dose is necessary; the maximum daily dose is 10 mg;
• if creatinine clearance is 30–60 mL/min, no adjustment of the initial dose (2.5 mg daily) 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, and the maximum daily dose is 5 mg;
• for patients with arterial hypertension undergoing hemodialysis (during which ramipril is minimally removed): the initial dose is 1.25 mg, and the maximum daily dose is 5 mg.

Amlodipine is not removed by hemodialysis. Amlodipine should be used with particular caution in patients undergoing hemodialysis.

When using POLAPRIL A, monitoring of renal function and serum potassium levels is required. If renal function deteriorates, POLAPRIL A should be discontinued and replaced with individual components with appropriate dose adjustments.

Hepatic Impairment. The maximum daily dose is 2.5 mg of ramipril. Doses of the drug for patients with mild to moderate hepatic insufficiency have not been established.

Since doses of 1.25 mg and 2.5 mg are not available in the POLAPRIL A combination, this medicinal product cannot be used.

Elderly Patients. Treatment in elderly patients should be initiated with a lower dose, and dose escalation should be done cautiously. Use of POLAPRIL A is not recommended in patients aged 75 years or older or in very frail patients.

Standard doses of amlodipine may be prescribed to elderly patients, but caution should be exercised when increasing the dose.

Method of Administration. Since food intake does not affect the absorption of ramipril and amlodipine, POLAPRIL A may be taken independently of meals. POLAPRIL A should be taken at the same time each day. Capsules should not be chewed or crushed.

Children. The drug is not recommended for use in children.

Overdose.

Overdose of Ramipril. Symptoms associated with overdose of ACE inhibitors may include excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte imbalances, and renal failure. The patient should be under close medical supervision, and treatment should be symptomatic and supportive. Recommended measures include initial decontamination (gastric lavage, use of adsorbents) and interventions aimed at restoring hemodynamic stability, including administration of alpha1-adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from systemic circulation by hemodialysis.

Overdose of Amlodipine. Experience with intentional overdose in humans is limited.

Symptoms. Available data indicate that significant overdose may cause excessive peripheral vasodilation and reflex tachycardia. Cases of severe and possibly prolonged systemic arterial hypotension, up to and including shock with fatal outcomes, have been reported.

Rare cases of non-cardiogenic pulmonary edema as a result of amlodipine overdose have been reported, which may present with delayed onset (24–48 hours after drug intake) and require mechanical ventilation. Early resuscitation measures (including fluid loading) to support perfusion and cardiac output may act as triggering factors.

Treatment. Clinically significant arterial hypotension caused by amlodipine overdose requires active cardiovascular support, including frequent monitoring of cardiac and respiratory function, special attention to circulating fluid volume and diuresis. The patient should be placed in a supine position with legs elevated.

Administration of a vasoconstrictor may be beneficial to restore vascular tone and adequate arterial pressure, provided there are no contraindications to its use. Intravenous administration of calcium gluconate may be useful to counteract calcium channel blockade effects.

In some cases, gastric lavage may be beneficial. Administration of activated charcoal within 2 hours after ingestion of 10 mg amlodipine has been shown to reduce the rate of amlodipine absorption in healthy volunteers. Since amlodipine is highly protein-bound, hemodialysis is unlikely to be beneficial.

Adverse Reactions

Regarding ramipril

The most common adverse effects during treatment with ramipril include hyperkalemia, headache, dizziness, hypotension, orthostatic hypotension, syncope, cough (non-productive cough), bronchitis, sinusitis, dyspnea, gastrointestinal inflammation, gastric indigestion, abdominal pain, dyspepsia, diarrhea, nausea, vomiting, skin rash (particularly maculopapular rash), muscle cramps, myalgia, chest pain, and fatigue. Serious adverse effects include hyperkalemia, neutropenia/agranulocytosis, pancytopenia, hemolytic anemia, myocardial infarction, angioedema, vasculitis, bronchospasm, acute pancreatitis, hepatic failure, acute renal failure, hepatitis, exfoliative dermatitis, toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme.

Regarding amlodipine

The most common adverse effects during treatment with amlodipine include somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, peripheral edema (particularly in the ankle region), edema, and fatigue. Serious adverse effects include leukopenia, thrombocytopenia, myocardial infarction, atrial fibrillation, ventricular tachycardia, vasculitis, acute pancreatitis, hepatitis, angioedema, erythema multiforme, exfoliative dermatitis, Stevens-Johnson syndrome, and toxic epidermal necrolysis.

The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); frequency not known (cannot be estimated from available data).

During treatment with ramipril and amlodipine separately, the adverse reactions listed below have been reported.

Reporting of suspected adverse reactions

Reporting of adverse reactions after drug registration is of great importance. It enables continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare and pharmacy professionals, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of therapeutic efficacy via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions. Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Packaging.

10 or 6 capsules in a blister. 3 or 5 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer.

Pharmaceutical Works «POLPHARMA» S.A.

Pharmaceutical Works «POLPHARMA» S.A.

Manufacturer's name and address of the place of business.

19 Pelplinska Street, 83-200 Starogard Gdanski, Poland
19, Pelplinska Str., 83-200 Starogard Gdanski, Poland