Hartyl tablets 10 mg No. 28

Instructions for Hartil tablets 10 mg No. 28

Composition

active ingredient: ramipril;

1 tablet contains ramipril 5 mg or 10 mg;

excipients: sodium bicarbonate, lactose monohydrate, croscarmellose sodium, pregelatinized starch, sodium stearyl fumarate, red iron oxide (E 172) (for 5 mg tablets), yellow iron oxide (E 172) (for 5 mg tablets).

Dosage form

Pills.

Main physicochemical properties:

5 mg tablets – light pink, flat, oval tablets without a shell, with a bevel, with possible inclusions, with a score on one side and on the lateral surfaces, marked R3, size 8.8 x 4.4 mm.

10 mg tablets – white or almost white, flat oval tablets without a shell, with a bevel, with a score on one side and on the lateral surfaces, marked R4, size 11.0 x 5.5 mm.

Pharmacotherapeutic group

Agents acting on the renin-angiotensin system. Angiotensin-converting enzyme (ACE) inhibitors. ATC code C09A A05.

Pharmacological properties

Pharmacodynamics.

Mechanism of action.

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 contributes to the reduction of aldosterone secretion. The response to monotherapy with ACE inhibitors was on average less pronounced in black (Afro-Caribbean) hypertensive patients (a population with a low-renin state in hypertension) than in patients of other races.

Antihypertensive properties. Administration of ramipril causes a significant decrease in peripheral arterial resistance. In general, there are no significant changes in renal plasma flow and glomerular filtration rate. Administration of ramipril to 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 antihypertensive effect after a single dose 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 is maintained for 24 hours.

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

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

Heart failure. In addition to conventional therapy with diuretics and, if necessary, cardiac glycosides, ramipril has been shown to be effective in patients with NYHA functional classes II-IV. The drug has beneficial effects on cardiac hemodynamics (reduction of left and right ventricular filling pressures, total peripheral vascular resistance, increase in cardiac output and improvement of cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety.

Prevention of cardiovascular diseases / nephroprotection.

A placebo-controlled prevention study (the HOPE study) was conducted in over 9,200 patients who received ramipril in addition to standard therapy. The study included patients at high risk of cardiovascular disease after 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, both individually and in combination (primary composite endpoint).

Table 1. 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 study participants receiving ramipril and 149 (8.4%) of the study participants receiving placebo developed significant nephropathy, corresponding to a relative risk reduction of 24%; 95% CI [3-40], p = 0.027.

The REIN study, a multicenter, randomized, double-blind, placebo-controlled, parallel-group study, was conducted to evaluate the effect of ramipril treatment on the magnitude of the decline in glomerular filtration rate (GFR) in 352 normotensive or hypertensive patients (aged 18–70 years) with mild (mean urinary protein excretion > 1 and < 3 g/day) or severe proteinuria (≥ 3 g/day) due to chronic non-diabetic nephropathy. Both subgroups were prospectively stratified.

The results of the main analysis of patients with the most severe proteinuria (the subgroup that discontinued early because of proven benefit in the ramipril group) showed that the mean rate of decline in GFR was lower with ramipril than with placebo: −0.54 (0.66) vs −0.88 (1.03) mL/min/month, p = 0.038. Thus, the between-group difference was 0.34 [0.03–0.65] mL/min/month and approximately 4 mL/min/year; 23.1% of patients in the ramipril group reached the combined secondary endpoint of doubling of plasma creatinine and/or end-stage renal disease (requiring hemodialysis or kidney transplantation) compared with 45.5% in the placebo group (p = 0.02).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Two large randomized controlled trials [ONTARGET (Telmisartan Monotherapy and Ramipril Combination Outcome Study) and VA NEPHRON-D (Veterans Diabetic Nephropathy Study)] have investigated 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 of particular interest (hyperkalemia, hypotension, and renal dysfunction).

Paediatric population In a randomised, double-blind, placebo-controlled clinical trial involving 244 paediatric hypertensive patients (73% of whom had primary hypertension) aged 6-16 years, participants were treated with low, medium or high doses of ramipril to achieve plasma concentrations of ramiprilat corresponding to the adult dose range of 1.25 mg; 5 mg and 20 mg based on body weight. After a 4-week period, 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 this was not statistically significant for the return to baseline pressure in all dose groups of the ramipril dose range studied [low dose (0.625 mg - 2.5 mg), medium dose (2.5 mg - 10 mg) or high dose (5 mg - 20 mg)] based on body weight. Ramipril did not show a linear dose-response effect in the pediatric population studied.

Pharmacokinetics.

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract: peak plasma concentrations are reached within one hour. Based on the amount of substance recovered in the urine, 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%.

Peak plasma concentrations of ramiprilat, the only active metabolite of ramipril, are reached 2–4 hours after administration.

Under conditions of usual doses (once a day), steady-state plasma concentrations are achieved on the 4th day of drug administration.

Distribution.

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

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

Elimination. Excretion of metabolites is mainly renal. 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 repeated doses of ramipril once daily, the effective half-life is 13–17 hours for doses of 5–10 mg and longer for lower doses of 1.25–2.5 mg. The difference is due to the saturable capacity of the enzyme for binding ramiprilat.

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

Patients with renal impairment (see section 4.2). Renal excretion of ramiprilat is reduced in patients with impaired renal function, and renal clearance of ramiprilat is proportional 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 hepatic function (see section 4.2). In patients with hepatic impairment, the metabolism of ramipril to ramiprilat is slowed due to reduced hepatic esterase activity, and plasma levels of ramipril are increased in these patients. Peak ramiprilat concentrations in these patients, however, were not different from those in subjects with normal hepatic function.

Breastfeeding: After a single oral dose of ramipril, levels in breast milk were below the detection limit. However, the effect of multiple dosing is unknown.

Preclinical safety data. When administered orally to rodents and dogs, ramipril was found to be devoid of acute toxic effects. Studies with long-term oral administration of the drug were conducted in rats, dogs and monkeys. In all three species, changes in electrolyte balance and blood picture were observed. In dogs and monkeys receiving the drug at a dose of 250 mg/kg body weight per day, a significant increase in the juxtaglomerular apparatus was observed, which is a manifestation of the pharmacodynamic activity of ramipril. Rats, dogs and monkeys tolerated daily doses of the drug, which were 2; 2.5 and 8 mg/kg body weight per day, respectively. At the same time, they did not experience any undesirable effects.

Reproductive toxicity studies conducted in rats, rabbits and monkeys did not reveal any teratogenic properties of the drug. No adverse effects on fertility were observed in either male or female rats.

Administration of ramipril to female rats during pregnancy and lactation resulted in irreversible renal damage (dilation of the renal pelvis) in the offspring at doses of 50 mg/kg body weight per day and above.

Numerous mutagenicity tests using various test systems have not revealed any mutagenic or genotoxic properties of ramipril.

Indication

Treatment of arterial hypertension.

Prevention of cardiovascular disease: reduction of cardiovascular morbidity and mortality in patients with:

severe cardiovascular disease of atherothrombotic origin (history of ischemic heart disease or stroke or peripheral vascular disease);

diabetes who have at least one cardiovascular risk factor (see section "Pharmacological properties").

Treatment of kidney disease:

initial glomerular diabetic nephropathy, as evidenced by the presence of microalbuminuria;

severe glomerular diabetic nephropathy, as evidenced by the presence of macroproteinuria, in patients who have at least one cardiovascular risk factor (see section "Pharmacological properties");

severe glomerular non-diabetic nephropathy, as evidenced by the presence of macroproteinuria ≥ 3 g/day (see section "Pharmacological properties").

Treatment of heart failure accompanied by clinical manifestations.

Secondary prevention after acute myocardial infarction: reduction of mortality during the acute stage of myocardial infarction in patients with clinical signs of heart failure, provided that treatment is started more than 48 hours after the onset of acute myocardial infarction.

Contraindication

Hypersensitivity to the active substance or to any of the excipients included in the preparation, or to other ACE (angiotensin-converting enzyme) inhibitors (see section "Composition").

History of angioedema (hereditary, idiopathic or previously experienced while taking ACE inhibitors or angiotensin II receptor antagonists).

Concomitant use with sacubitril/valsartan (see sections “Special warnings and precautions for use” and “Interaction with other medicinal products and other forms of interaction”)

Significant bilateral renal artery stenosis or renal artery stenosis in the presence of a single functioning kidney.

Pregnancy and planning pregnancy (see section "Use during pregnancy or breastfeeding").

Ramipril should not be used in patients with hypotension or hemodynamically unstable conditions.

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

The concomitant use of ACE inhibitors and extracorporeal therapies that result in contact of blood with negatively charged surfaces should be avoided (see section 4.5).

Interaction with other medicinal products and other types of interactions

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 worsening renal function (including acute renal failure) compared with the use of a single agent affecting the RAAS (see sections 5.1, 5.3 and 5.4).

Extracorporeal therapy methods that result in contact of blood with negatively charged surfaces, such as dialysis or hemofiltration using certain high flux membranes (e.g. polyacrylonitrile membranes) and low density lipoprotein apheresis using dextran sulfate, due to the increased risk of severe anaphylactoid reactions (see section 4.3). If such treatment is necessary, consideration should be given to using a different dialysis membrane or a different class of antihypertensive agent.

The combined use of Hartil® with aliskiren-containing drugs is contraindicated in patients with diabetes mellitus or moderately severe renal impairment and is not recommended for other categories of patients (see sections “Contraindications” and “Special Instructions for Use”).

Combinations requiring precautions.

Potassium salts, heparin, potassium-sparing diuretics and other active substances that increase plasma potassium levels (including angiotensin II antagonists, trimethoprim and its fixed combinations with sulfamethoxazole, tacrolimus, ciclosporin). Hyperkalaemia may occur, therefore careful monitoring of plasma potassium levels is necessary.

Antihypertensive drugs (e.g. diuretics) and other substances that may lower blood pressure (e.g. nitrates, tricyclic antidepressants, anaesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). An increased risk of arterial hypotension should be expected (see section "Special warnings and precautions for use" for diuretics).

Vasopressor sympathomimetics and other substances (e.g. isoproterenol, dobutamine, dopamine, epinephrine) that may reduce the antihypertensive effect of Hartil®. Close monitoring of blood pressure is recommended.

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatics and other substances that may cause changes in the blood picture. Increased likelihood of hematological reactions (see section "Special instructions").

Lithium salts: ACE inhibitors may reduce lithium excretion, which may lead to increased lithium toxicity. Lithium levels should be carefully monitored.

Antidiabetic agents, including insulin. Hypoglycemic reactions may occur. Close monitoring of blood glucose levels is recommended.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid. The antihypertensive effect of Hartil® is expected to be reduced. Furthermore, the concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of worsening of renal function and an increase in blood potassium levels.

Salt. Excessive salt consumption may weaken the hypotensive effect of the drug.

Specific hyposensitization. ACE inhibition increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom. It is believed that this effect may also be observed for other allergens.

Trimethoprim or the combination of trimethoprim and sulfamethoxazole (co-trimoxazole): Patients taking ACE inhibitors with the combination of trimethoprim and sulfamethoxazole are at increased risk of hyperkalemia.

Selective immunosuppressants or mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. There may be an increased risk of angioedema in patients receiving concomitant treatment with mTOR inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin. Such therapy should be initiated with caution (see section 4.4).

Neprilysin (NEP) inhibitors: A potential increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and a NEP (neutral endopeptidase) inhibitor, such as racecadotril (see section 4.4).

Sacubitril/valsartan: Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema.

Application features

Special categories of patients.

Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists is contraindicated during pregnancy. Unless continued ACE inhibitor/angiotensin II receptor antagonist 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, treatment with ACE inhibitors/angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.8).

Concomitant use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren has been shown to increase the risk of hypotension, hyperkalaemia and deterioration 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 and careful 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.

Patients at particular risk of hypotension.

Patients with markedly increased activity of the renin-angiotensin-aldosterone system (RAAS). Patients with markedly increased RAAS are at risk of a sudden significant decrease in blood pressure and deterioration of renal function due to ACE inhibition, especially if an ACE inhibitor or concomitant diuretic is to be administered for the first time or the dose is to be increased for the first time.

A significant increase in RAAS activity, which requires 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 perform extensive surgical interventions or during anesthesia with the use of drugs that cause arterial hypotension.

It is generally recommended that dehydration, hypovolemia, or electrolyte depletion be corrected before treatment is initiated (however, in patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

In patients with impaired liver function, the response to treatment with Hartil® may be either enhanced or reduced. In addition, in patients with severe cirrhosis of the liver, accompanied by edema and/or ascites, the activity of the renin-angiotensin system (RAS) may be significantly increased; therefore, special caution should be exercised when treating these patients.

Transient or persistent heart failure after myocardial infarction.

Patients at risk of cardiac or cerebral ischemia in the event of acute arterial hypotension. Special medical supervision is required in the initial phase of treatment.

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

Surgery: If possible, treatment with angiotensin-converting enzyme inhibitors such as ramipril should be discontinued 1 day before surgery.

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

Angioedema: Angioedema has been reported in patients treated with ACE inhibitors, including ramipril (see section 4.8).

The risk of angioedema is increased in patients receiving concomitant medications that may induce angioedema, such as mammalian target of rapamycin (mTOR) inhibitors (e.g. temsirolimus, everolimus, sirolimus) or vildagliptin or neprilysin (NEP) inhibitors (e.g. racecadotril).

The combination of ramipril with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections “Contraindications” and “Interaction with other medicinal products and other types of interactions”).

In case of angioedema, Hartil® should be discontinued. Emergency treatment should be initiated immediately. The patient should be under medical supervision for at least 12–24 hours and may be discharged after complete resolution of symptoms.

Cases of intestinal angioedema have been reported in patients treated with ACE inhibitors, including Hartil® (see section 4.8). These patients presented with abdominal pain (with or without nausea/vomiting).

Electrolyte balance control. Hyperkalemia. Hyperkalemia has been observed in some patients treated with ACE inhibitors, including Hartil®. Patients at risk for hyperkalemia include patients with renal insufficiency, patients over 70 years of age, patients with uncontrolled diabetes mellitus, patients taking potassium salts, potassium-sparing diuretics, and other active substances that increase plasma potassium, or patients with conditions such as dehydration, acute cardiac decompensation, metabolic acidosis. If the combined use of the above drugs is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other types of interactions").

Electrolyte balance control. Hyponatremia. Syndrome of inappropriate antidiuretic hormone secretion with subsequent development of hyponatremia has been observed in some patients treated with ramipril. It is recommended to regularly monitor serum sodium levels in the elderly and in other patients at risk of developing hyponatremia.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia have been observed rarely. Bone marrow suppression has also been reported. Monitoring of the white blood cell count is recommended to detect possible leukopenia. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagen disease (e.g. systemic lupus erythematosus or scleroderma) or those taking other medicinal products that may cause changes in the blood picture (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 non-black patients. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients than in non-black patients. This may be because black patients with hypertension are more likely to have low-renin hypertension.

Cough. Cough has been reported with ACE inhibitors. The cough is typically non-productive, persistent, and resolves after discontinuation of therapy. The possibility of cough due to ACE inhibitors should be considered in the differential diagnosis of cough.

Lactose. If you are lactose intolerant, please note that each 5 mg tablet contains 96.47 mg and each 10 mg tablet contains 193.2 mg of lactose monohydrate.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Sodium: This medicinal product contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially “sodium-free”.

Use during pregnancy or breastfeeding

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

Breastfeeding. Due to the lack of information regarding the use of ramipril during breastfeeding (see section "Pharmacological properties"), this drug is not recommended for use in breastfeeding women and alternative treatments with better established safety profiles during lactation are preferable, especially while breastfeeding a newborn or preterm infant.

Ability to influence reaction speed when driving vehicles or other mechanisms

Some side effects (e.g. symptoms of low blood pressure, such as dizziness) may impair the patient's ability to concentrate and reduce the speed of their reactions, which is risky in situations where these qualities are particularly important (e.g. when driving vehicles or operating other machinery).