Ramiton A 10mg/10mg capsules No. 30

INSTRUCTION
for medical use of a medicinal product

Ramiton A

Composition:

active ingredients: ramipril, amlodipine;

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

excipients:

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

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

Dosage form

Main physicochemical properties:

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

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

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

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

Pharmacotherapeutic group

Pharmacological properties.

Pharmacodynamics.

Mechanism of action of ramipril.

Ramiprilat, the active metabolite of ramipril, inhibits the enzyme dipeptidylcarboxypeptidase (synonyms: angiotensin-converting enzyme, kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to the active vasoconstrictor substance angiotensin II, as well as the breakdown of the active vasodilator bradykinin. The reduction in the formation of angiotensin II and the inhibition of the breakdown of bradykinin lead to vasodilation.

Since angiotensin II also stimulates the release of aldosterone, ramiprilat helps to reduce aldosterone secretion. The average response to ACE inhibitor monotherapy was lower in black (African) hypertensive patients (usually with low-renin states) than in white patients.

Pharmacodynamic action.

The use of ramipril causes a pronounced decrease in peripheral arterial resistance. In general, no significant changes in renal plasma flow and glomerular filtration rate were observed. The use of ramipril in patients with arterial hypertension leads to a decrease in blood pressure in the horizontal and vertical positions without a compensatory increase in heart rate. In most patients, the onset of the antihypertensive effect of a single dose of ramipril occurs 1–2 hours after oral administration of the drug. The maximum effect after a single dose is usually achieved 3–6 hours after oral administration. The antihypertensive effect persists for 24 hours.

The maximum antihypertensive effect of long-term treatment with ramipril is observed after 3–4 weeks. The antihypertensive effect has been shown to be maintained for 2 years with long-term therapy.

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

Clinical efficacy and safety.

Prevention of cardiovascular diseases.

A placebo-controlled preventive study (the HOPE study) was conducted in over 9200 patients who received ramipril in addition to standard therapy. This study included patients at high risk of cardiovascular disease after a history of atherothrombotic cardiovascular disease (history of coronary heart disease, stroke, or peripheral vascular disease) or patients with diabetes mellitus who had at least one additional risk factor (documented microalbuminuria, hypertension, elevated total cholesterol, low-density lipoprotein cholesterol, or smoking).

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

HOPE study: main results

The MICRO-HOPE study, which was previously planned as part of the HOPE study, examined the effect of adding ramipril 10 mg to existing treatment compared with placebo in 3,577 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).

The primary analysis showed that 117 (6.5%) of the ramipril-treated participants and 149 (8.4%) of the placebo-treated participants developed significant nephropathy, corresponding to a relative risk reduction of 24%; 95% CI [3-40], p = 0.027.

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

Two large randomized controlled trials [ONTARGET (Telmisartan Monotherapy and Ramipril Combination Overall Endpoint Study) and VA NEPHRON-D (Veterans Affairs-sponsored Diabetic Nephropathy Study)] have examined the combination of an ACE inhibitor with an angiotensin II receptor antagonist.

The ONTARGET study was conducted in patients with a history of cardiovascular or cerebrovascular disease or with type 2 diabetes mellitus with concomitant signs of target organ damage. The VA NEPHRON-D study included patients with type 2 diabetes mellitus and diabetic nephropathy.

These studies did not show a significant benefit of combination therapy with respect to renal and/or cardiovascular outcomes and mortality, while there was an increased risk of hyperkalemia, acute renal failure and/or hypotension compared with monotherapy. Given the similar pharmacodynamic characteristics of these drugs, these results 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 (Aliskiren in Type 2 Diabetes Cardiovascular and Renal Endpoints Trial) evaluated the benefits of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor antagonist in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated early due to an increased risk of adverse clinical outcomes. There was a higher incidence of cardiovascular death and stroke in the aliskiren group compared with the placebo group, as well as an increased incidence of serious adverse events (hyperkalemia, hypotension, and renal dysfunction).

Pediatric population.

In a randomized, double-blind, placebo-controlled clinical trial involving 244 pediatric hypertensive patients (73% of whom had primary hypertension) aged 6–16 years, participants received low, medium, or high doses of ramipril to achieve plasma concentrations of ramiprilat that corresponded to the adult dose range of 1.25 mg; 5 mg, and 20 mg based on body weight. After 4 weeks, ramipril was found to be ineffective on the endpoint of systolic blood pressure reduction, but it did reduce diastolic blood pressure at the highest dose of the range studied. Both medium and high doses of ramipril were shown to reduce systolic and diastolic blood pressure to a statistically significant extent in children with established hypertension.

This effect was not observed in a 4-week, randomized, double-blind, dose-escalation study evaluating the effect of drug withdrawal in 218 pediatric patients aged 6 to 16 years (75% of whom had primary hypertension). In this study, a modest rebound increase in both diastolic and systolic blood pressure was observed after drug withdrawal, but it was not statistically significant for the return to baseline pressure in all dose groups of the ramipril dose range studied [low dose (0.625-2.5 mg), medium dose (2.5-10 mg), or high dose (5-20 mg)] based on body weight. Ramipril did not show a linear dose-response effect in the pediatric population studied.

Amlodipine inhibits the transmembrane influx of calcium ions in heart cells and vascular smooth muscle (slow calcium channel blocker or calcium ion antagonist).

The mechanism of antihypertensive action is due to the direct relaxing effect of amlodipine on vascular smooth muscle, which contributes to a decrease in systemic peripheral vascular resistance.

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

1) amlodipine dilates peripheral arterioles, thereby reducing total peripheral resistance (after exercise). Since it does not cause reflex tachycardia, myocardial energy consumption and oxygen demand will decrease;

2) due to the described mechanism of action, amlodipine increases the supply of oxygen to the myocardium even in the case of coronary artery spasm (Prinzmetal's angina or variant angina).

Pharmacodynamic properties.

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

In patients with angina, the use of amlodipine once daily prolongs the total time of possible physical exertion, delays the onset of an angina attack and prolongs the time to significant ST segment depression, reduces the frequency of angina attacks and reduces the need for glyceryl trinitrate tablets.

Amlodipine does not have an adverse effect on metabolism and blood plasma lipids, therefore it is suitable for the treatment of patients with bronchial asthma, diabetes mellitus, and gout.

Use in patients with heart failure

In a long-term placebo-controlled study (PRAISE-2) in patients with NYHA class III and IV heart failure without clinical symptoms or objective findings suggestive of ischemic disease, receiving stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on all-cause cardiovascular mortality. In the same population, amlodipine was associated with an increased incidence of pulmonary edema.

Treatment to Prevent Heart Attack (ALLHAT)

A randomized, double-blind, morbidity and mortality study, the Antihypertensive and Lipid-Lowering Therapy for Heart Attack Prevention Trial (ALLHAT), was conducted to compare newer treatments: amlodipine 2.5–10 mg/day (a calcium channel blocker) or lisinopril 10–40 mg/day (an ACE inhibitor) as first-line therapy to the thiazide diuretic chlorthalidone 12.5–25 mg/day in mild to moderate hypertension.

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

The primary endpoint was fatal CHD or nonfatal myocardial infarction. There was no significant difference in the primary endpoint between amlodipine and chlorthalidone therapy: the hazard ratio (HR) was 0.98, 95% CI (0.90-1.07), p = 0.65. Among the secondary endpoints, the incidence of heart failure (a component of the composite cardiovascular endpoint) was significantly higher in the amlodipine group compared with the chlorthalidone group (10.2% vs. 7.7%, HR 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. HR 0.96, 95% CI [0.89−1.02] p = 0.20.

Pediatric population (age 6 years and older)

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

The long-term effects of amlodipine on growth, puberty, and general development have not been studied. The long-term efficacy of amlodipine therapy in childhood to reduce 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 concentrations of ramipril are reached within 1 hour. Taking into account the urinary excretion of ramipril, 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 a dose of 2.5 mg and 5 mg is 45%.

The maximum plasma concentration of ramiprilat, the only active metabolite of ramipril, is reached 2-4 hours after taking ramipril. Steady-state plasma concentrations of ramiprilat are reached by the 4th day of treatment at usual doses (once daily).

Distribution.

The binding of ramipril to blood proteins is approximately 73%, and that of ramiprilat is 56%.

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

Breeding.

Excretion of metabolites is carried out mainly by the kidneys.

The decrease in plasma ramiprilat concentration occurs in several phases. Due to the strong saturable binding to ACE and slow dissociation from the enzyme, ramiprilat is characterized by 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 doses of 5–10 mg and longer after lower doses of 1.25–2.5 mg. The difference is due to the saturable capacity of the enzyme to bind ramiprilat.

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

Patients with renal impairment.

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 increased plasma concentrations of ramiprilat, which decline more slowly than in subjects with normal renal function.

Patients with impaired liver function.

In patients with impaired hepatic function, the metabolism of ramipril to ramiprilat is slowed down, which is due to reduced activity of hepatic esterases, and plasma levels of ramipril in these patients are increased. However, the maximum concentration of ramiprilat in these patients did not differ from that in individuals with normal hepatic function.

Breast-feeding.

After a single oral dose of 10 mg ramipril, its levels in breast milk were not detected. However, the effect of multiple doses is unknown.

Pediatric population.

The pharmacokinetic profile of ramipril was studied in 30 pediatric patients with hypertension, aged 2–16 years and weighing >10 kg. After doses of 0.05 to 0.2 mg/kg, ramipril was rapidly and extensively metabolized to ramiprilat. Peak plasma concentrations of ramiprilat were reached after 2–3 hours. Ramiprilat clearance was significantly correlated with logarithm of body weight (p < 0.01) and dose (p < 0.001). Clearance and volume of distribution increased in proportion to age in each dose group. Exposure levels were comparable in children at a dose of 0.05 mg/kg to those in adults at a dose of 5 mg ramipril. A dose of 0.2 mg/kg in children resulted in exposure levels that were higher than the maximum recommended dose of 10 mg/day in adults.

Amlodipine.

Absorption.

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

Distribution.

The volume of distribution is 21 l/kg body weight. Steady-state plasma concentrations (5–15 ng/ml) are reached within 7–8 days of dosing. In vitro studies have shown that approximately 97.5% of circulating amlodipine is bound to plasma proteins.

Metabolism and excretion.

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

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

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

The total clearance is 7 ml/min/kg body weight (for patients with a body weight of 60 kg – 25 l/h). In elderly patients – 19 l/h.

Application to the elderly.

The time required to reach maximum plasma concentrations of amlodipine is similar in both elderly and younger patients. There is a tendency for amlodipine clearance to decrease in the elderly, resulting in an increase in the area under the concentration-time curve (AUC) and half-life. An increase in AUC and half-life of the drug has been reported in patients with congestive heart failure.

Patients with renal impairment.

Amlodipine is extensively metabolized to inactive metabolites. 10% of the parent compound is excreted unchanged in the 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 liver function.

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

Pharmacokinetic studies were conducted in 74 hypertensive children aged 12 to 17 years (including 34 patients aged 6 to 12 years and 28 patients aged 13 to 17 years) who received amlodipine at doses of 1.25-20 mg/day in 1 or 2 divided doses. Typically, oral clearance (CL/F) in children aged 6 to 12 years and adolescents aged 13 to 17 years was 22.5 and 27.4 L/h, respectively, for boys and 16.4 and 21.3 L/h, respectively, for girls. There is considerable inter-patient variability in exposure. Limited information is available in patients under 6 years of age.

Clinical characteristics.

Indication

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

Contraindication

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

Contraindications associated with the use of ramipril:

Concomitant use with aliskiren-containing medicinal products is contraindicated in patients with diabetes mellitus or renal impairment (glomerular filtration rate (GFR) < 60 ml/min/1.73 m2) (see sections “Interaction with other medicinal products and other forms of interaction” and “Pharmacodynamics”);

Concomitant use with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Cilazapril should not be started earlier than 36 hours after the last dose of sacubitril/valsartan (see section "Interaction with other medicinal products and other forms of interaction" and section "Special warnings and precautions for use");

extracorporeal treatment that results in blood coming into contact with negatively charged surfaces (see section “Interaction with other medicinal products and other types of interactions”);

II and III trimesters of pregnancy (see sections "Special instructions for use" and "Use during pregnancy and breastfeeding").

Contraindications associated with the use of amlodipine:

Interaction with other medicinal products and other types of interactions

Ramipril.

Contraindicated combinations.

Extracorporeal treatments that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration with certain membranes with high hydraulic permeability (e.g. polyacrylonitrile), and low-density lipoprotein apheresis with dextran sulfate, due to an increased risk of severe anaphylactoid reactions. If such treatments are required, consideration should be given to using a different type of dialysis membrane or a different class of antihypertensive agent.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections 4.3 and 4.4). Cilazapril treatment should not be initiated until 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of cilazapril (see sections 4.3 and 4.4).

Use with caution.

Dual blockade of the RAAS: Clinical trial data have shown that dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is associated with an increased incidence of adverse events such as hypotension, hyperkalemia and deterioration of renal function (including the development of acute renal failure) compared with the use of a single agent affecting the RAAS (see sections “Contraindications”, “Special instructions for use” and “Pharmacodynamics”).

mTOR inhibitors or vildagliptin: An increased incidence of angioedema has been observed in patients receiving concomitant ACE inhibitors, racecadotril and mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. Caution should be exercised at the start of therapy.

Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes: Although serum potassium usually remains 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 significant increases in serum potassium. Caution should also be exercised when cilazapril is administered concomitantly with other drugs that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic to amiloride. Therefore, the combination of cilazapril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

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

Trimethoprim and fixed-dose combinations with sulfamethoxazole (co-trimoxazole): An increased incidence of hyperkalemia has been observed in patients receiving ACE inhibitors and trimethoprim and fixed-dose combinations with sulfamethoxazole (co-trimoxazole). It is known that some patients receiving cilazapril may experience hyperkalemia. Caution should also be exercised when cilazapril is administered concomitantly with other drugs that increase serum potassium, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act like the potassium-sparing diuretic amiloride. Therefore, the combination of cilazapril with the above-mentioned drugs is not recommended. If concomitant use is indicated, they should be used with caution and with frequent monitoring of serum potassium.

Antihypertensive drugs (e.g. diuretics) and other drugs that may lower 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. isoproterenol, 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 the excretion of lithium and therefore may increase its toxicity. Monitoring of lithium levels in the blood is recommended.

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

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid: The antihypertensive effect of ramipril may be reduced. Therefore, the concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of worsening of renal function and an increase in blood potassium levels.

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

Amlodipine.

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

Effect of other drugs on amlodipine:

It is not recommended to use amlodipine with grapefruit or grapefruit juice, as bioavailability may be increased in some patients, leading to increased hypotensive effect of the drug.

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

Tacrolimus: With simultaneous administration of the drug with amlodipine, there is a risk of increasing the concentration of tacrolimus in the blood.

To avoid tacrolimus toxicity, the administration of amlodipine to a patient taking tacrolimus requires monitoring of tacrolimus blood levels and adjustment of its dosage if necessary.

mTOR (mammalian target of rapamycin) inhibitors. mTOR inhibitors such as sirolimus, temsirolimus, and everolimus are substrates of CYP3A. Amlodipine is a weak inhibitor of CYP3A. When co-administered with mTOR inhibitors, amlodipine may increase their exposure.

Dantrolene (infusion): Fatal ventricular fibrillation and cardiovascular collapse associated with hyperkalemia have been observed in animals following intravenous administration of verapamil and dantrolene. Because of the risk of hyperkalemia, it is recommended that calcium channel blockers, such as amlodipine, be avoided in patients predisposed to malignant hyperthermia and in the treatment of malignant hyperthermia.

The effect of amlodipine on other drugs.

Amlodipine may enhance the effect of other antihypertensive drugs.

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 with cyclosporine and amlodipine have been conducted in healthy volunteers or other populations, except in renal transplant patients, where variable increases in cyclosporine trough concentrations (mean 0-40%) were observed. Monitoring of cyclosporine levels should be considered in renal transplant patients receiving amlodipine; if necessary, a reduction in the cyclosporine dose should be considered.

Simvastatin: Co-administration of multiple doses of amlodipine 10 mg and simvastatin 80 mg resulted in a 77% increase in simvastatin exposure compared to simvastatin alone. For patients taking amlodipine, the dose of simvastatin should be limited to 20 mg daily.

Application features

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

Ramipril.

Dual blockade of the RAAS. There is evidence that the concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren increases the risk of hypotension, hyperkalemia and worsening of renal function (including acute renal failure). Therefore, dual blockade of the RAAS through the combined use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren is not recommended (see sections 4.5 and 5.1).

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

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

Special categories of patients.

Pregnancy: ACE inhibitors should not be used during pregnancy. Unless continued ACE inhibitor therapy is considered essential, patients planning pregnancy should be changed to alternative antihypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, ACE inhibitors should be stopped immediately, and, if appropriate, alternative treatment should be started (see sections 4.3 and 4.8).

Patients at high risk of developing arterial hypotension.

Patients with significantly increased RAAS activity. Patients with significantly increased RAAS activity are at risk of a sudden significant decrease in blood pressure and deterioration of renal function due to ACE inhibition, especially when an ACE inhibitor or concomitant diuretic is administered for the first time or when the dose is increased for the first time. A significant increase in RAAS activity, requiring medical supervision, including constant monitoring of blood pressure, can be expected, for example, in patients:

– with severe arterial hypertension;

– with decompensated congestive heart failure;

– with hemodynamically significant obstruction to the inflow or outflow of blood from the left ventricle (for example, with aortic or mitral valve stenosis);

– with unilateral renal artery stenosis in the presence of a second functioning kidney;

– who have or may develop fluid or electrolyte depletion (including those receiving diuretics);

– with liver cirrhosis and/or ascites;

– who are undergoing extensive surgical interventions or during anesthesia with the use of drugs that cause arterial hypotension.

As a rule, it is recommended to correct dehydration, hypovolemia,