Tratace®

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT TRITACE® (TRITACE®)

Composition:

Active substance: ramipril;

1 tablet of 5 mg contains 5 mg of ramipril;

Excipients: hypromellose, pregelatinized starch, microcrystalline cellulose, iron oxide red (E 172), sodium stearyl fumarate;

1 tablet of 10 mg contains 10 mg of ramipril;

Excipients: hypromellose, pregelatinized starch, microcrystalline cellulose, sodium stearyl fumarate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: pale red, elongated tablets with a break line on both sides; upper imprint*: 5 and company logo, lower imprint*: 5 and HMP (*the order of imprinting may vary);

10 mg tablets: white or almost white, elongated tablets with a break line on both sides; upper imprint: HMO/HMO, lower imprint: absent.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Single-component ACE inhibitors. Ramipril. ATC code C09A A05.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action. Ramiprilat, the active metabolite of prodrug ramipril, is an inhibitor of the enzyme dipeptidyl carboxypeptidase I (synonyms: angiotensin-converting enzyme; kininase II). In blood plasma and tissues, this enzyme catalyzes the conversion of angiotensin I to angiotensin II (an active vasoconstrictor substance) and the breakdown of the active vasodilator bradykinin. Reduced formation of angiotensin II and inhibition of bradykinin breakdown lead to vasodilation. Since angiotensin II also stimulates the release of aldosterone, ramiprilat causes a reduction in aldosterone secretion. The response to monotherapy with ACE inhibitors has generally been less pronounced in patients of non-Caucasian race (African-Caribbean origin) with arterial hypertension (a population typically characterized by low renin levels in arterial hypertension) compared to patients of other races.

Antihypertensive properties. Administration of ramipril leads to a significant reduction in peripheral arterial resistance. Generally, no substantial changes in renal plasma flow or glomerular filtration rate occur. Administration of ramipril to patients with arterial hypertension results in reduced blood pressure in both supine and upright positions, without compensatory increase in heart rate.

In most patients, the antihypertensive effect begins within 1–2 hours after oral administration of a single dose. The maximum effect after a single oral dose usually occurs within 3–6 hours. The antihypertensive effect after a single dose generally persists for 24 hours.

With long-term treatment using ramipril, the maximum antihypertensive effect develops within 3–4 weeks. It has been demonstrated that the antihypertensive effect is maintained for up to 2 years with prolonged therapy.

Abrupt discontinuation of ramipril does not cause rapid or excessive increase in blood pressure (rebound phenomenon).

Heart failure. Ramipril has been proven effective in patients with NYHA functional class II–IV heart failure when used as an adjunct to conventional therapy with diuretics and, if necessary, cardiac glycosides. The drug exerts beneficial effects on cardiac hemodynamics (reduction in filling pressure of the left and right ventricles, total peripheral vascular resistance, increase in cardiac output, and improvement in cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety.

Prevention of cardiovascular disease / nephroprotection.

A preventive, placebo-controlled study (the HOPE study) involving over 9,200 patients who received ramipril in addition to standard therapy was conducted. This study included patients at high risk of 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, both individually and in combination (primary combined endpoint).

Table 1. 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
Death from any cause	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

During the MICRO-HOPE study, which was prospectively planned as part of the HOPE study, the effect of adding ramipril at a dose of 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 mellitus (and at least one cardiovascular risk factor).

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

The REIN study, a multicenter, randomized, double-blind, placebo-controlled parallel-group trial, was conducted to evaluate the effect of ramipril treatment on the rate of decline in glomerular filtration rate (GFR) in 352 patients with normal or elevated blood pressure (aged 18–70 years) who had mild (urinary protein excretion >1 to <3 g/24 hours) or severe proteinuria (≥3 g/24 hours) due to chronic non-diabetic nephropathy. Both subgroups were prospectively stratified.

The main analysis results in patients with the most severe proteinuria (a subgroup that prematurely discontinued the study because benefit from ramipril treatment was demonstrated) 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, approximately 4 mL/min/year; 23.1% of patients in the ramipril group reached the combined secondary endpoint—doubling of plasma creatinine concentration and/or end-stage renal disease (requiring hemodialysis or kidney transplantation)—compared to 45.5% in the placebo group (p = 0.02).

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 study included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of target organ damage. The VA NEPHRON-D study 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 or mortality, while an increased risk of hyperkalemia, acute kidney injury, and/or arterial hypotension was observed compared to monotherapy. Given the similar pharmacodynamic profiles of these agents, 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 Cardio-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 prematurely due to an increased risk of adverse clinical outcomes. In the aliskiren group compared to placebo, there was a higher incidence of cardiovascular death and stroke, as well as an increased frequency of serious adverse events of special interest (hyperkalemia, arterial hypotension, and renal dysfunction).

Secondary prevention after acute myocardial infarction. The AIRE study included over 2000 patients with ongoing or recent symptoms of heart failure following acute myocardial infarction. Ramipril treatment was initiated 3–10 days after the acute myocardial infarction. This study demonstrated that after a mean follow-up period of 15 months, mortality was 16.9% in the ramipril group and 22.6% in the placebo group. This corresponds to an absolute mortality reduction of 5.7% and a relative risk reduction of 27% (95% CI [11–40%]).

Pediatric population. In a randomized, double-blind, placebo-controlled clinical trial involving 244 pediatric patients (73% of whom had primary arterial hypertension) aged 6–16 years with arterial 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. At the end of the 4-week period, ramipril was ineffective on the primary endpoint—reduction in systolic blood pressure—although it reduced diastolic pressure at the highest dose in the tested range. It was shown that both medium and high doses of ramipril significantly reduced systolic and diastolic blood pressure in children with confirmed arterial hypertension.

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

Pharmacokinetics.

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration is reached within 1 hour. Based on the amount of substance detected in urine, the absorption extent is at least 56%, and food in the gastrointestinal tract does not significantly affect it. 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 intake. After administration of usual daily doses of ramipril, steady-state plasma concentration of ramiprilat is achieved by approximately day 4 of treatment.

Distribution. Plasma protein binding of ramipril is approximately 73%, and that 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 renal excretion. The decline in ramiprilat plasma concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme complex, ramiprilat exhibits a prolonged terminal elimination phase at very low plasma concentrations.

After repeated once-daily doses of ramipril, the effective half-life is 13–17 hours for doses of 5–10 mg and longer for lower doses (1.25–2.5 mg). This difference is due to the saturable binding capacity of the enzyme for ramiprilat.

After single oral doses, neither ramipril nor its metabolites were detected in breast milk. However, the effect of repeated dosing is unknown.

Patients with renal impairment (see section "Dosage and administration"). In patients with impaired renal function, renal excretion of ramiprilat is reduced, and the renal clearance of ramiprilat is proportional to creatinine clearance. This leads to elevated plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

Patients with hepatic impairment (see section "Dosage and administration"). In patients with impaired liver function, metabolism of ramipril to ramiprilat is slowed due to reduced activity of hepatic esterases, and plasma levels of ramipril are elevated. However, maximum concentrations of ramiprilat in these patients do not differ from those in individuals with normal liver function.

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

Pediatric population. The pharmacokinetic profile of ramipril was studied in 30 pediatric patients with arterial hypertension aged 2–16 years with body weight >10 kg. After administration of doses ranging from 0.05 to 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 was significantly correlated with the logarithm of body weight (p<0.01) and with drug dose (p<0.001). Clearance and volume of distribution increased proportionally with age within each dosing group. Administration of a 0.05 mg/kg dose in children achieved exposure levels comparable to those in adults receiving 5 mg ramipril. Administration of a 0.2 mg/kg dose in children resulted in exposure levels higher than those achieved with the maximum recommended adult dose of 10 mg daily.

Preclinical safety data. Oral administration of ramipril to rodents and dogs revealed no acute toxic effects. Long-term oral toxicity studies were conducted in rats, dogs, and monkeys. In all three species, changes in electrolyte balance and blood parameters were observed. In dogs and monkeys receiving 250 mg/kg/day, marked enlargement of the juxtaglomerular apparatus was noted, reflecting the pharmacodynamic activity of ramipril. Rats, dogs, and monkeys tolerated daily doses of 2, 2.5, and 8 mg/kg body weight, respectively, without adverse effects.

Reproductive toxicity studies in rats, rabbits, and monkeys revealed no teratogenic properties of the drug. No adverse effects on fertility were observed in either male or female rats.

Administration of ramipril to pregnant and lactating rats resulted in irreversible kidney damage (renal pelvis dilation) in offspring at doses of 50 mg/kg/day and higher.

Numerous mutagenicity tests using various test systems revealed no mutagenic or genotoxic properties of ramipril.

Clinical characteristics.

Indications.

Treatment of arterial hypertension.

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

• Established atherothrombotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
• Diabetes mellitus with at least one cardiovascular risk factor (see section "Pharmacological properties").

Treatment of kidney disease:

• Early diabetic nephropathy, indicated by presence of microalbuminuria;
• Overt diabetic nephropathy, indicated by presence of macroproteinuria, in patients with at least one cardiovascular risk factor (see section "Pharmacological properties");
• Overt non-diabetic glomerular nephropathy, indicated by presence of macroproteinuria ≥ 3 g/day (see section "Pharmacological properties").

Treatment of heart failure associated with clinical symptoms.

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

Contraindications.

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

History of angioedema (hereditary, idiopathic, or previously experienced during treatment with ACE inhibitors or angiotensin II receptor antagonists).

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

Significant bilateral renal artery stenosis or renal artery stenosis in a patient with a single functioning kidney.

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

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

Concomitant use of Tritace® with medicinal products containing aliskiren 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").

Concomitant use of ACE inhibitors and extracorporeal treatment methods leading to blood contact with negatively charged surfaces should be avoided (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

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

Contraindicated combinations.

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 ramipril should be initiated only 36 hours after the last dose of sacubitril/valsartan. Treatment with sacubitril/valsartan should be initiated only 36 hours after the last dose of ramipril.

Extracorporeal treatment methods involving 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 using dextran sulfate, are contraindicated due to increased risk of severe anaphylactoid reactions (see section "Contraindications"). If such treatment is necessary, consideration should be given to using an alternative dialysis membrane or another class of antihypertensive agents.

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, cyclosporine). Hyperkalemia may occur; therefore, plasma potassium levels should be closely monitored.

Antihypertensive medicinal products (e.g., diuretics) and other substances capable of lowering blood pressure (e.g., nitrates, tricyclic antidepressants, anesthetics, alcohol, baclofen, alfuzosin, doxazosin, prazosin, tamsulosin, terazosin). Increased risk of arterial hypotension should be anticipated (see section "Special precautions for use" regarding diuretics).

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

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

Lithium salts. ACE inhibitors may reduce lithium excretion, potentially leading to increased lithium toxicity. Lithium levels should be closely monitored.

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

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

Salt. Excessive salt intake may reduce the antihypertensive effect of the medicinal product.

Specific allergen immunotherapy (hyposensitization). Due to ACE inhibition, the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom may increase. This effect is also considered possible with other allergens.

mTOR (mammalian target of rapamycin) inhibitors or vildagliptin. Increased risk of angioedema may occur in patients receiving concomitant therapy with mTOR inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin. Such therapy should be initiated with caution (see section "Special precautions for use").

Neprilysin inhibitors. There have been reports of a potential increased risk of angioedema with concomitant use of ACE inhibitors and neprilysin inhibitors (NEP), such as racecadotril (see section "Special precautions for use").

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

Special precautions for use.

Special patient groups

Pregnancy. Treatment with ACE inhibitors or angiotensin II receptor antagonists should not be initiated during pregnancy. Except in cases where continued treatment with an ACE inhibitor/angiotensin II receptor antagonist is absolutely necessary, patients who are planning to become pregnant should be switched to another antihypertensive agent considered safe during pregnancy. As soon as pregnancy is diagnosed, treatment with ACE inhibitors/angiotensin II receptor antagonists should be discontinued immediately and, if necessary, therapy with another agent should be initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren increases the risk of arterial hypotension, hyperkalaemia, 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 and careful 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.

Patients at particular risk of arterial hypotension.

Patients with markedly increased renin-angiotensin-aldosterone system activity. In patients with markedly increased renin-angiotensin-aldosterone system activity, there is a risk of sudden, significant reduction in blood pressure and worsening renal function due to ACE inhibition, particularly when the ACE inhibitor or concomitant diuretic is used for the first time or the dose is increased for the first time. Markedly increased activity of the renin-angiotensin-aldosterone system 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 of blood 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 anaesthesia with agents that may cause arterial hypotension.

Generally, correction of dehydration, hypovolemia, or electrolyte depletion is recommended prior to starting treatment (however, for patients with heart failure, such corrective measures should be carefully weighed against the risk of volume overload).

Transient or persistent heart failure after myocardial infarction.

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

Elderly patients. See section "Dosage and administration".

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

Monitoring of renal function. Renal function should be assessed before and during treatment, and dosage adjusted accordingly, particularly during the first weeks of therapy. Close monitoring is especially required in patients with impaired renal function (see section "Dosage and administration"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation, as well as in cases of renal vascular disease, including patients with hemodynamically significant unilateral renal artery stenosis.

Angioedema. Angioedema has been observed in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). The risk of angioedema is increased in patients receiving concomitant medicinal products that may cause angioedema, such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus) or vildagliptin or neprilysin inhibitors (NEP) (such as racecadotril).

Combination of ramipril with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

If angioedema occurs, treatment with Tritace® should be discontinued immediately. Emergency therapy must be initiated promptly. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

Cases of intestinal angioedema have been reported in patients receiving ACE inhibitors, including Tritace® (see section "Adverse reactions"). These patients presented with abdominal pain (with or without nausea/vomiting).

Anaphylactic reactions during desensitization. The likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom and other allergens are increased during ACE inhibitor therapy. Treatment with Tritace® should be temporarily discontinued prior to desensitization procedures.

Monitoring of electrolyte balance. Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including Tritace®. Patients at risk of hyperkalaemia 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, or patients with conditions such as dehydration, acute heart decompensation, or metabolic acidosis. If concomitant use of the above-mentioned agents is considered appropriate, regular monitoring of plasma potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Monitoring of electrolyte balance. Hyponatraemia. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) leading to hyponatraemia has been observed in some patients receiving ramipril. Regular monitoring of serum sodium levels is recommended in elderly patients and in other patients at risk of developing hyponatraemia.

Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leukopenia, monitoring of white blood cell counts 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 receiving other medicinal products that may cause blood count abnormalities (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

Ethnic differences. ACE inhibitors cause angioedema more frequently in black patients than in patients of other races. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in black patients compared to patients of other races. This may be due to the higher prevalence of low-renin hypertension in black patients with arterial hypertension.

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

Sodium content. This medicinal product contains less than 1 mmol (23 mg) of sodium per tablet, i.e., it is essentially "sodium-free".

Use during pregnancy or breastfeeding.

Pregnancy. This medicinal product is contraindicated in pregnant women or women who are planning to become pregnant. If pregnancy occurs during therapy, treatment should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during pregnancy (see section "Contraindications").

Breastfeeding. Due to lack of information on the use of ramipril during breastfeeding (see section "Pharmacological properties"), this medicinal product is not recommended for women who are breastfeeding. Preferably, other medicinal products with a more favorable safety profile during lactation should be used, especially when breastfeeding newborns or preterm infants.

Ability to influence reaction speed when driving or operating machinery. Some adverse effects (e.g., symptoms of low blood pressure such as dizziness) may impair a patient's ability to concentrate and reduce reaction speed, posing a risk in situations where these abilities are particularly important (e.g., when driving vehicles or operating machinery).

This is generally possible at the beginning of treatment or when switching from other therapies to treatment with Tritace®. After taking the first dose or any subsequent dose increase, driving vehicles or operating machinery should be avoided for several hours.

Method of Administration and Dosage

For oral use.

Tritace® is recommended to be taken daily at the same time. Tritace® can be taken before, during, or after meals, as food intake does not affect the bioavailability of the drug. Tritace® tablets should be swallowed whole with water. They must not be chewed or crushed.

If the prescribed dose cannot be administered, ramipril in the corresponding dosage strength should be used.

Adults.

Patients receiving diuretics. At the beginning of treatment with Tritace®, arterial hypotension may occur, and its development is more likely in patients concurrently receiving diuretics. In such cases, caution is recommended, as these patients may have reduced circulating blood volume and/or electrolyte depletion.

If possible, it is advisable to discontinue diuretic therapy 2–3 days before initiating treatment with Tritace® (see section "Special Warnings and Precautions for Use").

In hypertensive patients for whom discontinuation of diuretics is not feasible, treatment with Tritace® should be initiated at a dose of 1.25 mg (use ramipril in the corresponding dosage strength). Renal function and serum potassium levels should be closely monitored. Subsequent dosing of Tritace® should be adjusted according to the target blood pressure level.

Arterial hypertension.

The dose should be individually adjusted according to the patient's condition (see section "Special Warnings and Precautions for Use") and blood pressure monitoring results. Tritace® may be used as monotherapy or in combination with other classes of antihypertensive medicinal products (see sections "Contraindications", "Special Warnings and Precautions for Use", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Pharmacodynamics").

Initial dose. Treatment with Tritace® should be initiated gradually, starting with the recommended initial dose of 2.5 mg (use ramipril in the corresponding dosage strength) once daily.

In patients with significant activation of the renin-angiotensin-aldosterone system, marked reduction in blood pressure may occur after the initial dose. For such patients, the recommended initial dose is 1.25 mg (use ramipril in the corresponding dosage strength), and treatment should be initiated under medical supervision (see section "Special Warnings and Precautions for Use").

Dose titration and maintenance dose. The dose may be doubled every 2–4 weeks until the target blood pressure level is achieved; the maximum dose of Tritace® is 10 mg once daily. The drug is generally administered once daily.

Prevention of cardiovascular diseases.

Initial dose. The recommended initial dose of Tritace® is 2.5 mg (use ramipril in the corresponding dosage strength) once daily.

Dose titration and maintenance dose. Depending on individual tolerability, the dose should be gradually increased. It is recommended to double the dose after 1–2 weeks of treatment, and then increase it to the target maintenance dose of 10 mg once daily after another 2–3 weeks.

Treatment of kidney disease.

Patients with diabetes and microalbuminuria.

Initial dose. The recommended initial dose of Tritace® is 1.25 mg (use ramipril in the corresponding dosage strength) once daily.

Dose titration and maintenance dose. Depending on individual tolerability during continued treatment, the dose is increased. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg (use ramipril in the corresponding dosage strength), and then increased to 5 mg after another 2 weeks of treatment.

Patients with diabetes and at least one cardiovascular risk factor.

Initial dose. The recommended initial dose of Tritace® is 2.5 mg (use ramipril in the corresponding dosage strength) once daily.

Dose titration and maintenance dose. Depending on individual tolerability during continued treatment, the dose is increased. After 1–2 weeks of treatment, the daily dose of Tritace® should be doubled to 5 mg, and then increased to 10 mg after another 2–3 weeks of treatment. The target daily dose is 10 mg.

Patients with non-diabetic nephropathy, indicated by macroproteinuria ≥ 3 g/day.

Initial dose. The recommended initial dose of Tritace® is 1.25 mg (use ramipril in the corresponding dosage strength) once daily.

Dose titration and maintenance dose. Depending on individual tolerability, the dose is increased during continued treatment. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg (use ramipril in the corresponding dosage strength), and then increased to 5 mg after another 2 weeks of treatment.

Heart failure with clinical manifestations.

Initial dose. For patients whose condition has been stabilized with diuretic therapy, the recommended initial dose is 1.25 mg (use ramipril in the corresponding dosage strength) once daily.

Dose titration and maintenance dose. The dose of Tritace® should be titrated by doubling every 1–2 weeks until the maximum daily dose of 10 mg is reached. The dose should preferably be divided into two daily doses.

Secondary prevention after acute myocardial infarction in the presence of heart failure.

Initial dose. 48 hours after the onset of myocardial infarction, patients with clinically and hemodynamically stable conditions are given an initial dose of 2.5 mg (use ramipril in the corresponding dosage strength) twice daily for 3 days. If the initial dose of 2.5 mg (use ramipril in the corresponding dosage strength) is poorly tolerated, then a dose of 1.25 mg (use ramipril in the corresponding dosage strength) twice daily should be administered for 2 days, followed by an increase to 2.5 mg (use ramipril in the corresponding dosage strength) and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg (use ramipril in the corresponding dosage strength) twice daily, treatment should be discontinued.

Dose titration and maintenance dose. Subsequently, the daily dose should be increased by doubling every 1–3 days until the target maintenance dose of 5 mg twice daily is reached.

Whenever possible, the maintenance daily dose should be divided into two doses.

If the dose cannot be increased to 2.5 mg (use ramipril in the corresponding dosage strength) twice daily, treatment should be discontinued. Experience with treatment of patients with severe (NYHA functional class IV) heart failure immediately after myocardial infarction is still limited. However, if treatment of such patients with this drug is considered necessary, therapy should be initiated at a dose of 1.25 mg (use ramipril in the corresponding dosage strength) once daily, and any dose increase should be performed with extreme caution.

Special patient populations.

Patients with renal impairment. The daily dose for patients with renal impairment depends on creatinine clearance (see section "Pharmacological Properties"):

• if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose (2.5 mg/day (use ramipril in the corresponding dosage strength)) is required, and the maximum daily dose is 10 mg;
• if creatinine clearance is 30–60 mL/min, no adjustment of the initial dose (2.5 mg/day (use ramipril in the corresponding dosage strength)) is required, and the maximum daily dose is 5 mg;
• if creatinine clearance is 10–30 mL/min, the initial daily dose is 1.25 mg/day (use ramipril in the corresponding dosage strength), and the maximum daily dose is 5 mg;
• hypertensive patients undergoing hemodialysis: ramipril is only minimally removed during hemodialysis; the initial dose is 1.25 mg (use ramipril in the corresponding dosage strength), and the maximum daily dose is 5 mg; the drug should be taken several hours after a hemodialysis session.

Patients with hepatic impairment (see section "Pharmacological Properties"). Treatment with Tritace® in patients with hepatic impairment should be initiated under close medical supervision, and the maximum daily dose in such cases should not exceed 2.5 mg (use ramipril in the corresponding dosage strength).

Elderly patients. The initial dose should be lower, and subsequent dose titration should be performed more gradually due to the higher risk of adverse effects, especially in very elderly and frail patients. In such cases, a lower initial dose of 1.25 mg ramipril (use ramipril in the corresponding dosage strength) should be prescribed.

Also refer to the information provided above regarding dosing for patients receiving diuretics.

Children. Tritace® is not recommended for use in children (under 18 years of age), as there is insufficient data on efficacy and safety of this medicinal product in this patient population.

Overdose.

Symptoms associated with overdose of ACE inhibitors may include excessive peripheral vasodilation (with marked arterial hypotension, shock), bradycardia, electrolyte imbalances, and renal failure. Close monitoring of the patient is required, along with symptomatic and supportive therapy. Proposed therapeutic measures include primary detoxification (gastric lavage, administration of adsorbents), and measures aimed at restoring stable hemodynamics, including administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from systemic circulation by hemodialysis.

Adverse reactions

The safety profile of Tritace® includes data on persistent cough and reactions caused by arterial hypotension. Serious adverse reactions include angioneurotic edema, hyperkalemia, hepatic or renal dysfunction, pancreatitis, severe skin reactions, and neutropenia/agranulocytosis.

The frequency of adverse reactions is classified as follows: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000); not known (cannot be estimated from the available data). Within each category, adverse events are listed in order of decreasing severity.

Table 2.

System organ class	Adverse reactions by frequency
	Common	Uncommon	Rare	Very rare	Not known
Cardiac disorders		Myocardial ischemia, including angina or myocardial infarction; tachycardia; arrhythmia; palpitations; peripheral edema
Blood and lymphatic system disorders		Eosinophilia	Decreased leukocyte count (including neutropenia or agranulocytosis), decreased erythrocyte count, decreased hemoglobin levels, decreased platelet count		Bone marrow failure, pancytopenia, hemolytic anemia
Nervous system disorders	Headache, dizziness	Vertigo, paresthesia, ageusia, dysgeusia	Tremor, loss of balance		Cerebral ischemia, including ischemic stroke and transient ischemic attack; psychomotor impairment; burning sensation; parosmia
Eye disorders		Visual disturbances, including blurred vision	Conjunctivitis
Ear and labyrinth disorders			Hearing impairment, tinnitus
Respiratory, thoracic and mediastinal disorders	Non-productive irritative cough, bronchitis, sinusitis, dyspnea	Bronchospasm, including asthma exacerbation; nasal congestion
Gastrointestinal disorders	Inflammatory conditions in the gastrointestinal tract, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting	Pancreatitis (in isolated cases fatal outcomes reported exclusively with ACE inhibitors), increased pancreatic enzyme levels, angioedema of the small intestine, upper abdominal pain, including associated with gastritis, constipation, dry mouth	Glossitis		Aphthous stomatitis
Renal and urinary disorders		Renal function impairment, including acute renal failure; increased urine output, worsening of underlying proteinuria, increased blood urea levels, increased serum creatinine levels
Skin and subcutaneous tissue disorders	Rash, including maculopapular	Angioedema; in very rare cases – airway obstruction due to angioedema, which may be fatal; pruritus, hyperhidrosis	Exfoliative dermatitis, urticaria, onycholysis	Photosensitivity reaction	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pemphigus, exacerbation of psoriasis, psoriatic dermatitis, pemphigoid or lichenoid exanthema or enanthema, alopecia
Musculoskeletal and connective tissue disorders	Muscle cramps, myalgia	Arthralgia
Endocrine disorders					Syndrome of inappropriate antidiuretic hormone secretion (SIADH)
Metabolism and nutrition disorders	Increased blood potassium levels	Anorexia, decreased appetite			Decreased blood sodium levels
Vascular disorders	Arterial hypotension, orthostatic hypotension, syncope	Hot flushes	Vascular stenosis, hypoperfusion, vasculitis		Raynaud's phenomenon
General disorders	Chest pain, fatigue	Pyrexia	Asthenia
Immune system disorders					Anaphylactic and anaphylactoid reactions, increased levels of antinuclear antibodies
Hepatobiliary disorders		Elevated liver enzymes and/or conjugated bilirubin	Cholestatic jaundice, hepatic cell damage		Acute liver failure, cholestatic or cytolytic hepatitis (in very rare cases with fatal outcome)
Reproductive system and breast disorders		Transient erectile impotence, decreased libido			Gynecomastia
Psychiatric disorders		Depressed mood, anxiety, nervousness, restlessness, sleep disturbances, including somnolence	Confusional state		Attention disorders

Pediatric population. The safety of ramipril was studied in 325 children and adolescents aged 2–16 years in two clinical trials. According to the results, the nature and severity of adverse reactions in children were similar to those observed in adults; however, the frequency of certain reactions was higher in children than in adults, namely:

Tachycardia, nasal congestion, and rhinitis: common (i.e., from ≥ 1/100 to < 1/10) in the pediatric population and uncommon (i.e., from ≥ 1/1000 to < 1/100) in adult patients.

Conjunctivitis: common (i.e., from ≥ 1/100 to < 1/10) in the pediatric population and rare (i.e., from ≥ 1/10,000 to < 1/1000) in adult patients.

Tremor and urticaria: uncommon (i.e., from ≥ 1/1000 to < 1/100) in the pediatric population and rare (i.e., from ≥ 1/10,000 to < 1/1000) in adult patients.

The overall safety profile of ramipril in children and adults does not differ significantly.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after drug registration is an important measure. It enables continuous monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals should report any adverse reactions through the pharmacovigilance system of Ukraine.

Shelf life. 3 years.

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

Packaging. No. 28 (14x2): 14 tablets in a blister; 2 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer. SANOFI S.R.L.

Manufacturer's address and place of business.

S.S. 17 KM 22, SCOPIPITO (L'AQUILA), 67019, Italy