Diróton®

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

Composition:

Active substance: lisinopril;

1 tablet contains 5 mg, 10 mg, or 20 mg of lisinopril in the form of lisinopril dihydrate;

Excipients: magnesium stearate; talc; mannitol (E 421); maize starch; calcium hydrogen phosphate dihydrate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Dirotón®, 5 mg tablets:

flat, white or almost white, round tablets with beveled edges, engraved with "5" on one side and a line on the other;

Dirotón®, 10 mg tablets:

square-shaped, slightly biconvex, white or almost white tablets, engraved with "10" on one side and a line on the other;

Dirotón®, 20 mg tablets:

pentagonal biconvex tablets, white or almost white, engraved with "20" on one side and a line on the other.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors.

ATC code C09A A03.

Pharmacological properties.

Pharmacodynamics.

Lisinopril is an inhibitor of peptidyl-dipeptidase. It inhibits angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I into the vasoconstrictive peptide angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE leads to reduced concentrations of angiotensin II, resulting in decreased vasoconstrictor activity and reduced aldosterone secretion. The latter reduction may lead to increased serum potassium concentration.

Since the primary mechanism by which lisinopril lowers blood pressure is believed to be inhibition of the renin-angiotensin-aldosterone system (RAAS), lisinopril reduces blood pressure even in patients with low renin levels. ACE is identical to kininase II, an enzyme that degrades bradykinin. It remains uncertain whether increased levels of bradykinin, a potent vasodilator peptide, contribute significantly to the therapeutic effects of lisinopril.

In addition to lowering blood pressure, lisinopril reduces albuminuria due to changes in the histology and hemodynamics of the glomerular apparatus of the kidneys. Treatment with lisinopril does not affect glycemic control, as evidenced by the lack of significant impact on levels of glycated hemoglobin (HbA1c).

Agents acting on the renin-angiotensin system (RAS)

It is known that two large-scale randomized controlled trials (ONTARGET [ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial] and VA NEPHRON-D [The Veterans Affair Nephropathy in Diabetes]) evaluated the use of a combination of an ACE inhibitor with an angiotensin II receptor blocker.

The ONTARGET trial included patients with a history of cardiovascular or cerebrovascular disease or type 2 diabetes with evidence of organ ischemia.

The VA NEPHRON-D trial included patients with type 2 diabetes and diabetic nephropathy. In these studies, no significant positive effect on renal and/or cardiovascular outcomes or mortality was demonstrated, while there was a higher risk of hyperkalemia, acute kidney injury, and/or hypotension compared to monotherapy.

These results are also applicable to other ACE inhibitors and angiotensin II receptor blockers due to their similar pharmacodynamic properties.

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

It is known that the ALTITUDE trial (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) was conducted to evaluate the potential benefits of adding aliskiren to standard therapy with an ACE inhibitor or angiotensin II receptor blocker in patients with type 2 diabetes and chronic kidney disease, cardiovascular disease, or both. The trial was terminated prematurely due to an increased risk of adverse events. The rate of fatal cardiovascular events and stroke was higher in the aliskiren group compared to placebo, and adverse reactions, including serious ones (hyperkalemia, hypotension, and renal failure), occurred more frequently in the aliskiren group than in the placebo group.

It is known that in a clinical study involving 115 children aged 6 to 16 years with arterial hypertension, patients with body weight less than 50 kg received 0.625 mg, 2.5 mg, or 20 mg of lisinopril once daily, while patients with body weight over 50 kg received 1.25 mg, 5 mg, or 40 mg of lisinopril once daily. At the end of the second week of the study, once-daily administration of lisinopril reduced blood pressure in a dose-dependent manner, with consistent antihypertensive effects demonstrated at doses higher than 1.25 mg.

This effect was confirmed during the drug withdrawal phase, during which diastolic pressure was approximately 9 mm Hg higher in patients randomized to placebo compared to those randomized to receive medium and high doses of lisinopril. Dose-dependent antihypertensive effects of lisinopril were observed across certain demographic subgroups: age, Tanner stage, sex, and race.

Pharmacokinetics.

Lisinopril is an orally active ACE inhibitor that does not contain a sulfhydryl group.

Absorption.

After oral administration of lisinopril, maximum serum concentration (C_max) is reached approximately 7 hours later, although there is a tendency toward a slight delay in the time required to reach peak serum concentrations in patients with acute myocardial infarction. Based on urinary excretion, the average absorption rate of lisinopril is approximately 25% following doses of 5–80 mg. Interpatient variability may range from 6 to 60%. Absolute bioavailability of lisinopril decreases to approximately 16% in patients with heart failure. Food intake does not affect the absorption of lisinopril.

Distribution.

Lisinopril does not bind to other serum proteins except circulating ACE. Animal studies indicate that lisinopril poorly penetrates the blood-brain barrier.

Elimination.

Lisinopril is not metabolized and is excreted unchanged exclusively by the kidneys into urine. With repeated dosing, the effective half-life of accumulation is 12.6 hours. The clearance of lisinopril is approximately 50 mL/min in healthy volunteers. Decreases in serum concentrations have a prolonged terminal phase, which does not lead to drug accumulation. This terminal phase may represent saturated binding to ACE and is not proportional to dose.

Hepatic impairment.

Hepatic dysfunction in patients with cirrhosis resulted in reduced absorption of lisinopril (approximately 30%, as determined by urinary recovery), but due to reduced clearance, also led to increased exposure (approximately 50%) compared to healthy volunteers.

Renal impairment.

Renal dysfunction reduces the renal excretion of lisinopril. This reduction is clinically significant only when glomerular filtration rate is less than 30 mL/min. In mild to moderate renal impairment (creatinine clearance of 30–80 mL/min), mean area under the curve (AUC) increases by only 13%. In severe renal impairment (creatinine clearance of 5–30 mL/min), mean AUC increases 4.5-fold compared to normal. Lisinopril can be removed by dialysis. During 4 hours of hemodialysis, plasma concentrations of lisinopril decreased on average by 60%, with a dialysis clearance of 40–55 mL/min.

Heart failure.

Patients with heart failure have greater exposure to lisinopril compared to healthy subjects (AUC increased on average by 125%), but due to urinary excretion of lisinopril, have reduced absorption of approximately 16% compared to healthy volunteers.

Children.

The pharmacokinetic profile of lisinopril was studied in 29 patients aged 6 to 16 years with arterial hypertension and glomerular filtration rate above 30 mL/min/1.73 m². After administration of doses of 0.1 to 0.2 mg/kg, steady-state plasma concentrations of lisinopril were achieved within 6 hours, and the extent of absorption, based on urinary excretion, was approximately 28%. These values were similar to those obtained in adult patients. AUC and C_max values in children in this study were consistent with those observed in adults.

Elderly patients.

In elderly patients, lisinopril levels are higher; AUC is approximately 60% higher than in younger patients.

Clinical characteristics.

Indications.

• Arterial hypertension.
• Heart failure (symptomatic treatment).
• Acute myocardial infarction (short-term treatment for 6 weeks in hemodynamically stable patients initiated no later than 24 hours after acute myocardial infarction).
• Treatment of kidney disease in patients with arterial hypertension, type 2 diabetes, and early nephropathy.

Contraindications.

− Hypersensitivity to the active substance or any of the excipients of the medicinal product.

− Hypersensitivity to any other angiotensin-converting enzyme (ACE) inhibitor.

− History of angioedema associated with previous treatment with other ACE inhibitors.

− Hereditary or idiopathic angioedema.

− Pregnancy or women planning to become pregnant (see "Use during pregnancy or breastfeeding").

− Breastfeeding period.

− Concomitant use of Diroton® with aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (glomerular filtration rate <60 mL/min/1.73 m²).

− Concomitant use with sacubitril/valsartan; initiation of Diroton® is not recommended within 36 hours after the last dose of sacubitril/valsartan (see also sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents.

Concomitant use of other antihypertensive agents (e.g., nitroglycerin and other nitrates or other vasodilators) may enhance the hypotensive effect of Diroton®.

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, and aliskiren is associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to treatment with a single RAAS-acting agent (see sections "Pharmacodynamics", "Special precautions for use", and "Contraindications").

Medicinal products that may increase the risk of angioedema.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special precautions for use").

Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, sirolimus, everolimus), neutral endopeptidase inhibitors (e.g., racecadotril), tissue plasminogen activator, or vildagliptin may increase the risk of angioedema (see section "Special precautions for use").

Diuretics.

Adding a diuretic to treatment in patients receiving lisinopril generally enhances the antihypertensive effect.

Patients receiving diuretics, especially those who have recently started therapy, may experience excessive reduction in blood pressure after initiating lisinopril. The risk of symptomatic hypotension following lisinopril administration can be reduced by discontinuing the diuretic prior to starting lisinopril (see sections "Special precautions for use" and "Dosage and administration").

Potassium-sparing diuretics, potassium-containing dietary supplements or salt substitutes, and other medicinal products that may increase serum potassium levels

Although serum potassium levels usually remain within normal limits during lisinopril therapy, hyperkalemia may occur in some patients. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes may lead to significant increases in serum potassium, particularly in patients with impaired renal function. Caution should be exercised when lisinopril is used concomitantly with other agents that may increase serum potassium levels, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim has effects similar to potassium-sparing diuretics like amiloride. Therefore, concomitant use of lisinopril with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, these agents should be used with caution and with periodic monitoring of serum potassium levels (see section "Special precautions for use").

Cyclosporine. Concomitant use of ACE inhibitors and cyclosporine may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.

Heparin. Concomitant use of ACE inhibitors and heparin may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.

When lisinopril is used concomitantly with potassium-wasting diuretics, the diuretic-induced hypokalemia may be attenuated.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses ≥3 g/day.

Concomitant use of ACE inhibitors with NSAIDs (e.g., acetylsalicylic acid used as an anti-inflammatory agent, COX-2 inhibitors, and nonselective NSAIDs) may result in reduced antihypertensive efficacy. Concomitant use of ACE inhibitors and NSAIDs may lead to worsening of renal function, and there is also a risk of developing acute renal failure and increased serum potassium levels, particularly in patients with a history of renal impairment. These effects are usually reversible. Such combinations should be prescribed with caution, especially in elderly patients. Patients should receive adequate hydration, and monitoring of renal function should be considered immediately after initiation of combination therapy and periodically thereafter.

Acetylsalicylic acid, thrombolytic agents, beta-blockers, nitrates.

Lisinopril may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytic agents, beta-blockers, and/or nitrates.

Lithium.

Cases of reversible increases in serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium toxicity and exacerbate existing lithium intoxication in patients receiving ACE inhibitors. Concomitant use of lisinopril with lithium is not recommended; however, if such combination is necessary, serum lithium levels should be closely monitored (see section "Special precautions for use").

Antidiabetic agents.

Concomitant use of antidiabetic agents (insulin, oral hypoglycemic agents) with ACE inhibitors may enhance the glucose-lowering effect, increasing the risk of hypoglycemia. This effect is more likely during the first week of combination therapy and in patients with renal impairment.

Sympathomimetic agents.

Sympathomimetic agents may reduce the antihypertensive effect of ACE inhibitors.

Tricyclic antidepressants, neuroleptics, anesthetic agents.

Concomitant use of tricyclic antidepressants, neuroleptics, or anesthetic agents may enhance the hypotensive effect of Diroton® (see section "Special precautions for use").

Gold.

Nitritoid reactions (symptoms of vasodilation, including flushing, nausea, dizziness, and hypotension, which may be severe) following gold injections (e.g., sodium aurothiomalate) occur more frequently in patients receiving ACE inhibitors concomitantly.

Tissue plasminogen activators.

Concomitant use with tissue plasminogen activators may increase the risk of angioedema.

Special precautions for use.

Symptomatic hypotension .

Symptomatic hypotension occurs less frequently in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving lisinopril, arterial hypotension is more likely in cases of fluid volume depletion caused by diuretic therapy, salt-restricted diet, dialysis, diarrhea, or vomiting, as well as in severe renin-dependent hypertension (see also sections "Interaction with other medicinal products and other forms of interaction" and "Side effects"). Symptomatic hypotension may occur in patients with symptomatic heart failure, with or without renal impairment. Symptomatic hypotension is more likely to occur in patients with more severe degrees of heart failure, when high doses of loop diuretics are used, in the presence of hyponatremia, or with functional renal impairment. For patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustments should be carefully monitored. This also applies to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or cerebral ischemia.

In the event of arterial hypotension, the patient should be placed in a supine position (as a mandatory measure); intravenous fluid administration (administration of physiological saline) is recommended if necessary. Transient hypotension is generally not a contraindication for continued use of the drug. Subsequent treatment usually proceeds without complications after normalization of blood pressure through increased blood volume.

In some patients with heart failure and normal or low blood pressure, further reduction in blood pressure may occur during treatment with lisinopril. This effect is expected and usually does not require discontinuation of therapy. If hypotension becomes symptomatic, dose reduction or discontinuation of treatment with Dironaton® may become necessary.

In the event of acute myocardial infarction, lisinopril is contraindicated if vasodilator therapy may worsen the patient's hemodynamic status (e.g., if systolic blood pressure is 100 mm Hg or lower) or in cases of cardiogenic shock. If systolic blood pressure is 120 mm Hg or lower, low doses should be used during the first 3 days after infarction. Maintenance doses should be reduced to 5 mg or temporarily to 2.5 mg if systolic blood pressure is 100 mm Hg or lower. If arterial hypotension persists (systolic blood pressure less than 90 mm Hg for more than 1 hour), treatment with this drug should be discontinued.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy .

As with all ACE inhibitors, lisinopril should be administered with caution to patients with mitral valve stenosis or left ventricular outflow obstruction, such as aortic stenosis or hypertrophic cardiomyopathy.

Renal impairment .

In patients with renal impairment (creatinine clearance < 80 mL/min), the initial dose of lisinopril should be adjusted according to creatinine clearance values (see Table 1 in the section "Dosage and administration") and clinical response to treatment. Routine monitoring of serum potassium and creatinine levels is part of standard medical practice in treating such patients.

In patients with heart failure, arterial hypotension occurring after initiation of ACE inhibitor therapy may lead to impaired renal function. In such cases, acute renal failure may develop, which is usually reversible.

In some patients with bilateral renal artery stenosis or renal artery stenosis in a single kidney, treatment with ACE inhibitors may increase blood urea nitrogen and serum creatinine levels, which usually return to normal after discontinuation of therapy. The likelihood of this is particularly high in patients with pre-existing renal impairment. In patients with renovascular hypertension, there is an increased risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under strict medical supervision with low doses and careful dose titration. Since diuretic therapy is an additional risk factor, it should be discontinued, and renal function should be monitored during the first weeks of lisinopril therapy.

In some patients with arterial hypertension who do not have concomitant renal vascular disease, increases in blood urea and serum creatinine levels may occur, usually mild and transient, especially if lisinopril is administered concomitantly with diuretics. This may occur primarily in patients with pre-existing renal dysfunction. Dose reduction and/or discontinuation of the diuretic and/or lisinopril may become necessary.

Treatment should not be initiated in the event of acute myocardial infarction in patients showing signs of renal impairment (serum creatinine level above 177 µmol/L and/or albuminuria above 500 mg/24 hours). If renal impairment develops during treatment (serum creatinine level above 265 µmol/L or more than double the baseline level), the physician should consider discontinuing treatment.

Hypersensitivity, angioedema .

Rare cases of angioedema of the face, extremities, lips, tongue, pharynx, and/or larynx have been reported in patients receiving ACE inhibitors, including lisinopril. This may occur at any time during treatment. In such cases, the drug must be discontinued immediately, and the patient should receive appropriate treatment and remain under medical supervision until symptoms completely resolve. In cases where swelling is localized to the tongue and does not impair breathing, prolonged observation may be required, as antihistamine and corticosteroid therapy may be insufficient.

Very rarely, angioedema involving laryngeal or tongue swelling may be fatal. If swelling extends to the tongue, glottis, or larynx, airway obstruction may develop, particularly in patients who have previously undergone surgery on the respiratory tract. In such cases, immediate emergency measures should be taken, which may include administration of adrenaline and/or securing airway patency. The patient must remain under close medical supervision until symptoms have completely and stably resolved.

ACE inhibitors may cause more pronounced angioedema in patients of Black race compared to patients of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing angioedema in response to drugs of this class (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan should not be initiated earlier than 36 hours after the last dose of lisinopril. Treatment with lisinopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Initiation of treatment with racécadotril, mTOR inhibitors, or vildagliptin in patients already receiving ACE inhibitors should be done with caution.

Hemodialysis .

Anaphylactoid reactions have been reported in patients undergoing dialysis with high-flux polycrylonitrile membranes (e.g., AN 69) while concurrently receiving ACE inhibitors. This combination should be avoided, and consideration should be given to using a different type of dialysis membrane or another class of antihypertensive agents.

Low-density lipoprotein (LDL) apheresis .

Life-threatening anaphylactoid reactions (such as profound arterial hypotension, respiratory distress, vomiting, allergic skin reactions) have rarely occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These reactions were avoided by temporarily discontinuing ACE inhibitors before each apheresis session.

Desensitization .

In patients receiving ACE inhibitors during desensitization therapy (e.g., for hymenoptera venom), persistent anaphylactoid reactions have occurred. These reactions were avoided by temporarily discontinuing ACE inhibitors, but recurred upon inadvertent re-exposure to the drug.

Neutropenia/agranulocytosis .

Neutropenia/agranulocytosis, thrombocytopenia, and anemia may develop during treatment with ACE inhibitors. Neutropenia has rarely been observed in patients with normal renal function and in the absence of other complications. Neutropenia and agranulocytosis resolved after discontinuation of ACE inhibitor therapy. Dironaton® should be used with particular caution in patients with collagen vascular diseases (e.g., systemic lupus erythematosus or scleroderma), during concomitant immunosuppressive therapy (e.g., corticosteroids, cytotoxic agents, antimetabolites), with allopurinol or procainamide, or with a combination of these risk factors, especially in the presence of renal impairment. Use of ACE inhibitors in such patients may be associated with particularly severe infections, which in some cases do not respond to intensive antibiotic treatment.

In such patients, periodic monitoring of white blood cell counts should be performed during treatment with Dironaton®, and patients should be warned to report any signs of infection.

Ethnic considerations (race) .

ACE inhibitors cause angioedema more frequently in patients of Black race than in patients of other races. As with other ACE inhibitors, lisinopril may be less effective in reducing blood pressure in patients of Black race compared to patients of other races, due to a higher prevalence of low-renin hypertension in this population.

Hepatic impairment .

Very rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and rapidly progressing to fulminant hepatic necrosis and (sometimes) death. The cause of this process is unknown.

If patients receiving Dironaton® develop jaundice or marked elevation in liver enzyme activity, the drug should be discontinued and appropriate medical care provided.

Dual blockade of the RAAS .

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, and aliskiren increases the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combined use of ACE inhibitors, angiotensin II receptor blockers, and aliskiren is contraindicated (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

If dual blockade is considered absolutely necessary, it should only be performed under specialist supervision with frequent and careful monitoring of renal function, electrolytes, and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Hyperkalemia .

ACE inhibitors may cause hyperkalemia due to inhibition of aldosterone secretion. This effect is usually clinically insignificant in patients with normal renal function. However, hyperkalemia may develop in patients with renal impairment, diabetes mellitus, and/or in patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), or other drugs capable of increasing serum potassium levels (such as heparin, trimethoprim, or the combination drug co-trimoxazole, known as trimethoprim/sulfamethoxazole, and especially aldosterone antagonists or angiotensin receptor blockers). Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors. If concomitant use of these drugs is necessary, regular monitoring of serum potassium levels and renal function is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Cough .

Cough has been reported during treatment with ACE inhibitors. The cough is usually dry, non-productive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgical procedures/anesthesia .

In patients undergoing surgery or receiving antihypertensive agents during anesthesia, lisinopril may block the formation of angiotensin II due to compensatory renin release. If arterial hypotension occurs and is considered to be due to this mechanism, treatment may include increasing circulating blood volume.

Diabetes mellitus .

More careful monitoring of glucose levels is required during the first month of treatment with ACE inhibitors in addition to prior insulin or oral hypoglycemic therapy (see section "Interaction with other medicinal products and other forms of interaction").

Lithium-containing preparations .

Generally, the combination of lithium and lisinopril is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Use during pregnancy or breastfeeding.

Pregnancy.

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

Breastfeeding.

Since information on the possible use of lisinopril during breastfeeding is lacking, lisinopril is contraindicated during this period.

Ability to affect reaction speed when driving or operating machinery.

When driving vehicles or operating machinery, the possibility of dizziness or fatigue should be taken into account.

Administration and Dosage

The dosage should be individualized according to the patient's condition and blood pressure response. Administer orally once daily, at the same time each day, regardless of food intake.

A 2.5 mg dose can be obtained by dividing a 5 mg Dирotone® tablet into two equal halves.

Arterial Hypertension.

Dирotone® can be used as monotherapy or in combination with other classes of antihypertensive agents.

Initial Dose. The recommended initial dose is usually 10 mg. In patients with highly active RAAS (particularly those with renovascular hypertension, sodium chloride depletion and/or dehydration, cardiac decompensation, or severe arterial hypertension), an excessive reduction in blood pressure may occur after the first dose. Therefore, such patients should be monitored by a physician at the beginning of treatment, and the recommended initial dose is 2.5–5 mg. Patients with renal impairment also require a reduced initial dose (see Table 1 below).

Maintenance Dose. The usual effective maintenance dose is 20 mg once daily. If the desired therapeutic effect is not achieved after 2–4 weeks of treatment at the prescribed dose, the dose may be increased further. The maximum daily dose should not exceed 80 mg.

Whenever possible, in patients receiving diuretics, diuretic therapy should be discontinued 2–3 days prior to initiating lisinopril. If this is not feasible, the initial dose of lisinopril should not exceed 5 mg/day. Renal function and serum potassium levels must be monitored. Subsequent doses of Dирotone® should be adjusted according to blood pressure response. Diuretic therapy may be reintroduced if necessary.

Symptomatic hypotension may occur following initiation of lisinopril therapy. This is more likely in patients receiving diuretics during lisinopril treatment. Since dehydration and/or excessive sodium chloride loss may be present in these patients, the drug should be administered with caution.

Patients with Renal Impairment.

Dosage adjustment in patients with renal impairment should be based on creatinine clearance, as shown in Table 1 below.

Dosage Adjustment in Patients with Renal Impairment

Table 1

Creatinine clearance (ml/min)	Initial dose (mg/day)
31−80	5−10
10−30	2.5−5
<10 (including patients on dialysis)*	2.5*

*Dosage and/or frequency of administration must be calculated based on arterial pressure response.

The dose may be gradually increased until arterial pressure normalizes or until the maximum dose of 40 mg/day is reached.

Use in children with hypertension aged 6 to 16 years.

The recommended initial dose is 2.5 mg/day for patients with body weight from 20 to 50 kg and 5 mg/day for patients with body weight ≥ 50 kg. The dose should be individually adjusted up to a maximum of 20 mg/day for patients with body weight from 20 to 50 kg and up to 40 mg/day for patients with body weight

≥ 50 kg. Doses exceeding 0.61 mg/kg (or those exceeding 40 mg) have not been studied in children (see section "Pharmacological properties").

Children with impaired renal function should be given a lower initial dose or the dosing interval should be prolonged.

Heart failure.

Dirhoton® may be used in patients with symptomatic heart failure as an additional therapy to diuretics and, if necessary, to digitalis or beta-blockers. Treatment should be conducted under medical supervision to monitor the initial effect on arterial pressure. The initial daily dose of lisinopril is 2.5 mg, which may be gradually increased to a maintenance dose.

The recommended dose escalation after 2 weeks is no more than 10 mg.

The dose of Dirhoton® should be increased to the maximum daily dose tolerated by the patient – 35 mg/day.

Dosage selection should be based on the clinical response of each individual patient.

Patients at high risk of symptomatic hypotension, such as those with salt depletion with or without hyponatremia, hypovolemia, or those receiving intensive diuretic therapy, should have their condition optimized, if possible, prior to initiating Dirhoton® therapy. Renal function and serum potassium levels should be monitored.

Acute myocardial infarction.

Patients should receive, as appropriate, standard recommended treatments such as thrombolytics, acetylsalicylic acid, and beta-blockers. Intravenous or transdermal nitroglycerin may be used concomitantly with Dirhoton®.

Initial dose (first 3 days after infarction).

Treatment with Dirhoton® may be initiated within the first 24 hours after onset of symptoms. Treatment should not be initiated if systolic arterial pressure is below 100 mm Hg. The initial dose of Dirhoton® is 5 mg orally, followed by 5 mg after 24 hours, 10 mg after 48 hours, and then 10 mg once daily.

In cases of low systolic pressure (≤ 120 mm Hg) or during the first 3 days after infarction, a low dose (2.5 mg/day) is indicated.

In renal impairment (creatinine clearance <80 mL/min), the initial dose of Dirhoton® should be adjusted according to the patient's creatinine clearance (see Table 1).

Maintenance dose. The maintenance dose is 10 mg once daily. In cases of arterial hypotension (systolic pressure ≤100 mm Hg), the maintenance daily dose is 5 mg/day; if necessary, this dose may be reduced to 2.5 mg. If prolonged arterial hypotension occurs after administration of Dirhoton® (systolic pressure remains below 90 mm Hg for more than 1 hour), treatment should be discontinued.

Therapy is recommended for 6 weeks, after which the patient's condition should be reassessed. Patients with symptoms of heart failure should continue treatment with Dirhoton®.

Diabetic nephropathy.

For patients with type II diabetes, arterial hypertension, and early-stage nephropathy, the dose is 10 mg once daily, which may be increased to 20 mg once daily, if necessary, to achieve a sustained diastolic arterial pressure below 90 mm Hg.

In renal impairment (creatinine clearance <80 mL/min), the initial dose of Dirhoton® should be adjusted according to the patient's creatinine clearance (see Table 1).

Children

In children with hypertension aged >6 years, the drug has limited efficacy and safety data; however, data for other indications are lacking (see section "Pharmacological properties"). Lisinopril is not recommended for treating children for indications other than arterial hypertension.

Lisinopril is not recommended for treating children under 6 years of age or children with severe renal impairment (GFR <30 mL/min/1.73 m²) (see section "Pharmacological properties").

Use in elderly patients.

Clinical studies have not shown differences in efficacy or safety of lisinopril treatment based on age. Since reduced renal function is common in elderly patients, the initial dose of lisinopril should be selected according to the recommendations in Table 1. Subsequently, the dose should be adjusted based on response and arterial pressure.

Use in patients with kidney transplant.

There is no experience with the use of lisinopril in patients with kidney transplant; therefore, treatment with Dirhoton® is not recommended in such patients.

Children.

Dirhoton® may be administered to children only for arterial hypertension and in those aged 6 years and older.

Overdose.

Data on Dirhoton® overdose in humans are limited. Symptoms associated with ACE inhibitors overdose may include arterial hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, restlessness, and cough.

In case of overdose, intravenous administration of physiological saline is recommended. In cases of arterial hypotension, the patient should be placed in a supine position. If available, infusion of angiotensin II and/or intravenous administration of catecholamines may be used.

If the drug was recently ingested, measures to eliminate lisinopril from the body should be taken (e.g., induce vomiting, gastric lavage, use of adsorbents and sodium sulfate). Lisinopril can be removed from systemic circulation by hemodialysis (see section "Special precautions for use"). Vital signs, serum electrolyte concentrations, and serum creatinine should be monitored frequently. Cardiac pacing is indicated in cases of therapy-resistant bradycardia.

Adverse reactions.

During treatment with Dirhoton® and other ACE inhibitors, the following adverse reactions have been observed and reported with the following frequencies: very common (≥ 1/10), common (from ≥ 1/100 to < 1/10), uncommon (from ≥ 1/1000 to < 1/100), rare (from ≥ 1/10000 to < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from the available data).

From the blood and lymphatic system
Uncommon:	decrease in hemoglobin, decrease in hematocrit;
Rare:	bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section "Special precautions for use"), hemolytic anemia, lymphadenopathy, autoimmune disease.
From the immune system
Frequency unknown:	anaphylactic/anaphylactoid reaction.
From the metabolism and nutrition
Rare:	hypoglycemia.
From the nervous system and psychiatric disorders
Common:	dizziness, headache;
Uncommon:	mood changes, paresthesia, vertigo, taste disturbances, sleep disorders, hallucinations;
Uncommon:	confusion, olfactory disturbances;
Frequency unknown:	depression symptoms, syncope.
From the cardiac and vascular system
Common:	orthostatic effects (including arterial hypotension);
Uncommon:	myocardial infarction or cerebrovascular accident, possibly due to excessive arterial hypotension in patients at high risk (see section "Special precautions for use"), palpitations, tachycardia, Raynaud's phenomenon.
From the respiratory system, thorax and mediastinum
Common:	cough;
Uncommon:	rhinitis;
Rare:	bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia.
Gastrointestinal disorders
Common:	diarrhea, vomiting;
Uncommon:	nausea, abdominal pain and digestive disorders;
Uncommon:	dry mouth;
Rare:	pancreatitis, intestinal angioneurotic edema, hepatitis (hepatocellular or cholestatic), jaundice and hepatic failure (see section "Special precautions for use").
From the skin and subcutaneous tissue
Uncommon:	rash, pruritus;
Uncommon:	urticaria, alopecia, psoriasis, hypersensitivity/angioedema: angioedema of the face, extremities, lips, tongue, glottis and/or larynx (see section "Special precautions for use");
Rare:	sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pseudolymphoma of the skin.
A syndrome complex has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies (ANA), increased erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity or other dermatological manifestations. From the kidneys and urinary tract
Common:	renal function impairment;
Uncommon:	uremia, acute renal failure;
Rare:	oliguria/anuria.
Endocrine disorders
Uncommon:	syndrome of inappropriate antidiuretic hormone secretion (SIADH).
From the reproductive system and breast
Uncommon:	impotence;
Uncommon:	gynecomastia.
General disorders and administration site reactions
Uncommon:	fatigue, asthenia.
Investigations
Uncommon:	increased blood urea nitrogen, increased serum creatinine, increased liver enzymes, hyperkalemia;
Uncommon:	increased serum bilirubin, hyponatremia.

Clinical safety data indicate that lisinopril is generally well tolerated in pediatric patients with arterial hypertension, and that the safety profile in this age group is comparable to that in adults.

Reporting of suspected adverse reactions

Reporting of adverse reactions following marketing authorization of the medicinal product is of great importance. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals, pharmacists, patients, and their legal representatives are encouraged to report all suspected adverse reactions and lack of efficacy through the automated pharmacovigilance information system at: https://aisf.dec.gov.ua/.

Shelf life. 3 years.

Storage conditions.

Store in a place inaccessible to children, at a temperature not exceeding 30 °C.

Packaging.

14 tablets in a blister pack, with 1, 2, or 4 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Gedeon Richter Plc., Hungary.

Manufacturer's address and location of operations.

H-1103 Budapest, Dózsa György út 19–21, Hungary.