Ramipril astra

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT RAMIPRIL ASTRA (RAMIPRIL ASTRA)

Composition:

Active substance: ramipril;

One 5 mg tablet contains: ramipril 5 mg;

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

One 10 mg tablet contains: ramipril 10 mg;

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: flat cylindrical tablets with bevelled edges and a score line, pale pink to pink in color; specks on the tablet surface are permissible;

10 mg tablets: flat cylindrical tablets with bevelled edges and a score line, white or almost white.

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: ACE, 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. Reduction in angiotensin II formation 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 results in a significant reduction in peripheral arterial pressure. Significant changes in renal plasma flow or glomerular filtration rate usually do not occur. Use of ramipril in patients with arterial hypertension leads to a reduction in blood pressure both in the 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.

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

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

Heart failure. Ramipril has been proven effective in patients with heart failure (NYHA functional classes II–IV) when used as an adjunct to conventional therapy with diuretics and, if necessary, cardiac glycosides. The drug has a beneficial effect on cardiac hemodynamics (reduction in filling pressures 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 diseases / Nephroprotection

A preventive, placebo-controlled trial (the HOPE study) involving over 9,200 patients who received ramipril in addition to standard therapy was conducted. The study included patients at high risk of developing cardiovascular disease due to established 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 levels of total cholesterol, LDL-cholesterol, or smoking).

This study demonstrated that ramipril significantly and statistically reliably reduces the incidence of myocardial infarction, cardiovascular death, and stroke, both individually and in combination (primary composite endpoint).

Table 1

HOPE Study: Main Results

Parameter	Ramipril	Placebo	Relative risk (95 % confidence interval (CI))	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 compared with 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 aged 18–70 years with normal or elevated blood pressure who had mild (mean urinary protein excretion >1 to <3 g/day) or severe (≥3 g/day) proteinuria 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 was prematurely terminated because benefit from ramipril treatment had been demonstrated) showed that the mean monthly 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 with 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)] investigated 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 with type 2 diabetes and evidence of target organ damage. The VA NEPHRON-D study included patients with type 2 diabetes and diabetic nephropathy.

These studies did not show 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 characteristics of these drugs, these findings are also applicable to other ACE inhibitors and angiotensin II receptor antagonists.

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

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

Secondary prevention after acute myocardial infarction. The AIRE study included over 2000 patients with transient or persistent symptoms of heart failure following acute myocardial infarction. Ramipril treatment was initiated 3–10 days after the onset of 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 represents 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% with primary hypertension) aged 6–16 years with hypertension, participants received low, medium, or high doses of ramipril to achieve plasma concentrations of ramiprilat corresponding to adult dose ranges of 1.25 mg, 5 mg, and 20 mg, adjusted for body weight. After 4 weeks, ramipril was ineffective in reducing systolic blood pressure, the primary endpoint, but reduced diastolic blood pressure at the highest dose tested. It was shown that both medium and high doses of ramipril significantly reduced systolic and diastolic blood pressure in children with confirmed hypertension.

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

Pharmacokinetics.

Absorption. After oral administration, ramipril is rapidly absorbed from the gastrointestinal tract. Maximum plasma concentration (Cmax) is reached within 1 hour. Based on the amount of drug recovered in urine, the extent of absorption is at least 56%, and it is not significantly affected by the presence of food in the gastrointestinal tract. The bioavailability of the active metabolite ramiprilat after oral administration of ramipril at doses of 2.5 mg and 5 mg is 45%.

Cmax of ramiprilat, the sole active metabolite of ramipril, is reached 2–4 hours after ramipril administration. After repeated administration of once-daily ramipril at usual doses, steady-state plasma concentrations of ramiprilat are achieved by approximately day 4 of treatment.

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 glucuronides of ramipril and ramiprilat.

Elimination. Metabolites are primarily excreted via the kidneys. The decline in plasma ramiprilat concentration is multiphasic. Due to strong saturable binding to ACE and slow dissociation from the enzyme, ramiprilat has 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 a single oral dose, 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, the metabolism of ramipril to ramiprilat is slowed due to reduced hepatic esterase activity, and plasma levels of ramipril are elevated. However, the maximum concentration of ramiprilat in these patients does not differ from that in individuals with normal liver function.

Breastfeeding. After a single oral dose of ramipril, its concentration in breast milk was 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 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. Cmax of ramiprilat was reached within 2–3 hours. Ramiprilat clearance was strongly correlated with the logarithm of body weight (p < 0.01) and with the dose of the drug (p < 0.001). Clearance and volume of distribution increased proportionally with age within each dosing group. Administration of a dose of 0.05 mg/kg in children achieved exposure levels comparable to those in adults receiving a 5 mg dose of ramipril. Administration of a dose of 0.2 mg/kg in children resulted in exposure levels higher than those achieved with the maximum recommended dose of 10 mg daily in adults.

Preclinical safety data. Oral administration of ramipril to rodents and dogs did not reveal acute toxic effects. Long-term oral toxicity studies were conducted in rats, dogs, and monkeys. Electrolyte imbalances and hematological changes were observed in all three species. In dogs and monkeys receiving ramipril at 250 mg/kg/day, marked increases in the juxtaglomerular apparatus were observed, 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 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 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 did not reveal 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 atherosclerotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
• diabetes mellitus and at least one cardiovascular risk factor (see section "Pharmacological properties").

Treatment of kidney disease:

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

Treatment of heart failure with clinical manifestations.

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 contained in the medicinal product, or to other ACE 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 "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").

Severe 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 or breastfeeding").

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

Concomitant use of Ramipril Astra with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (eGFR < 60 mL/min/1.73 m²) (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other types of interactions").

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 types of interactions").

Interaction with other medicinal products and other types of interactions.

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 reactions such as arterial hypotension, hyperkalemia, and renal function impairment (including acute renal failure), compared to treatment with a single RAAS-acting agent (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

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"). Ramipril therapy should be initiated only 36 hours after the last dose of sacubitril/valsartan. Sacubitril/valsartan therapy 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 reducing arterial 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 the medicinal product. Careful monitoring of arterial pressure is recommended.

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

Lithium salts. ACE inhibitors may reduce lithium excretion, potentially leading to increased lithium toxicity. Plasma 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 Ramipril Astra is expected. Additionally, concomitant use of ACE inhibitors and NSAIDs may be associated with an increased risk of renal function impairment and elevated blood potassium levels.

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

Specific hyposensitization. Due to ACE inhibition, the frequency and severity of anaphylactic and anaphylactoid reactions to insect venom may increase. This effect is considered to potentially extend to other allergens as well.

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, 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 considered absolutely necessary, patients planning pregnancy 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, replaced with another suitable medication (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 renal impairment (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 "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

If such dual blockade therapy is considered absolutely necessary, it should only be administered under specialist supervision and with frequent, 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 (RAAS) activity. In patients with markedly increased RAAS activity, there is a risk of sudden, pronounced reduction in blood pressure and impaired renal function following ACE inhibition, especially when an ACE inhibitor or concomitant diuretic is used for the first time or when the dose is increased for the first time. A significant increase in RAAS activity requiring medical supervision, including continuous blood pressure monitoring, may be expected, for example, in patients:

• with severe arterial hypertension;
• with decompensated congestive heart failure;
• with haemodynamically 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.

Dehydration, hypovolaemia, or electrolyte depletion should generally be corrected before 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 ischaemia 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, especially during the first weeks of therapy. Particularly careful monitoring is required in patients with impaired renal function (see section "Dosage and administration"). There is a risk of worsening renal function, particularly in patients with congestive heart failure or after kidney transplantation, as well as in cases of renal vascular disease, including patients with haemodynamically 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 such as 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 forms of interaction").

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

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

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

Monitoring of electrolyte balance. Hyperkalaemia. Hyperkalaemia has been observed in some patients receiving ACE inhibitors, including Ramipril Astra. 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 necessary, 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. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anaemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leucopenia, 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 affect blood counts (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

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

Cough. Cough has been reported during treatment with 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 planning pregnancy. If pregnancy occurs during treatment, the drug 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 use in breastfeeding women; alternative medicinal products with a more favourable safety profile during lactation should be preferred, especially when breastfeeding newborns or preterm infants.

Ability to affect reaction speed when driving or operating machinery.

Some adverse reactions (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 usually possible at the beginning of treatment or when switching from other antihypertensive therapies to Ramipril Astra. Driving vehicles or operating machinery should be avoided for several hours after taking the first dose or any subsequent dose increase.

Dosage and Administration

The product is for oral use.

Ramipril Astra should be taken daily at the same time each day. The product may be taken before, during, or after meals, as food intake does not affect its bioavailability. Ramipril Astra tablets should be swallowed whole with water. They must not be chewed or crushed.

If the prescribed dose is not available, ramipril in the appropriate strength should be used.

Adults

Patients receiving diuretics
At the beginning of treatment with Ramipril Astra, arterial hypotension may occur, particularly in patients concurrently receiving diuretics. In such cases, caution is advised, as these patients may have reduced circulating blood volume and/or electrolyte depletion.

If possible, it is recommended to discontinue diuretic therapy 2–3 days prior to initiating Ramipril Astra (see section "Special Warnings and Precautions for Use").

In patients with arterial hypertension who cannot discontinue diuretic therapy, treatment with Ramipril Astra should be initiated at a dose of 1.25 mg (use ramipril in the appropriate strength). Renal function and serum potassium levels should be closely monitored. Subsequent dosing of Ramipril Astra should be adjusted according to the target blood pressure level.

Arterial Hypertension

Dosage should be individualized according to the patient's condition (see section "Special Warnings and Precautions for Use") and blood pressure monitoring results. Ramipril Astra may be used as monotherapy or in combination with other classes of antihypertensive agents (see sections "Pharmacodynamics", "Contraindications", "Interaction with Other Medicinal Products and Other Forms of Interaction", and "Special Warnings and Precautions for Use").

Initial Dose
Treatment with Ramipril Astra should be initiated gradually, starting with the recommended initial dose of 2.5 mg (use ramipril in the appropriate strength) once daily.

In patients with significant activation of the renin-angiotensin-aldosterone system (RAAS), 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 appropriate 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 is achieved; the maximum daily dose of Ramipril Astra is 10 mg. The drug is usually administered once daily.

Prevention of Cardiovascular Disease

Initial Dose
The recommended initial dose of Ramipril Astra is 2.5 mg (use ramipril in the appropriate 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 again after 2–3 weeks to reach the target maintenance dose of 10 mg once daily.

Treatment of Kidney Disease

Patients with Diabetes and Microalbuminuria

Initial Dose
The recommended initial dose of Ramipril Astra is 1.25 mg (use ramipril in the appropriate strength) once daily.

Dose Titration and Maintenance Dose
Depending on individual tolerability, the dose should be increased during continued treatment. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg (use ramipril in the appropriate strength), and then 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 Ramipril Astra is 2.5 mg (use ramipril in the appropriate strength) once daily.

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

Patients with Non-Diabetic Nephropathy Characterized by Macroproteinuria ≥ 3 g/day

Initial Dose
The recommended initial dose of Ramipril Astra is 1.25 mg (use ramipril in the appropriate strength) once daily.

Dose Titration and Maintenance Dose
Depending on individual patient tolerability, the dose should be increased during continued treatment. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg (use ramipril in the appropriate strength), and then to 5 mg after another 2 weeks of treatment.

Heart Failure with Clinical Symptoms

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

Dose Titration and Maintenance Dose
The dose of Ramipril Astra should be titrated by doubling every 1–2 weeks up to the maximum daily dose of 10 mg. It is preferable to divide the dose into two administrations per day.

Secondary Prevention Following 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 should be given an initial dose of 2.5 mg (use ramipril in the appropriate strength) twice daily for 3 days. If the initial dose of 2.5 mg (use ramipril in the appropriate strength) is poorly tolerated, a dose of 1.25 mg (use ramipril in the appropriate strength) twice daily should be administered for 2 days, followed by an increase to 2.5 mg (use ramipril in the appropriate strength) and then to 5 mg twice daily. If the dose cannot be increased to 2.5 mg (use ramipril in the appropriate 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 administrations.

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

Special Patient Categories

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 appropriate 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 appropriate 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 appropriate strength), and the maximum daily dose is 5 mg;
• Patients with arterial hypertension undergoing hemodialysis: Ramipril is only minimally removed during hemodialysis; the initial dose is 1.25 mg (use ramipril in the appropriate strength), and the maximum daily dose is 5 mg; the product should be taken several hours after a hemodialysis session.

Patients with Hepatic Impairment (see section "Pharmacological Properties")
Treatment with Ramipril Astra 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 appropriate strength).

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

See also the information above regarding dosing for patients receiving diuretics.

Children

Ramipril Astra is not recommended for use in children (under 18 years of age), as there is insufficient data on the efficacy and safety of this product in such patients.

Overdose

Symptoms associated with overdose of angiotensin-converting enzyme (ACE) inhibitors may include excessive peripheral vasodilation (with severe hypotension or shock), bradycardia, electrolyte imbalances, and renal failure. The patient should be closely monitored, and symptomatic and supportive therapy should be administered. Proposed therapeutic measures include initial decontamination (gastric lavage, administration of adsorbents) and interventions aimed at restoring hemodynamic stability, including administration of alpha-1 adrenergic agonists or angiotensin II (angiotensinamide). Ramiprilat, the active metabolite of ramipril, is poorly removed from systemic circulation by hemodialysis.

Adverse reactions.

The safety profile of Ramipril Astra 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 available data). Within each group, adverse reactions 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, paraesthesia, 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 irritating cough, bronchitis, sinusitis, dyspnea	Bronchospasm, including asthma exacerbation; nasal congestion
Gastrointestinal disorders	Inflammatory events in the gastrointestinal tract, digestive disorders, abdominal discomfort, dyspepsia, diarrhea, nausea, vomiting	Pancreatitis (in isolated cases fatal outcome 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 blood 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 exanthem or enanthem, alopecia
Musculoskeletal and connective tissue disorders	Muscle spasms, 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	Flushing sensation	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 disturbance

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. ≥ 1/100 to < 1/10) in the pediatric population and uncommon (i.e. ≥ 1/1000 to < 1/100) in adult patients.

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

Tremor and urticaria: uncommon (i.e. ≥ 1/1000 to < 1/100) in the pediatric population and rare (i.e. ≥ 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 authorization of the medicinal product is of great importance. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all cases of suspected adverse reactions and lack of efficacy of the medicinal product via the Automated Pharmacovigilance Information System at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

Store in the original packaging at a temperature not exceeding 25 ºC.

Keep out of reach of children.

Packaging. 10 tablets in a blister; 3 blisters in a cardboard box.

Prescription category. Prescription only.

Manufacturer. ASTRAFARM LLC.

Manufacturer's address and location of its business operations.

6, Kyivska Street, city of Vyshneve, Bucha district, Kyiv region, 08132, Ukraine.