Angiram

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT ANGIRAM (ANGIRAM)

Composition:

Active substance: ramipril;

1 tablet contains 2.5 mg of ramipril;

Excipients: sodium hydrogen carbonate, lactose monohydrate, sodium croscarmellose, iron oxide yellow (E 172), sodium stearyl fumarate, pregelatinized starch;

Active substance: ramipril;

1 tablet contains 5 mg of ramipril;

Excipients: sodium hydrogen carbonate, lactose monohydrate, sodium croscarmellose, iron oxide red (E 172), sodium stearyl fumarate, pregelatinized starch;

Active substance: ramipril;

1 tablet contains 10 mg of ramipril;

Excipients: sodium hydrogen carbonate, lactose monohydrate, sodium croscarmellose, sodium stearyl fumarate, pregelatinized starch.

Pharmaceutical form. Tablets.

Main physico-chemical properties:

2.5 mg tablets: flat, uncoated tablets with a bevel, round-shaped, yellowish to yellow in color, with embossing "H" and "18" and a line between them on one side, and flat on the other side;

5 mg tablets: flat, uncoated tablets with a bevel, round-shaped, light pink marbled in appearance, with embossing "H" and "19" and a line between them on one side, and flat on the other side;

10 mg tablets: flat, uncoated tablets with a bevel, round-shaped, white to almost white in color, with embossing "H" and "20" and a line between them on one side, and flat on the other side.

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

Pharmacological Properties.

Mechanism of action. Ramiprilat, the active metabolite of the 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 Black race (Afro-Caribbean origin) with arterial hypertension (a population typically characterized by low renin levels in arterial hypertension) compared to patients of other racial groups.

Pharmacodynamics.

Antihypertensive properties. Administration of ramipril results in a significant reduction in peripheral arterial resistance. Generally, no significant changes in renal plasma flow or glomerular filtration rate occur. Administration of ramipril to patients with arterial hypertension leads to a reduction in 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 is usually achieved within 3–6 hours. The antihypertensive effect after a single dose typically lasts for 24 hours.

During long-term treatment with 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 during prolonged therapy.

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

Heart failure. Ramipril has been shown to be effective in patients with heart failure (NYHA classes II–IV) when used as an adjunct to conventional therapy with diuretics and, if necessary, cardiac glycosides. The drug favorably affects cardiac hemodynamics (reducing filling pressures of the left and right ventricles, total peripheral vascular resistance, and increasing cardiac output and improving cardiac index). It also reduces neuroendocrine activation.

Clinical efficacy and safety.

Prevention of cardiovascular diseases / nephroprotection. A preventive, placebo-controlled study (HOPE) was conducted involving over 9,200 patients who received ramipril in addition to standard therapy. 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), as well as patients with diabetes mellitus who had at least one additional risk factor (documented microalbuminuria, arterial hypertension, elevated total cholesterol, elevated LDL cholesterol, or smoking).

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

Table 1. HOPE study: main results

Indicator	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

In 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 versus placebo in 3577 patients aged 55 years and older (no upper age limit) with normal or elevated blood pressure, most of whom had type 2 diabetes (and at least one cardiovascular risk factor).

The primary analysis results demonstrated that overt nephropathy developed in 117 (6.5%) participants receiving ramipril and in 149 (8.4%) receiving placebo, representing 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 and <3 g/day) or severe proteinuria (≥3 g/day) 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 participation in the study because benefit from ramipril treatment was proven) demonstrated that the mean rate of decline in GFR per month was lower with ramipril than with placebo: −0.54 (0.66) versus −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).

Dual blockade of the renin-angiotensin-aldosterone system. 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 concomitant 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 and 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 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 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 acute or chronic heart failure symptoms following acute myocardial infarction. Ramipril treatment was initiated 3–10 days after the onset of acute myocardial infarction. The 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 reduction in mortality of 5.7% and a relative risk reduction of 27% (95% CI [11–40%]).

Paediatric population. In a randomized, double-blind, placebo-controlled clinical trial involving 244 paediatric patients with hypertension (73% of whom had primary hypertension), aged 6–16 years, participants received low, medium, or high doses of ramipril to achieve plasma concentrations of ramiprilat corresponding to adult dose ranges of 1.25 mg, 5 mg, and 20 mg, adjusted for body weight. After a 4-week period, ramipril was ineffective in reducing systolic blood pressure, the primary endpoint; however, diastolic blood pressure was reduced with 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 study evaluating the effect of drug withdrawal, involving 218 paediatric patients aged 6–16 years (75% of whom had primary hypertension). In this study, after drug discontinuation, a moderate rebound increase in both diastolic and systolic blood pressure was observed, but it was not statistically significant for return to baseline levels across all dose groups 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 paediatric population, ramipril did not exhibit a linear dose-dependent effect.

Pharmacokinetics.

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

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

Distribution. 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. Metabolite excretion occurs predominantly via renal excretion. The decline in plasma ramiprilat 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. 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 higher plasma concentrations of ramiprilat, which decline more slowly than in individuals with normal renal function.

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

Breastfeeding. 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.

Paediatric population. The pharmacokinetic profile of ramipril was studied in paediatric 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. Maximum plasma concentrations of ramiprilat were reached within 2–3 hours. Ramiprilat clearance correlated significantly 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 a 5 mg dose of 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 administration studies were conducted in rats, dogs, and monkeys. Electrolyte imbalances and hematological changes were observed in all three species. In dogs and monkeys receiving 250 mg/kg/day, marked increases in the juxtaglomerular apparatus were noted, reflecting the pharmacodynamic activity of ramipril. Rats, dogs, and monkeys tolerated daily doses of 2, 2.5, and 8 mg/kg/day, respectively, without adverse effects.

Reproductive toxicity studies in rats, rabbits, and monkeys revealed no teratogenic properties of ramipril. 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 atherosclerotic cardiovascular disease (history of ischemic heart disease, stroke, or peripheral vascular disease);
• diabetes mellitus and at least one cardiovascular risk factor.

Treatment of kidney disease:

• early diabetic glomerular nephropathy, indicated by the presence of microalbuminuria;
• advanced diabetic glomerular nephropathy, indicated by the presence of macroproteinuria, in patients with at least one cardiovascular risk factor;
• advanced non-diabetic glomerular nephropathy, indicated by the presence of macroproteinuria ≥ 3 g/day.

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 contained in the medicinal product, or to other angiotensin-converting enzyme (ACE) inhibitors.

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.

Contraindicated in pregnant women or women planning to become pregnant (see section "Use during pregnancy and breastfeeding").

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

Should not be used concomitantly with aliskiren-containing products in patients with diabetes mellitus or moderate to severe renal impairment (eGFR < 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 studies have demonstrated that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor antagonists, or aliskiren is associated with increased incidence of adverse events such as arterial hypotension, hyperkalemia, and worsening of renal function (including acute renal failure), compared to use of a single RAAS-acting agent (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"). 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. 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 in fixed combination 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").

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

Allopurinol, immunosuppressants, corticosteroids, procainamide, cytostatic agents, 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. Reduced antihypertensive effect of Angiram is expected. Furthermore, concomitant use of ACE inhibitors and NSAIDs may be associated with 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 immunotherapy (hyposensitization). Inhibition of ACE increases the likelihood and severity of anaphylactic and anaphylactoid reactions to insect venom. 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 cautiously (see section "Special precautions for use").

Neprilysin inhibitors. Increased risk of angioedema has been reported with concomitant use of ACE inhibitors and neprilysin inhibitors (NEP), e.g., 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, women 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, therapy with another drug should be initiated (see sections "Contraindications" and "Use in pregnancy or breastfeeding").

Patients at particular risk of arterial hypotension.

Patients with markedly increased activity of the renin-angiotensin-aldosterone system (RAAS). There is a risk of sudden and pronounced reduction in blood pressure and worsening of renal function due to ACE inhibition, particularly when initiating ACE inhibitor therapy or increasing the dose for the first time, especially if combined with diuretics. Markedly increased RAAS activity requiring medical supervision, including continuous blood pressure monitoring, may be expected, for example, in patients:

• with severe arterial hypertension;
• with decompensated congestive heart failure;
• with hemodynamically significant obstruction to inflow or outflow 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 extensive surgical procedures or anesthesia with agents that may cause arterial hypotension.

Dehydration, hypovolemia, or electrolyte depletion should generally be corrected prior to initiating therapy (however, in patients with heart failure, such corrective measures should be carefully evaluated due to the risk of volume overload).

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, hyperkalemia, and worsening renal function (including development of acute renal failure). Therefore, dual RAAS blockade 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.

Transient or persistent heart failure following 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 elective 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. 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 reported in patients receiving ACE inhibitors, including ramipril (see section "Adverse reactions"). The risk is higher in patients concurrently receiving medicinal products that may induce angioedema, such as mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, everolimus, sirolimus), 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, administration of Angiram should be discontinued immediately. Emergency treatment should be initiated without delay. The patient should remain under medical supervision for at least 12–24 hours and may be discharged only after complete resolution of symptoms.

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

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

Monitoring of electrolyte balance. Hyperkalemia. Hyperkalemia has been observed in some patients receiving ACE inhibitors, including Angiram. Patients at increased risk of hyperkalemia include those with renal impairment, patients aged 70 years or older, patients with uncontrolled diabetes mellitus, patients receiving potassium supplements, potassium-sparing diuretics, or other active substances that increase plasma potassium levels, and 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. Hyponatremia. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) with subsequent development of hyponatremia has been observed in some patients receiving ramipril. Regular monitoring of serum sodium levels is recommended, particularly in elderly patients and other patients at risk of developing hyponatremia.

Neutropenia/agranulocytosis. Cases of neutropenia/agranulocytosis, as well as thrombocytopenia and anemia, have been reported rarely. Bone marrow suppression has also been reported. To detect possible leukopenia, monitoring of white blood cell count is recommended. More frequent monitoring is advisable at the beginning of treatment and in patients with impaired renal function, concomitant collagenosis (e.g., systemic lupus erythematosus or scleroderma), or those 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 cause angioedema more frequently in patients of Black race than in other racial groups. As with other ACE inhibitors, the antihypertensive effect of ramipril may be less pronounced in patients of Black race compared to other racial groups. This may be due to the higher prevalence of low-renin hypertension in Black patients with arterial hypertension.

Cough. Cough has been reported during ACE inhibitor therapy. 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 in 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 data on the use of ramipril during breastfeeding, this drug is not recommended for nursing mothers. Alternative medicinal products with a more favorable safety profile during lactation should be preferred, 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., driving vehicles or operating machinery).

This is generally possible at the beginning of treatment or when switching from other antihypertensive therapies to Angiram. Driving vehicles or operating machinery should be avoided for several hours after taking the first dose or any subsequent dose increase.

Method of Administration and Dosage

The drug is for oral use.

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

If the prescribed dose cannot be achieved with Angiram tablets, other ramipril dosage forms with appropriate strengths should be used.

Adults.

Patients receiving diuretics. At the initiation of Angiram therapy, arterial hypotension may occur, particularly in patients concurrently receiving diuretics. In such cases, caution is recommended, as these patients may have reduced circulating blood volume and/or electrolyte depletion.

It is advisable to discontinue diuretic therapy 2–3 days before starting Angiram, if possible (see section "Special Precautions").

In hypertensive patients in whom diuretic discontinuation is not feasible, Angiram therapy should be initiated at a dose of 1.25 mg. Renal function and serum potassium levels should be closely monitored. Subsequent Angiram dosage should be adjusted according to the target blood pressure level.

Arterial Hypertension.

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

Initial dose. Angiram therapy should be initiated gradually, starting with the recommended initial dose of 2.5 mg (administer ramipril at 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 (administer ramipril at the corresponding dosage strength), and therapy should be initiated under medical supervision (see section "Special Precautions").

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 Angiram is 10 mg daily. The drug is generally taken once daily.

Prevention of Cardiovascular Diseases.

Initial dose. The recommended initial dose of Angiram is 2.5 mg (administer ramipril at the corresponding dosage strength) once daily.

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

See also the dosage information above for patients receiving diuretics.

Treatment of Kidney Disease.

In patients with diabetes and microalbuminuria.

Initial dose. The recommended initial dose of Angiram is 1.25 mg (administer ramipril at the corresponding dosage 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 (administer ramipril at the corresponding dosage strength), and then to 5 mg after another 2 weeks of treatment.

In patients with diabetes and at least one cardiovascular risk factor.

Initial dose. The recommended initial dose of Angiram is 2.5 mg (administer ramipril at the corresponding dosage 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 Angiram 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.

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

Initial dose. The recommended initial dose of Angiram is 1.25 mg (administer ramipril at the corresponding dosage strength) once daily.

Dose titration and maintenance dose. Depending on individual patient tolerability during continued treatment, the dose should be increased. After 2 weeks of treatment, the daily dose should be doubled to 2.5 mg, and then to 5 mg after another 2 weeks of treatment.

Heart failure with clinical manifestations.

Initial dose. In patients whose condition has been stabilized with diuretic therapy, the recommended initial dose is 1.25 mg (administer ramipril at the corresponding dosage strength) daily.

Dose titration and maintenance dose. The Angiram dose should be titrated by doubling every 1–2 weeks until the maximum daily dose of 10 mg is reached. It is preferable to divide the daily dose into two administrations.

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

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

See also the dosage information above for patients receiving diuretics.

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.

When possible, the maintenance daily dose should be divided into two administrations.

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

Special patient categories.

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

• if creatinine clearance is ≥ 60 mL/min, no adjustment of the initial dose (2.5 mg daily — administer ramipril at 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 daily — administer ramipril at 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 (administer ramipril at 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 daily dose is 1.25 mg (administer ramipril at 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 impaired hepatic function (see section "Pharmacological Properties"). Angiram therapy in patients with impaired liver function should be initiated under close medical supervision, and the maximum daily dose in such cases should not exceed 2.5 mg (administer ramipril at 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, particularly in very old and frail patients. In such cases, a lower initial dose of 1.25 mg ramipril (administer ramipril at the corresponding dosage strength) should be prescribed.

See also the dosage information above for patients receiving diuretics.

Children.

Angiram is not recommended for use in children (under 18 years of age) due to insufficient data on efficacy and safety in this patient population.

Overdose.

Symptoms associated with ACE inhibitor overdose 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 treatment. Proposed therapeutic measures include primary detoxification (gastric lavage, administration of adsorbents) and interventions 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 Angiram 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 (≥ 1/1000 to < 1/100); rare (≥ 1/10000 to < 1/1000); very rare (< 1/10000); not known (cannot be calculated from available data). Within each group, adverse events are listed in order of decreasing severity.

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

Pediatric population.
The safety of ramipril has been studied in children and adolescents aged 2–16 years in 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: frequently (i.e. ≥ 1/100 to < 1/10) in the pediatric population and uncommonly (i.e. ≥ 1/1,000 to < 1/100) in the adult population.

Conjunctivitis: frequently (i.e. ≥ 1/100 to < 1/10) in the pediatric population and rarely (i.e. ≥ 1/10,000 to < 1/1,000) in the adult population.

Tremor and urticaria: uncommonly (i.e. ≥ 1/1,000 to < 1/100) in the pediatric population and rarely (i.e. ≥ 1/10,000 to < 1/1,000) in the adult population.

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

Suspected adverse reactions reporting.

Reporting of suspected adverse reactions after drug authorization is an important step. It allows continuous monitoring of the benefit-risk balance of the medicinal product.

Healthcare professionals are required to report any cases of adverse reactions through the pharmacovigilance system of Ukraine.

Shelf life.

2 years.

Storage conditions.

Store out of reach of children, at a temperature not exceeding 25 °C.

Packaging.

Tablets 2.5 mg: 10 tablets per blister, 3 blisters per cardboard pack.

Tablets 5 mg: 10 tablets per blister, 3 blisters per cardboard pack.

Tablets 10 mg: 10 tablets per blister, 3 blisters per cardboard pack.

Prescription category.

By prescription only.

Manufacturer.

1. Aurobindo Pharma Limited - Unit III / Aurobindo Pharma Limited - Unit III.
2. Aurobindo Pharma Ltd, Formulation Unit XV / Aurobindo Pharma Ltd, Formulation Unit XV.

Manufacturer's address and location of operations.

1. Survey No. 313, 314 - Block I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India / Survey no.: 313, 314 - Block I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India.
2. Plot No.17A, E.Bonangi (Village), Parawada (Mandal), Visakhapatnam, Andhra Pradesh, 531021, India / Plot No.17A, E.Bonangi (Village), Parawada (Mandal), Visakhapatnam, Andhra Pradesh, 531021, India.