Cartil® - am

INSTRUCTIONS for medical use of the medicinal product HARTIL®-AM (HARTIL®-AM)

Composition:

Active substances: ramipril; amlodipine;

1 capsule contains 5 mg ramipril and 5 mg amlodipine (equivalent to 6.95 mg amlodipine besylate); or 5 mg ramipril and 10 mg amlodipine (equivalent to 13.9 mg amlodipine besylate); or 10 mg ramipril and 5 mg amlodipine (equivalent to 6.95 mg amlodipine besylate); or 10 mg ramipril and 10 mg amlodipine (equivalent to 13.9 mg amlodipine besylate);

Excipients: crospovidone, hypromellose, microcrystalline cellulose, glycerol dibehenate;

Capsule shell composition (cap and body):

5 mg/5 mg capsules: diamond blue FCF + FD & C blue 1 (E 133), alura red AC + FD & C red 40 (E 129), titanium dioxide (E 171), gelatin;

5 mg/10 mg capsules: iron oxide red (E 172), titanium dioxide (E 171), azorubine, carmoisine (E 122), indigocarmine (E 132), gelatin;

10 mg/5 mg capsules: iron oxide red (E 172), titanium dioxide (E 171), diamond blue FCF + FD & C blue 1 (E 133), alura red AC + FD & C red 40 (E 129), gelatin;

10 mg/10 mg capsules: azorubine, carmoisine (E 122), indigocarmine (E 132), titanium dioxide (E 172), gelatin.

Medicinal form. Capsules.

Main physicochemical properties:

5 mg/5 mg capsules:

Hard gelatin capsules of Coni Snap type, size 2, unmarked, self-closing, with an opaque amethyst (dark pink) body and an opaque amethyst (dark pink) cap, filled with a mixture of granules and powder, free from mechanical inclusions, white or almost white, odorless or almost odorless.

5 mg/10 mg capsules:

Hard gelatin capsules of Coni Snap type, size 0, unmarked, self-closing, with an opaque flesh-colored (light pink) body and an opaque dark burgundy cap, filled with a mixture of granules and powder, free from mechanical inclusions, white or almost white, odorless or almost odorless.

10 mg/5 mg capsules:

Hard gelatin capsules of Coni Snap type, size 0, unmarked, self-closing, with an opaque flesh-colored (light pink) body and an opaque amethyst (dark pink) cap, filled with a mixture of granules and powder, free from mechanical inclusions, white or almost white, odorless or almost odorless.

10 mg/10 mg capsules:

Hard gelatin capsules of Coni Snap type, size 0, unmarked, self-closing, with an opaque dark burgundy body and an opaque dark burgundy cap, filled with a mixture of granules and powder, free from mechanical inclusions, white or almost white, odorless or almost odorless.

Pharmacotherapeutic group. ACE inhibitors and calcium channel blockers.

ATC code C09BB07.

Pharmacological Properties.

Pharmacodynamics.

Mechanism of action of ramipril.

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidyl-carboxypeptidase (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. Reduced formation of angiotensin II and inhibition of bradykinin degradation lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat promotes a reduction in aldosterone secretion. The average response to monotherapy with ACE inhibitors has been lower in black patients (Africans) with arterial hypertension (typically with low renin levels) compared to white patients.

Pharmacodynamic effects.

Administration of ramipril causes a pronounced reduction in peripheral arterial resistance. Generally, no significant changes in renal plasma flow or glomerular filtration rate are observed. Administration of ramipril to patients with arterial hypertension leads to a reduction in blood pressure in both supine and upright positions, without compensatory increase in heart rate. In most patients, the onset of the antihypertensive effect of a single dose of ramipril occurs within 1–2 hours after oral administration. The maximum effect after a single dose is usually achieved within 3–6 hours after oral administration. The antihypertensive effect persists for 24 hours.

The maximum antihypertensive effect during long-term treatment with ramipril generally becomes evident after 3–4 weeks. It has been demonstrated that the antihypertensive effect during prolonged therapy is maintained for up to 2 years.

Abrupt discontinuation of ramipril does not lead to rapid or excessive rebound increase in blood pressure.

Mechanism of action of amlodipine

Amlodipine inhibits transmembrane influx of calcium ions into cardiac and vascular smooth muscle cells (a slow calcium channel blocker or calcium ion antagonist).

The mechanism of antihypertensive action is due to the direct vasorelaxant effect of amlodipine on vascular smooth muscle, leading to a reduction in systemic peripheral vascular resistance.

The exact mechanism by which amlodipine relieves angina is not fully elucidated, but it may have two effects:

1. amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (afterload). Since it does not cause reflex tachycardia, myocardial energy consumption and oxygen demand are reduced;

2. due to the above mechanism of action, amlodipine increases oxygen delivery to the myocardium even in cases of coronary artery spasm (Prinzmetal’s angina or variant angina).

Pharmacodynamic properties

In patients with arterial hypertension, a single dose of amlodipine provides clinically significant reduction in blood pressure over 24 hours in both supine and standing positions. Due to its slow onset of action, amlodipine does not cause acute arterial hypotension.

In patients with angina, administration of amlodipine once daily prolongs total exercise duration, delays the onset of angina attacks, and prolongs the time to significant ST-segment depression, reduces the frequency of angina attacks, and decreases the need for sublingual glyceryl trinitrate tablets.

Amlodipine has no adverse effects on carbohydrate metabolism or plasma lipids, making it suitable for treatment of 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 1 hour. Based on urinary excretion, the extent of absorption is at least 56%, and is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at doses of 2.5 mg and 5 mg is 45%.

The maximum plasma concentration of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after administration of ramipril. The steady-state plasma concentration of ramiprilat under conditions of daily dosing is achieved by day 4 of treatment.

Distribution

Protein binding of ramipril is approximately 73%, and of ramiprilat – 56%.

Metabolism

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

Excretion

Excretion of metabolites occurs predominantly via the kidneys.

The decline in ramiprilat plasma concentration occurs in several phases. Due to strong saturable binding to ACE and slow dissociation from the enzyme, ramiprilat exhibits a prolonged terminal elimination phase at very low plasma concentrations.

After multiple doses of ramipril, the effective half-life of ramiprilat is 13–17 hours after a 5–10 mg dose, and longer after lower doses of 1.25–2.5 mg. This difference is due to the enzyme's saturable binding capacity for ramiprilat.

After a single oral dose, ramipril and its metabolites were not detected in breast milk. However, the effect of multiple doses is unknown.

Patients with impaired renal function.

Renal excretion of ramiprilat is reduced in patients with impaired renal function, and the renal clearance of ramiprilat is proportionally related to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Patients with impaired hepatic function.

In patients with impaired liver function, the metabolism of ramipril to ramiprilat is slowed due to reduced activity of hepatic esterases, resulting in elevated plasma levels of ramipril. However, the maximum plasma concentration of ramiprilat in these patients does not differ from that in individuals with normal liver function.

Amlodipine

Absorption

After oral administration, amlodipine is almost completely absorbed, reaching maximum plasma concentration 6–12 hours after administration. Food intake does not affect the bioavailability of the drug. Absolute bioavailability is 64–80%.

Distribution

Volume of distribution is 21 L/kg body weight. Steady-state plasma concentration (5–15 ng/mL) is achieved within 7–8 days of drug administration. In vitro studies have shown that 93–98% of circulating amlodipine in blood is protein-bound.

Metabolism and excretion

Amlodipine is extensively metabolized in the liver (approximately 90%) to inactive pyridine derivatives.

Approximately 10% of the parent compound and 60% of inactive metabolites are excreted in urine, and 20–25% in feces.

The decline in plasma concentration is biphasic. The terminal elimination half-life from plasma is approximately 35–50 hours, taking into account once-daily dosing.

Total clearance is 7 mL/min/kg body weight (for a 60 kg patient – 25 L/h). In elderly patients – 19 L/h.

Use in elderly patients

The time required to reach maximum plasma concentration of amlodipine is similar in both elderly and younger patients. In elderly individuals, there is a tendency toward reduced clearance of amlodipine, leading to increased area under the concentration-time curve (AUC) and prolonged elimination half-life. Increased AUC and half-life of the drug have also been observed in patients with chronic heart failure.

Patients with impaired renal function

Amlodipine is extensively metabolized to inactive metabolites. About 10% of the parent compound is excreted unchanged in urine. Changes in plasma concentrations of amlodipine are not related to the degree of renal impairment. These patients can be treated with the usual dose of amlodipine. Amlodipine is not dialyzable.

Patients with impaired hepatic function.

The elimination half-life of amlodipine is prolonged in patients with impaired liver function.

Clinical characteristics.

Indications.

For the treatment of arterial hypertension in patients whose blood pressure is adequately controlled by individual drugs administered simultaneously at the same doses as those contained in the combination, but as separate tablets.

Contraindications.

Contraindications associated with the use of ramipril:

• History of angioedema (hereditary, idiopathic, or due to previous use of ACE inhibitors or angiotensin II receptor antagonists);
• Concomitant use of the drug with medicinal products containing aliskiren 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 types of interactions" and "Pharmacodynamics");
• Concomitant use with sacubitril/valsartan is contraindicated due to increased risk of angioedema;
• Extracorporeal treatments leading to blood contact with negatively charged surfaces;
• Severe bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney;
• Arterial hypotension or hemodynamically unstable conditions;
• Hypersensitivity to the active substance;
• Use is contraindicated in pregnant women and women planning to become pregnant (see section "Use in pregnancy and lactation").

Contraindications associated with the use of amlodipine:

• Hypersensitivity to the active substance;
• Severe arterial hypotension;
• Shock (including cardiogenic shock);
• Left ventricular outflow tract obstruction (e.g., severe aortic valve stenosis);
• Hemodynamically unstable heart failure following acute myocardial infarction.

Contraindications associated with the use of ramipril/amlodipine:

• Hypersensitivity to the active substances, dihydropyridine derivatives, ACE inhibitors (angiotensin-converting enzyme), or to any excipient.

Interaction with other medicinal products and other types of interactions.

Ramipril

Contraindicated combinations.

Extracorporeal treatments leading to 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 with dextran sulfate, due to increased risk of severe anaphylactoid reactions. If such treatment is required, consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Treatment with the medicinal product should be initiated only 36 hours after the last dose of sacubitril/valsartan. Treatment with sacubitril/valsartan should be initiated only 36 hours after the last dose of ramipril.

Use with caution

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 use of a single agent affecting the RAAS (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

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

Potassium salts, heparin, potassium-sparing diuretics, and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim, tacrolimus, cyclosporine): Hyperkalemia may occur; therefore, careful monitoring of plasma potassium levels is required.

Trimethoprim and fixed-dose combinations with sulfamethoxazole (co-trimoxazole):

Increased incidence of hyperkalemia has been observed in patients receiving ACE inhibitors together with trimethoprim and fixed-dose combinations with sulfamethoxazole (co-trimoxazole).

Antihypertensive agents (e.g., diuretics) and other agents that may reduce blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, ethanol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin): increased risk of arterial hypotension is possible.

Vasopressor sympathomimetics and other substances (e.g., isoprenaline, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of ramipril: Blood pressure monitoring is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics, and other substances that may alter blood cell counts: Increased likelihood of hematological reactions.

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

Antidiabetic agents, including insulin: Hypoglycemic reactions are possible. Blood glucose monitoring is recommended.

Nonsteroidal anti-inflammatory drugs and acetylsalicylic acid: Possible reduction in the antihypertensive effect of ramipril. Therefore, concomitant use of ACE inhibitors and nonsteroidal anti-inflammatory drugs may lead to increased risk of worsening renal function and elevated blood potassium levels.

Neprilysin inhibitors (NEP): Increased risk of angioedema has been reported with concomitant use of ACE inhibitors (such as ramipril) and NEP inhibitors (such as racecadotril).

Amlodipine

Amlodipine is safe for concomitant use with thiazide diuretics,
β-blockers, long-acting nitrates, sublingually administered nitroglycerin, nonsteroidal anti-inflammatory drugs, antibiotics, and oral hypoglycemic agents.

Effect of other medicinal products on amlodipine

• CYP3A4 inhibitors: When amlodipine was co-administered with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients, plasma concentrations of amlodipine increased by approximately 22% and 50%, respectively. However, the clinical significance of these findings is unclear. It cannot be excluded that strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, ritonavir) may increase amlodipine plasma concentrations more than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors. However, adverse effects related to this interaction have not been reported.
• CYP3A4 inducers: Data on the effect of CYP3A4 inducers on amlodipine are lacking. Concomitant use of CYP3A4 inducers (e.g., rifampicin, St. John’s wort preparations) may lead to decreased plasma concentrations of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers.

Clinical interaction studies have shown that cimetidine, aluminium/magnesium (antacid), and sildenafil do not affect the pharmacokinetics of amlodipine.

Tacrolimus

Concomitant administration of the drug with amlodipine carries a risk of increased blood tacrolimus concentrations.

To avoid tacrolimus toxicity, administration of amlodipine in patients receiving tacrolimus requires monitoring of blood tacrolimus levels and dose adjustment of tacrolimus if necessary.

mTOR inhibitors (mammalian target of rapamycin)

mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are CYP3A substrates. Amlodipine is a weak CYP3A inhibitor. When used concomitantly, amlodipine may increase exposure to mTOR inhibitors.

Dantrolene (infusions)

In animals, ventricular fibrillation with fatal outcome and cardiovascular collapse associated with hyperkalemia were observed after intravenous administration of verapamil and dantrolene. Due to the risk of hyperkalemia, it is recommended to avoid using calcium channel blockers such as amlodipine in patients susceptible to malignant hyperthermia and during treatment of malignant hyperthermia.

Effect of amlodipine on other medicinal products

Amlodipine may potentiate the effect of other antihypertensive agents.

Clinical interaction studies did not show any effect of amlodipine on the pharmacokinetics of atorvastatin, digoxin, ethanol, warfarin, or cyclosporine. Amlodipine does not affect laboratory parameters.

Cyclosporine

No drug interaction studies have been conducted with cyclosporine and amlodipine in healthy volunteers or other populations, except in kidney transplant patients, where 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. Concomitant repeated 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.

Special precautions for use.

Ramipril.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired 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 during pregnancy is contraindicated. If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately, and alternative therapy should be initiated if necessary (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Patients at high risk of developing 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, significant reduction in blood pressure and worsening of renal function due to ACE inhibition, especially when an ACE inhibitor or concomitant diuretic is used for the first time or the 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 blood inflow or outflow 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 anesthesia with agents that may cause arterial hypotension.

In general, correction of dehydration, hypovolemia, or electrolyte deficiency is recommended before initiating treatment (however, in patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

Transient or persistent heart failure after myocardial infarction.

Patients at risk of cardiac or cerebral ischemia 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 before 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. Particularly careful monitoring 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"). If angioedema develops, treatment with Hartil®-AM should be discontinued immediately. Emergency therapy should be initiated promptly. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

Angiointestinal angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitization. The use of ACE inhibitors increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens. Ramipril should be temporarily discontinued prior to desensitization procedures.

Hyperkalemia. Hyperkalemia has been observed in some patients receiving ACE inhibitors, including ramipril. Patients at risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients taking potassium salts or potassium-sparing diuretics, patients receiving other active substances that increase plasma potassium levels, or patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of the above-mentioned drugs is considered necessary, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Hypnatremia.

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) with subsequent development of hyponatremia has been observed in some patients taking ramipril. Serum sodium levels should be monitored regularly in elderly patients and in other patients at risk of hyponatremia.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leukopenia, monitoring of blood leukocyte 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 taking other medicinal products that may cause blood count changes (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Ethnic differences. ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients compared to patients of other races. 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.

Amlodipine.

The safety and efficacy of amlodipine for the management of hypertensive crisis have not been established.

Patients with heart failure.

Patients with heart failure require special consideration. In a long-term placebo-controlled study involving patients with severe heart failure (NYHA class III and IV), the incidence of pulmonary edema was higher in the amlodipine group than in the placebo group, although this was not associated with worsening of heart failure.

Use in patients with hepatic impairment.

In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged, but dosage recommendations have not yet been established. Therefore, amlodipine should be used with caution in such patients.

Use in elderly patients.

Dosage increases in elderly patients should be performed cautiously.

Patients with renal impairment.

Standard doses should be used in this patient group. Plasma concentrations of amlodipine do not correlate with the degree of renal impairment. Amlodipine is not removed by dialysis.

Amlodipine does not affect laboratory test results.

Grapefruit or grapefruit juice should not be used concomitantly with amlodipine, as in some patients bioavailability may be increased, leading to an enhanced hypotensive effect.

Anaphylactic reactions during desensitization

In combination with amlodipine:

Others.

The capsule shell of the 5 mg/5 mg and 10 mg/5 mg formulations contains Alura red AC+ FD and Carmoisine (E 129), and the capsule shell of the 5 mg/10 mg and 10 mg/10 mg formulations contains Azorubine and Carmoisine (E 122). These colorants may cause allergic reactions.

Use during pregnancy or breastfeeding.

Ramipril

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

Epidemiological data on the teratogenic risk associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. If continued therapy with an ACE inhibitor is considered necessary, women planning pregnancy should be switched to an alternative antihypertensive agent with an established safety profile during pregnancy. If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and alternative therapy initiated.

It is known that ACE inhibitor use during the second and third trimesters of pregnancy causes fetal toxicity in humans (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If an ACE inhibitor is used during the second trimester of pregnancy, ultrasound monitoring of fetal renal function and skull development is recommended. Newborns whose mothers received ACE inhibitors should be closely monitored for arterial hypotension, oliguria, and hyperkalemia. Due to insufficient data on ramipril use during breastfeeding, it is not recommended, and alternative treatments are preferred, especially if the infant is newborn or premature.

Amlodipine

Pregnancy.

Use during pregnancy is recommended only when no safer alternative exists and when the disease itself poses a greater risk to mother and fetus.

Breastfeeding.

Amlodipine passes into human milk. The fraction of the maternal dose received by the infant has been estimated at 3–7%, up to a maximum of 15%. The effect of amlodipine on the infant is unknown.

The decision to continue or discontinue breastfeeding or to continue or discontinue amlodipine therapy should be made considering the benefit of breastfeeding for the child and the benefit of amlodipine therapy for the mother.

Given the above information, the use of Hartil®-AM during pregnancy or breastfeeding is contraindicated.

Ability to affect reaction speed when driving or operating machinery.

Some adverse effects (e.g., symptoms of reduced blood pressure such as dizziness) may impair the ability to concentrate and react, thus potentially affecting reaction speed when driving or operating machinery.

These adverse reactions were observed at the beginning of treatment or when switching from other medications. After taking the first dose or increasing the dose, driving or operating machinery is not recommended for several hours.

Administration and Dosage.

Hartil®-AM is indicated for patients whose blood pressure is adequately controlled with separately administered monotherapy agents at the same doses recommended for the fixed combination.

The recommended initial daily dose is 1 capsule of the 2.5 mg/2.5 mg strength.

Hartil®-AM should be taken once daily at the same time each day, independently of food intake.

The capsule must not be chewed or crushed.

The fixed-dose combination is not suitable for initial therapy.

If necessary, the dose of Hartil®-AM may be adjusted or the components individually titrated in a free combination.

The daily dose may be increased up to the maximum dose of 10 mg/10 mg (1 capsule of Hartil®-AM 10 mg/10 mg once daily).

Adults

Patients receiving diuretic therapy should be treated with caution, as excessive fluid and/or sodium chloride depletion may occur in these patients. Renal function and serum potassium levels should be monitored.

Special patient groups.

Patients with hepatic impairment

In patients with impaired liver function, treatment with ramipril should be initiated only under close medical supervision.

The maximum daily dose should not exceed 2.5 mg of ramipril.

Dosage for patients with mild to moderate hepatic insufficiency has not been established; therefore, dose selection should be cautious, starting with the lowest available dose.

Patients with renal impairment

The optimal initial and maintenance dose for patients with renal impairment should be individually adjusted by separate titration of ramipril and amlodipine.

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

• if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose is required; 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; 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: ramipril is only slightly removed during hemodialysis; the initial dose is 1.25 mg and the maximum daily dose is 5 mg; the drug should be administered several hours after a hemodialysis session.

Dosage adjustment of amlodipine is not required in patients with renal impairment.

Amlodipine is not dialyzable. Amlodipine should be administered with particular caution to patients undergoing dialysis.

During treatment with Hartil®-AM, renal function and serum potassium levels should be monitored. If renal function deteriorates, Hartil®-AM should be discontinued and the doses of its components appropriately adjusted.

Elderly patients

Initial doses of ramipril should be as low as possible; subsequent dose titration should be performed gradually due to the increased risk of adverse reactions. The use of Hartil®-AM is not recommended in patients aged 75 years or older or in very frail patients.

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

Children

Hartil®-AM is not recommended for use in children due to lack of data on safety and efficacy in this patient population.

Overdose.

Ramipril

Symptoms caused by overdose of ACE inhibitors may include excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte imbalance, and renal failure. The patient should be closely monitored. Symptomatic and supportive treatment should be administered. Recommended measures include primary detoxification (gastric lavage, administration of sorbents) and interventions to restore hemodynamic stability, 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.

Amlodipine

Data on cases of intentional overdose in humans are limited.

Symptoms. Based on available data, it is assumed that severe overdose may lead to excessive peripheral vasodilation and possibly reflex tachycardia, profound and prolonged systemic arterial hypotension, including cardiogenic shock; however, fatal outcomes have not been reported.

Treatment. Clinically significant hypotension due to amlodipine overdose requires active treatment measures, including continuous monitoring of cardiac and respiratory function, elevation of the limbs, and monitoring of circulating blood volume and diuresis. Administration of a vasoconstrictor agent, if not contraindicated, may be helpful in restoring vascular tone and blood pressure. Intravenous calcium gluconate may be effective in counteracting the effects of calcium channel blockade.

In some cases, gastric lavage may be effective. In healthy volunteers, administration of activated charcoal 2 hours after ingestion of 10 mg amlodipine reduced the rate of amlodipine absorption.

Since amlodipine is highly protein-bound, dialysis is unlikely to be effective.

Adverse Reactions

Adverse reactions observed during the use of the active ingredients separately are listed according to frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Ramipril:

Blood and lymphatic system disorders:
Uncommon – eosinophilia;
Rare – decreased leukocyte count (including neutropenia and agranulocytosis), decreased erythrocyte count, decreased hemoglobin levels, decreased platelet count;
Frequency not known – bone marrow failure, pancytopenia, hemolytic anemia.

Immune system disorders:
Uncommon – allergic reactions;
Frequency not known – anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies.

Metabolic and nutritional disorders:
Common – increased blood potassium levels;
Uncommon – anorexia, decreased appetite;
Frequency not known – decreased blood sodium levels.

Psychiatric disorders:
Uncommon – depressive mood, anxiety, nervousness, restlessness, sleep disturbances including somnolence;
Rare – confusion;
Frequency not known – attention disturbances.

Nervous system disorders:
Common – headache, dizziness;
Uncommon – vertigo, paresthesia, ageusia, dysgeusia;
Rare – tremor, balance disorder;
Frequency not known – cerebral ischemia, including ischemic stroke and transient ischemic attack, psychomotor function disturbances, burning sensation, parosmia.

Eye disorders:
Uncommon – visual disturbances, including blurred vision;
Rare – conjunctivitis.

Ear and labyrinth disorders:
Rare – hearing disturbances, tinnitus.

Cardiac disorders:
Common – arterial hypotension, orthostatic hypotension, syncope;
Uncommon – myocardial ischemia, including angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema, flushing;
Rare – vascular stenosis, hypoperfusion, vasculitis;
Frequency not known – Raynaud's syndrome.

Respiratory, thoracic and mediastinal disorders:
Common – non-productive irritating cough, bronchitis, sinusitis, dyspnea;
Uncommon – bronchospasm, including asthma exacerbation, nasal congestion.

Gastrointestinal disorders:
Common – gastrointestinal inflammation, digestive disorders, gastrointestinal discomfort, dyspepsia, diarrhea, nausea, vomiting;
Uncommon – pancreatitis (isolated cases with fatal outcome during ACE inhibitor use), increased pancreatic enzyme levels, angioedema of the small intestine, upper abdominal pain including gastritis, constipation, dry mouth;
Rare – glossitis;
Frequency not known – aphthous stomatitis.

Hepatobiliary disorders:
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 isolated cases with fatal outcome).

Skin and subcutaneous tissue disorders:
Common – skin rashes, particularly maculopapular;
Uncommon – angioedema; in exceptional cases, airway obstruction due to angioedema may be fatal; pruritus, increased sweating;
Rare – exfoliative dermatitis, urticaria, onycholysis;
Very rare – photosensitivity reaction;
Frequency not known – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia.

Musculoskeletal and connective tissue disorders:
Common – muscle cramps, myalgia;
Uncommon – arthralgia.

Renal and urinary disorders:
Uncommon – renal function impairment, including acute renal failure, increased diuresis, worsening of pre-existing proteinuria, increased blood urea and creatinine levels.

Reproductive system and breast disorders:
Uncommon – transient erectile impotence, decreased libido;
Frequency not known – gynecomastia.

General disorders and administration site conditions:
Common – chest pain, weakness;
Uncommon – pyrexia;
Rare – asthenia.

Endocrine disorders:
Syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Amlodipine

When amlodipine is used, the most commonly reported adverse reactions include: somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle edema, edema, and fatigue.

Blood and lymphatic system disorders:
Very rare – leukopenia, thrombocytopenia.

Metabolic and nutritional disorders:
Uncommon – hyperglycemia.

Psychiatric disorders:
Uncommon – mood changes (including anxiety), insomnia, depression;
Rare – confusion.

Nervous system disorders:
Common – headache, dizziness, somnolence (especially at the beginning of treatment);
Uncommon – tremor, taste disturbances, syncope, hypesthesia, paresthesia;
Very rare – arterial hypertension, peripheral neuropathy;
Frequency not known – extrapyramidal disorder.

Eye disorders:
Uncommon – visual disturbances (including diplopia).

Ear and labyrinth disorders:
Uncommon – tinnitus.

Cardiac disorders:
Common – tachycardia, flushing;
Uncommon – arterial hypotension;
Very rare – myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation), vasculitis.

Respiratory, thoracic and mediastinal disorders:
Uncommon – dyspnea, rhinitis;
Very rare – cough.

Gastrointestinal disorders:
Common – abdominal pain, dyspepsia, intestinal motility disorders (including constipation and diarrhea), nausea;
Uncommon – vomiting, dry mouth;
Very rare – pancreatitis, gastritis, gingival hyperplasia, hypertrophic gingivitis.

Hepatobiliary disorders:
Very rare – jaundice*, hepatitis* (in most cases associated with cholestasis).

Skin and subcutaneous tissue disorders:
Uncommon – alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthema;
Very rare – angioedema, Quincke's edema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, photosensitivity;
Frequency not known – toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders:
Common – ankle edema;
Uncommon – arthralgia, myalgia, muscle spasms, back pain.

Renal and urinary disorders:
Uncommon – micturition disorders, nocturia, increased frequency of urination.

Reproductive system and breast disorders:
Uncommon – impotence, gynecomastia.

General disorders and administration site conditions:
Common – edema, fatigue;
Uncommon – chest pain, asthenia, malaise.

Investigations (laboratory findings):
Uncommon – weight increase or decrease;
Very rare – increased liver enzyme levels*.

*In most cases associated with cholestasis.

Reporting suspected adverse reactions.
Reporting suspected adverse reactions after marketing authorization is an important procedure. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions via the national reporting system.

Shelf life. 2.5 years.

Storage conditions.
Store at a temperature not exceeding 25 °C. Keep in the original packaging to protect from moisture. Keep out of reach and sight of children.

Packaging.
7 capsules in a blister; 4 blisters or 8 blisters in a cardboard box;
or 10 capsules in a blister; 3 or 9 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer.
Egis Pharmaceuticals Ltd.

Address of manufacturer and location of business operations.
1165 Budapest, Bekényföldi Street 118-120, Hungary.
9900 Kermend, Matyas kiraly Street 65, Hungary.