Ramiton a

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAMITON A

Composition:

Active substances: ramipril, amlodipine;

1 capsule contains 5 mg ramipril and 5 mg amlodipine (equivalent to 6.934 mg amlodipine besylate), or 10 mg ramipril and 5 mg amlodipine (equivalent to 6.934 mg amlodipine besylate), or 5 mg ramipril and 10 mg amlodipine (equivalent to 13.868 mg amlodipine besylate), or 10 mg ramipril and 10 mg amlodipine (equivalent to 13.868 mg amlodipine besylate);

Excipients:

Capsules 5 mg/5 mg or 5 mg/10 mg or 10 mg/5 mg: microcrystalline cellulose; anhydrous calcium hydrogen phosphate; pregelatinized corn starch; low moisture pregelatinized corn starch; sodium starch glycolate (type A); sodium stearyl fumarate; iron oxide red (E 172); titanium dioxide (E 171); gelatin;

Capsules 10 mg/10 mg: microcrystalline cellulose, anhydrous calcium hydrogen phosphate, pregelatinized corn starch, low moisture pregelatinized corn starch, sodium starch glycolate (type A), sodium stearyl fumarate, iron oxide yellow (E 172), iron oxide black (E 172), iron oxide red (E 172), titanium dioxide (E 171), gelatin.

Pharmaceutical form. Hard capsules.

Main physicochemical properties:

Hard capsules 5 mg/5 mg: hard gelatin capsules, size № 1; cap: opaque, pink; body: opaque, white; capsule content: white or almost white powder.

Hard capsules 5 mg/10 mg: hard gelatin capsules, size № 1; cap: opaque, red-brown; body: opaque, white; capsule content: white or almost white powder.

Hard capsules 10 mg/5 mg: hard gelatin capsules, size № 1; cap: opaque, dark pink; body: opaque, white; capsule content: white or almost white powder.

Hard capsules 10 mg/10 mg: hard gelatin capsules, size № 1; cap: opaque, brown; body: opaque, white; capsule content: white or almost white powder.

Pharmacotherapeutic group. Combined preparations of ACE inhibitors. ACE inhibitors in combination with calcium antagonists. Ramipril and amlodipine. 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. Overall, significant changes in renal plasma flow and glomerular filtration rate have not been observed. Administration of ramipril to patients with arterial hypertension results in a reduction of arterial blood pressure in both supine and upright positions without compensatory increase in heart rate. In most patients, the onset of 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 becomes evident after 3–4 weeks. It has been demonstrated that the antihypertensive effect is maintained throughout 2 years of continuous therapy.

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

Clinical efficacy and safety.

Prevention of cardiovascular diseases.

A preventive, placebo-controlled study (HOPE study) was conducted involving over 9,200 patients who received ramipril in addition to standard therapy. This study included patients at high risk of developing cardiovascular disease due to prior atherothrombotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease) or patients with diabetes mellitus who had at least one additional risk factor (documented microalbuminuria, arterial hypertension, elevated total cholesterol, low-density lipoprotein cholesterol, or smoking).

This study demonstrated that ramipril significantly reduces the incidence of myocardial infarction, cardiovascular death, and stroke when used either alone or in combination (primary composite endpoint).

HOPE study: main results

Parameter	Ramipril	Placebo	Relative risk (95% confidence interval)	p value
	%	%
All patients	n = 4,645	n = 4,652
Primary combined endpoint	14	17.8	0.78 (0.7–0.86)	< 0.001
Myocardial infarction	9.9	12.3	0.80 (0.7–0.9)	< 0.001
Cardiovascular death	6.1	8.1	0.74 (0.64–0.87)	< 0.001
Stroke	3.4	4.9	0.68 (0.56–0.84)	< 0.001
Secondary endpoints
All-cause mortality	10.4	12.2	0.84 (0.75–0.95)	0.005
Need for revascularization	16.0	18.3	0.85 (0.77–0.94)	0.002
Hospitalization due to unstable angina	12.1	12.3	0.98 (0.87–1.1)	not significant
Hospitalization due to heart failure	3.2	3.5	0.88 (0.7–1.1)	0.25
Complications related to diabetes	6.4	7.6	0.84 (0.72–0.98)	0.03

In the MICRO-HOPE study, which was pre-planned as part of the HOPE study, the effect of adding ramipril 10 mg to existing treatment regimens was evaluated compared to placebo in 3577 patients aged 55 years and older (no upper age limit) with normal or elevated blood pressure, most of whom had type 2 diabetes (and at least one cardiovascular risk factor).

Primary analysis results demonstrated that overt nephropathy developed in 117 (6.5%) participants receiving ramipril and in 149 (8.4%) participants receiving placebo, corresponding to a 24% relative risk reduction; 95% CI [3–40], p = 0.027.

Double blockade of the renin-angiotensin-aldosterone system (RAAS).

Two large-scale randomized controlled trials [ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (Veterans Affairs Nephropathy in Diabetes)] evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with concomitant target organ damage. The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy.

These studies did not demonstrate significant benefits of combination therapy regarding renal and/or cardiovascular outcomes and mortality, while an increased risk of hyperkalemia, acute renal failure, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic characteristics of these drug classes, these findings are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

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

The ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Endpoints) evaluated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. This trial was terminated early due to an increased risk of adverse clinical outcomes. In the aliskiren group, compared to placebo, there was a higher incidence of fatal cardiovascular events and stroke, as well as an increased frequency of serious adverse events (hyperkalemia, arterial hypotension, and renal dysfunction).

Pediatric population.

In a randomized, double-blind, placebo-controlled clinical trial involving 244 pediatric patients aged 6–16 years with arterial hypertension (73% of whom had primary hypertension), participants received low, medium, or high doses of ramipril to achieve plasma concentrations of ramiprilat corresponding to adult dose ranges of 1.25 mg, 5 mg, and 20 mg, adjusted for body weight. After 4 weeks, ramipril was ineffective in reducing systolic blood pressure, the primary endpoint, but reduced diastolic blood pressure at the highest dose tested. Both medium and high doses of ramipril were shown to produce statistically significant reductions in systolic and diastolic blood pressure in children with confirmed hypertension.

This effect was not observed in a 4-week randomized, double-blind, dose-escalation trial assessing the effect of drug withdrawal in 218 pediatric patients aged 6–16 years (75% with primary hypertension). In this trial, after drug discontinuation, a moderate rebound increase in both diastolic and systolic blood pressure was observed, but it was not statistically significant for return to baseline levels across all dose groups tested for ramipril [low doses (0.625–2.5 mg), medium doses (2.5–10 mg), or high doses (5–20 mg)], adjusted for body weight. In the studied pediatric population, ramipril did not demonstrate a linear dose-response relationship.

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

The precise mechanism by which amlodipine relieves angina is not fully understood, but it may involve two actions:

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

In patients with angina, once-daily administration of amlodipine prolongs total exercise duration, delays the onset of angina, 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 metabolism or plasma lipids, making it suitable for treating patients with bronchial asthma, diabetes mellitus, and gout.

Use in patients with heart failure

In a long-term, placebo-controlled trial (PRAISE-2) in patients with NYHA class III–IV heart failure without clinical or objective evidence of ischemic heart disease, who were receiving stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine did not affect overall cardiovascular mortality. In this same population, amlodipine was associated with an increased incidence of pulmonary edema.

Therapy for prevention of heart attack (ALLHAT)

A randomized, double-blind trial on morbidity and mortality, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), compared newer treatment approaches: amlodipine 2.5–10 mg/day (a calcium channel blocker) or lisinopril 10–40 mg/day (an ACE inhibitor) as first-line therapy versus the thiazide diuretic chlorthalidone 12.5–25 mg/day in mild to moderate hypertension.

A total of 33,357 hypertensive patients aged 55 years and older were randomized and followed for a mean of 4.9 years. Patients had at least one additional risk factor for ischemic heart disease (IHD), including prior myocardial infarction or stroke (>6 months before enrollment) or documented other atherosclerotic cardiovascular disease (51.5% total), type 2 diabetes (36.1%), high-density lipoprotein <35 mg/dL (11.6%), left ventricular hypertrophy diagnosed by ECG or echocardiography (20.9%), or current cigarette smoking (21.9%).

The primary endpoint was fatal IHD or nonfatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine and chlorthalidone therapy: risk ratio (RR) 0.98, 95% CI (0.90–1.07), p = 0.65. Among secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared to the chlorthalidone group (10.2% vs. 7.7%, RR 1.38, 95% CI [1.25–1.52], p < 0.001). However, there was no significant difference in all-cause mortality between amlodipine and chlorthalidone therapy: RR 0.96, 95% CI [0.89–1.02], p = 0.20.

Pediatric population (aged 6 years and older)

In a study involving 268 children aged 6–17 years with predominantly secondary hypertension, comparison of amlodipine doses of 2.5 mg and 5.0 mg with placebo showed that both doses significantly reduced systolic blood pressure compared to placebo. The difference between the two doses was not statistically significant.

Long-term effects of amlodipine on growth, sexual maturation, and overall development have not been studied. Long-term efficacy of amlodipine therapy in childhood for reducing cardiovascular morbidity and mortality in adulthood has also not been established.

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 food. The bioavailability of the active metabolite ramiprilat after oral administration of 2.5 mg and 5 mg ramipril is 45%.

Maximum plasma concentration of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after ramipril administration. Steady-state plasma concentration of ramiprilat with usual dosing (once daily) is achieved by day 4 of treatment.

Distribution.

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

Metabolism.

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

Elimination.

Metabolite excretion occurs predominantly via the kidneys.

Plasma concentration decline of ramiprilat occurs in multiple 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 5–10 mg doses 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 renal clearance of ramiprilat is proportionally related to creatinine clearance. This results in 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, metabolism of ramipril to ramiprilat is slowed due to reduced hepatic esterase activity, leading to elevated plasma levels of ramipril. However, maximum ramiprilat concentrations in these patients do not differ from those in individuals with normal liver function.

B breastfeeding.

After single oral administration of 10 mg ramipril, its level in breast milk was not detected. However, the effect of multiple dosing is unknown.

Pediatric population.

The pharmacokinetic profile of ramipril was studied in 30 pediatric patients with hypertension aged 2–16 years and body weight >10 kg. After doses of 0.05–0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Maximum plasma concentration of ramiprilat was reached within 2–3 hours. Ramiprilat clearance correlated significantly with the logarithm of body weight (p < 0.01) and with dose (p < 0.001). Clearance and volume of distribution increased proportionally with age within each dosing group. Administration of 0.05 mg/kg in children achieved exposure levels comparable to those in adults receiving 5 mg ramipril. Administration of 0.2 mg/kg in children achieved exposure levels higher than those achieved with the maximum recommended adult dose of 10 mg/day.

Amlodipine.

Absorption.

After oral administration, amlodipine is almost completely absorbed, reaching maximum plasma concentration 6–12 hours after intake. 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 approximately 97.5% of circulating amlodipine in blood is bound to plasma proteins.

Metabolism and elimination.

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

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

Plasma concentration decline is biphasic. Terminal plasma half-life is approximately 35–50 hours with once-daily dosing.

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

Use in elderly individuals.

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

Patients with impaired renal function.

Amlodipine is extensively metabolized to inactive metabolites. 10% of the parent compound is excreted unchanged in urine. Changes in plasma amlodipine concentrations 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.

Information on amlodipine use in patients with hepatic impairment is limited. In patients with hepatic insufficiency, amlodipine clearance is reduced, leading to prolonged half-life and increased AUC by approximately 40–60%.

Pediatric population.

Pharmacokinetic studies were conducted in 74 children with hypertension aged 12–17 years (including 34 patients aged 6–12 years and 28 patients aged 13–17 years) receiving amlodipine doses of 1.25–20 mg daily in one or two doses. Typical oral clearance (CL/F) in children aged 6–12 years and adolescents aged 13–17 years was 22.5 and 27.4 L/hour, respectively, for boys, and 16.4 and 21.3 L/hour, respectively, for girls. There is considerable inter-patient variability in exposure. Information in patients under 6 years of age is limited.

Clinical characteristics.

Indications.

Treatment of arterial hypertension in adult patients whose blood pressure is adequately controlled with ramipril and amlodipine administered simultaneously at the same doses as in the combination.

Contraindications.

Hypersensitivity to ramipril, amlodipine, dihydropyridine derivatives, angiotensin-converting enzyme (ACE) inhibitors, or to any excipient.

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 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. Cilazapril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use");
• Extracorporeal treatments leading to blood contact with negatively charged surfaces (see section "Interaction with other medicinal products and other types of interactions");
• Severe bilateral renal artery stenosis or stenosis of the renal artery in a single functioning kidney;
• Arterial hypotension or hemodynamically unstable conditions;
• Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy and lactation").

Contraindications associated with the use of amlodipine:

• 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.

Interaction with other medicinal products and other types of interactions.

Ramipril.

Contraindicated combinations.

Extracorporeal treatment methods 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 a different 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 cilazapril should be initiated only 36 hours after the last dose of sacubitril/valsartan. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of cilazapril (see sections "Contraindications" and "Special precautions for use").

Use with caution.

Dual blockade of the 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 acute renal failure), compared to use of a single agent acting on the RAAS (see sections "Contraindications", "Special precautions for use", and "Pharmacodynamics").

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

Potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes: Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving cilazapril. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Caution is also required when cilazapril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of cilazapril with the above-mentioned agents is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium levels.

Cyclosporine: Hyperkalemia may occur during concomitant use of ACE inhibitors with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin: Hyperkalemia may occur during concomitant use of ACE inhibitors with heparin. Monitoring of serum potassium levels is recommended.

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 and trimethoprim or fixed-dose combinations with sulfamethoxazole (co-trimoxazole). Hyperkalemia may occur in some patients receiving cilazapril. Caution is also required when cilazapril is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of cilazapril with the above-mentioned agents is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium levels.

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

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 risk of hematological reactions.

Salts of lithium: ACE inhibitors may reduce lithium excretion and thereby increase its toxicity. Monitoring of lithium levels in blood is recommended.

Antidiabetic agents, including insulin: Hypoglycemic reactions are possible. Monitoring of blood glucose levels is recommended.

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

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

Amlodipine.

Amlodipine is safe to use concomitantly with thiazide diuretics, β-blockers, long-acting nitrates, sublingual nitroglycerin, NSAIDs, antibiotics, and oral hypoglycemic agents.

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 lead to a significant increase in amlodipine exposure, which may also increase the risk of hypotension. The clinical significance of such changes may be more pronounced in elderly patients. Clinical monitoring of the patient and dose adjustment may be necessary.
• CYP3A4 inducers: Plasma concentrations of amlodipine may vary during concomitant use with known CYP3A4 inducers. Therefore, blood pressure should be monitored and dose adjustment considered during and after concomitant administration of such drugs, especially when used with strong CYP3A4 inducers (such as rifampicin, St. John's wort preparations).

The use of amlodipine together with grapefruit or grapefruit juice is not recommended, as bioavailability may be increased in some patients, leading to enhanced hypotensive effect of the medicinal product.

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

Tacrolimus. When administered concomitantly with amlodipine, there is a risk of increased blood concentration of tacrolimus.

To avoid tacrolimus toxicity, administration of amlodipine to a patient receiving tacrolimus requires monitoring of tacrolimus blood levels and dose adjustment if 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 increase their exposure.

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 medicinal products.

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

Cyclosporine. No interaction studies between cyclosporine and amlodipine have been conducted in healthy volunteers or other populations, except in kidney transplant patients, where an increase in cyclosporine trough concentration (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.

Clarithromycin is a CYP3A4 inhibitor. In patients receiving clarithromycin with amlodipine, there may be an increased risk of hypotension. Close monitoring of patients is recommended when amlodipine is used concomitantly with clarithromycin.

Simvastatin. Repeated co-administration 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.

Special precautions for use.

It is recommended to use the medicinal product with caution in patients who are concurrently taking diuretics, as volume and/or salt depletion may occur. Renal function and serum potassium levels should be monitored.

Ramipril.

Dual blockade of the RAAS. There is evidence that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of 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 must not be used concomitantly in patients with diabetic nephropathy.

Special patient categories.

Pregnancy. ACE inhibitors should not be used during pregnancy. If continuation of ACE inhibitor therapy is not considered necessary, patients planning pregnancy should switch to an alternative antihypertensive treatment with an established safety profile during pregnancy. Upon diagnosis of pregnancy, 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 hypotension.

Patients with markedly increased RAAS activity. In patients with markedly increased RAAS activity, there is a risk of sudden and significant reduction in blood pressure and worsening of renal function due to ACE inhibition, particularly when initiating or increasing the dose of an ACE inhibitor or concomitant diuretic. A marked increase in RAAS activity requiring medical supervision, including continuous blood pressure monitoring, may be expected, for example, in patients:

• with severe arterial hypertension;
• with decompensated congestive heart failure;
• with hemodynamically significant obstruction to inflow or outflow 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 hypotension.

Generally, correction of dehydration, hypovolemia, or electrolyte depletion is recommended prior to 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 due to acute hypotension. Close medical supervision is required during the initial phase of treatment.

Elderly patients. See section "Method of administration and dosage."

Surgery.

If possible, treatment with ACE inhibitors such as ramipril should be discontinued one day prior to surgery.

Monitoring of renal function.

Renal function should be assessed before and during treatment, and dosage adjusted accordingly, especially during the first weeks of therapy. Particularly careful monitoring is required in patients with impaired renal function (see section "Method of administration and dosage"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation.

Angioedema.

Angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions").

If angioedema occurs, the medicinal product should be discontinued immediately. Emergency treatment should be initiated without delay. 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 reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Treatment with sacubitril/valsartan must not be initiated earlier than 36 hours after the last dose of cilazapril. Treatment with cilazapril must not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of Quincke's edema (e.g., swelling of the airways or tongue, with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when administering racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin to patients already taking an ACE inhibitor.

Patients concurrently receiving mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus) may have an increased risk of developing angioedema, such as swelling of the airways or tongue, with or without respiratory distress (see section "Interaction with other medicinal products and other forms of interaction").

Anaphylactic reactions during desensitization.

The use of ACE inhibitors may increase 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 increased risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, or other active substances that increase plasma potassium levels (e.g., heparin, co-trimoxazole, also known as trimethoprim/sulfamethoxazole), or patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of the above-mentioned medicinal products is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Serum potassium.

ACE inhibitors may cause hyperkalemia due to inhibition of aldosterone release. This effect is usually not significant in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function and/or in patients taking potassium supplements (including salt substitutes), potassium-sparing diuretics, trimethoprim, or co-trimoxazole (also known as trimethoprim/sulfamethoxazole), particularly when combined with aldosterone antagonists or angiotensin receptor blockers. Concomitant use of potassium-sparing diuretics and angiotensin receptor blockers with ACE inhibitors should be done with caution, and serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Hyponatremia.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) with subsequent hyponatremia has been observed in some patients taking ramipril. Regular monitoring of serum sodium levels is recommended 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 white blood cell count is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those 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 patients of black race than in other racial groups. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of black race compared to other racial groups. This may be due to the higher prevalence of low-renin hypertension in black patients with arterial hypertension.

Cough.

Cough has been reported with the use of ACE inhibitors. The cough is typically dry, persistent, and resolves upon discontinuation of therapy. When performing differential diagnosis of cough, ACE inhibitor-induced cough should be considered.

Amlodipine.

The safety and efficacy of amlodipine for the treatment 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 (see section "Pharmacodynamics"). Calcium channel blockers, including amlodipine, should be used with caution in patients with congestive heart failure, as they may increase the risk of future cardiovascular events and mortality.

Use in patients with hepatic impairment.

In patients with hepatic impairment, the elimination half-life of amlodipine is prolonged, but dosage recommendations are not yet established. Therefore, amlodipine therapy should be initiated at the lower end of the dosage range, and caution should be exercised both during initial treatment and dose escalation. Patients with severe hepatic impairment may require slow dose titration and close monitoring.

Use in elderly patients.

Dosage increases should be performed cautiously in elderly patients.

Patients with renal impairment.

This patient group should receive the usual doses of the medicinal product. 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.

Important information on excipients.

This medicinal product contains sodium; therefore, patients on a sodium-restricted diet should use it with caution.

Use during pregnancy or breastfeeding.

Pregnancy.

Ramipril.

Use of ACE inhibitors during the first trimester of pregnancy is not recommended (see section "Special precautions for use"). Use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on the teratogenic risk following ACE inhibitor use in the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. If continuation of ACE inhibitor therapy is considered necessary, pregnant women or women planning pregnancy should switch 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 cranial ossification) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If an ACE inhibitor is used during the second trimester, ultrasound monitoring of fetal renal function and skull ossification is recommended. Newborns whose mothers received ACE inhibitors should be closely monitored for hypotension, oliguria, and hyperkalemia.

Amlodipine.

The safety of amlodipine use during human pregnancy has not been established.

Reproductive toxicity has been observed in animal studies at high doses.

Use during pregnancy is recommended only when safer alternatives are unavailable and when the disease itself poses a greater risk to the mother and fetus.

Given the above information, this medicinal product is not recommended during the first trimester of pregnancy and is contraindicated during the second and third trimesters of pregnancy.

Breastfeeding.

Ramipril.

Due to insufficient data on ramipril use during breastfeeding, it is not recommended, and alternative treatments are preferred, especially when breastfeeding a newborn or preterm infant.

Amlodipine.

Amlodipine passes into breast milk. The infant's exposure has been estimated at 3–7% of the maternal dose, with a maximum of 15%. The effect of amlodipine on the infant is unknown.

The decision to continue/stop breastfeeding or to continue/stop amlodipine therapy should be made considering the benefits of breastfeeding for the child and the benefits of amlodipine therapy for the mother.

Given the above information, this medicinal product is not recommended during breastfeeding. The decision to continue/stop breastfeeding or to continue/stop amlodipine therapy should be made considering the benefits of breastfeeding for the child and the benefits of amlodipine therapy for the mother.

Fertility. Reversible biochemical changes in sperm heads have been reported in some patients taking calcium channel blockers. There are insufficient clinical data on the potential effect of amlodipine on fertility. An adverse effect on male fertility was observed in one rat study.

Ability to affect reaction speed when driving or operating machinery.

A slight or moderate effect on the ability to drive or operate machinery is possible. Some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair concentration and reaction ability, thereby affecting reaction speed when driving or operating machinery.

These adverse reactions were observed at the beginning of treatment or when switching from other medicinal products. Driving and operating machinery should be avoided for several hours after taking the first dose or increasing the dose. Caution is advised, especially at the beginning of therapy.

Method of Administration and Dosage.

The medicinal product is indicated for patients whose blood pressure is adequately controlled with separately prescribed monotherapy agents at doses corresponding to those recommended for the fixed combination.

The recommended initial daily dose is 1 capsule.

The medicinal product 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 combination is not suitable for initial therapy of arterial hypertension.

If necessary, the dose of the medicinal product may be adjusted or the components individually titrated in a free combination.

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

Adults.

Caution should be exercised in patients receiving diuretics, 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.

Treatment with ramipril should be initiated only under close medical supervision in patients with hepatic impairment.

The maximum daily dose of ramipril should be 2.5 mg; therefore, this medicinal product is not used in patients with hepatic impairment.

Patients with renal impairment.

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

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 dose adjustment is required (initial dose 2.5 mg daily); 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, but 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 minimally removed by hemodialysis;
  • the initial dose is 1.25 mg, and the maximum daily dose is 5 mg;
  • the medicinal product should be taken several hours after a hemodialysis session.

Dose 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.

Renal function and serum potassium levels should be monitored during treatment with the medicinal product. If renal function worsens, the medicinal product 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 potential for adverse reactions. Use of the medicinal product is not recommended in patients aged 75 years or older or in very frail patients.

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

Children.

The medicinal product is not recommended for use in children due to lack of data on safety and efficacy in this age group.

Overdose.

Ramipril.

Symptoms caused by overdose of ACE inhibitors may include excessive peripheral vasodilation (with marked hypotension, shock), bradycardia, electrolyte imbalance, and renal failure. The patient's condition should be closely monitored. Symptomatic and supportive treatment should be administered. Proposed measures include primary detoxification (gastric lavage, administration of sorbents) and interventions to restore hemodynamic stability, including administration of α-1-adrenergic agonists or angiotensin II (angiotensinamide).

Ramiprilat, the active metabolite of ramipril, is poorly removed from systemic circulation by hemodialysis.

Amlodipine.

Data on intentional human overdose are limited.

Symptoms. Based on available data, it is believed that severe overdose may lead to excessive peripheral vasodilation and possibly reflex tachycardia, profound and prolonged systemic arterial hypotension, including cardiogenic shock with fatal outcome.

Rare cases of non-cardiogenic pulmonary edema have been reported as a consequence of amlodipine overdose, which may present with delayed onset (24–48 hours after ingestion) and may require mechanical ventilation. Contributing factors to the development of non-cardiogenic pulmonary edema may include early resuscitation measures (including fluid overload) aimed at maintaining perfusion and cardiac output.

Treatment. Clinically significant arterial hypotension due to amlodipine overdose requires active treatment measures, including frequent monitoring of cardiac and respiratory function, placing the patient in a supine position with legs elevated, monitoring circulating blood volume and diuresis. Administration of a vasoconstrictor agent may be beneficial to restore vascular tone and blood pressure, provided there are no contraindications to its use. Intravenous calcium gluconate may be effective in counteracting 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 (≥ 1/1,000 to < 1/100), rare (≥ 1/10,000 to < 1/1,000), very rare (< 1/10,000), frequency not known (cannot be estimated from the available data).

Ramipril.

The safety profile of ramipril includes adverse reactions such as persistent dry cough and reactions due to hypotension. Serious adverse reactions include stroke, myocardial infarction, angioedema, hyperkalemia, renal or hepatic failure, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

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

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

Respiratory, thoracic and mediastinal disorders:
Common – non-productive irritative cough, bronchitis, sinusitis, dyspnea; uncommon – bronchospasm, including asthma exacerbation, nasal congestion; frequency not known – lung cancer.

Gastrointestinal disorders:
Common – gastrointestinal inflammation, digestive disorders, gastrointestinal discomfort, dyspepsia, diarrhea, nausea, vomiting; uncommon – pancreatitis (isolated cases with fatal outcome when using ACE inhibitors), increased pancreatic enzyme levels, angioneurotic edema 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 damage; frequency not known – acute liver failure, cholestatic or cytolytic hepatitis (in isolated cases with fatal outcome).

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

Endocrine disorders:
Frequency not known – syndrome of inappropriate antidiuretic hormone secretion.

Metabolism and nutrition disorders:
Common – increased blood potassium levels; uncommon – anorexia, decreased appetite; frequency not known – decreased blood sodium levels.

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 disturbances, burning sensation, parosmia.

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

Cardiac disorders:
Uncommon – myocardial ischemia, including angina or myocardial infarction, tachycardia, arrhythmia, palpitations, peripheral edema.

Vascular disorders:
Common – arterial hypotension, orthostatic hypotension, syncope; uncommon – flushing, hyperemia; rare – vascular stenosis, hypoperfusion, vasculitis; frequency not known – Raynaud's syndrome.

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

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

Skin and subcutaneous tissue disorders:
Common – skin rash, including maculopapular rash; 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 exanthem or enanthem, alopecia.

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

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.

Amlodipine.

The most frequently reported adverse reactions during amlodipine use include somnolence, dizziness, headache, palpitations, flushing, abdominal pain, nausea, ankle edema, swelling, and fatigue.

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

Ear and labyrinth disorders:
Uncommon – tinnitus.

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).

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

Metabolism and nutrition disorders:
Uncommon – hyperglycemia.

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.

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

Cardiac disorders:
Common – tachycardia; very rare – myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia, and atrial fibrillation).

Vascular disorders:
Common – hyperemia, flushing; uncommon – arterial hypotension; very rare – vasculitis.

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

Immune system disorders:
Very rare – allergic reactions.

Skin and subcutaneous tissue disorders:
Uncommon – alopecia, purpura, skin discoloration, increased sweating, pruritus, rash, exanthem; 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 cramps, back pain.

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

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

Laboratory findings:
Uncommon – increased or decreased body weight; very rare – increased liver enzyme levels*.

*In most cases associated with cholestasis.

Reporting of suspected adverse reactions.

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

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 °C. Keep out of reach of children.

Packaging.

6 capsules in a blister, 5 blisters in a carton.

Prescription status. Prescription only.

Marketing authorization holder. JSC "Pharmaceutical company "Darnytsia".

Address of the marketing authorization holder and location of its business activities.

13 Borispilska Street, Kyiv, 02093, Ukraine.

Manufacturer. Adamed Pharma S.A.

Address of the manufacturer and location of its business activities.

Schoolna 33, Ksawerow, 95–054, Poland.

Józefa Piłsudskiego 5, Pabianice, 95–200, Poland.