Scopril

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

Composition:

Active substance: lisinopril;

1 tablet contains 10 mg or 20 mg of lisinopril (as lisinopril dihydrate);

Excipients: magnesium stearate, maize starch, mannite (E 421), calcium hydrogen phosphate, pregelatinized starch, povidone, yellow iron oxide (E 172) and red iron oxide (E 172) (in 20 mg tablets).

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: round, biconvex, light yellow tablets, with a score line on one side;

20 mg tablets: round, biconvex, creamy-pink tablets, with a score line on one side.

Pharmacotherapeutic group.

Angiotensin-converting enzyme (ACE) inhibitors. Single-component ACE inhibitors. ATC code C09AA03.

Pharmacological properties.

Pharmacodynamics.

Lisinopril is an angiotensin-converting enzyme (ACE) inhibitor. ACE is a peptidyl dipeptidase that catalyzes the conversion of angiotensin I into the vasoconstrictive peptide, angiotensin II, which also stimulates aldosterone secretion. Inhibition of ACE leads to a reduction in plasma angiotensin II concentration, resulting in decreased vasoconstrictor activity and aldosterone secretion. This may increase serum potassium concentrations.

Since the mechanism of action in arterial hypertension involves suppression of the renin-angiotensin-aldosterone system, lisinopril exerts its antihypertensive effect even in hypertensive patients with low renin levels. ACE is identical to kininase, the enzyme that degrades bradykinin. The role of increased bradykinin levels (which has pronounced vasodilatory properties) during lisinopril therapy has not been fully elucidated and requires further investigation.

Pharmacokinetics.

Absorption. After oral administration, lisinopril is slowly and incompletely absorbed from the gastrointestinal tract. The bioavailability of the drug is approximately 25%, with inter-subject variability ranging from 6% to 60%. Concomitant food intake does not affect absorption. Maximum plasma concentration is reached approximately 6–8 hours after administration.

Distribution. Steady-state serum concentrations are achieved within 2–3 days after initiation of treatment. Lisinopril does not bind to plasma proteins except for ACE.

Metabolism and elimination. Lisinopril is not metabolized and is excreted unchanged in urine.

It is removed during hemodialysis.

Pharmacokinetics in special patient populations. In patients with impaired renal function, elimination of lisinopril decreases proportionally to the degree of functional impairment (this reduction becomes clinically significant when glomerular filtration rate is below 30 mL/min).

In heart failure, renal clearance of lisinopril is reduced.

Elderly patients have higher plasma concentrations of lisinopril and higher AUC values (increased by approximately 60%) compared to younger patients.

Clinical characteristics.

Indications.

Arterial hypertension.

Chronic heart failure.

Acute myocardial infarction in patients with stable hemodynamic parameters (systolic BP > 100 mm Hg).

Diabetic nephropathy in type II diabetes mellitus.

Contraindications.

Hypersensitivity to lisinopril or to any other component of the medicinal product or to other ACE inhibitors.

History of angioedema (including angioedema associated with ACE inhibitor use, idiopathic or hereditary angioedema).

Aortic or mitral stenosis or hypertrophic cardiomyopathy with significant hemodynamic disturbances.

Bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Acute myocardial infarction with unstable hemodynamics.

Acute myocardial infarction with arterial hypotension (systolic pressure ≤ 100 mm Hg).

Cardiogenic shock.

Primary hyperaldosteronism.

Severe heart failure, severe arterial or renovascular hypertension.

Acute renal failure with persistently elevated blood pressure.

Concomitant use of high-flux membranes made of polyacrylonitrile-sodium-2-methylallylsulfonate (e.g., AN 96) during emergency dialysis.

Serum creatinine level ≥ 220 μmol/L.

Concomitant administration with aliskiren in patients with diabetes mellitus and renal impairment (glomerular filtration rate < 60 mL/min/1.73 m²).

Concomitant use with sacubitril/valsartan (lisinopril must not be administered earlier than 36 hours after the last dose of sacubitril/valsartan).

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

Interaction with other medicinal products and other forms of interaction.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) with angiotensin II receptor blockers, ACE inhibitors, or aliskiren is associated with an increased risk of adverse effects such as arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to monotherapy with these medicinal products.

Diuretics.

Concomitant use with diuretics results in additive antihypertensive effects. In patients already receiving diuretics, especially those recently started on diuretic therapy, administration of lisinopril may occasionally cause excessive reduction in blood pressure. The likelihood of symptomatic arterial hypotension induced by lisinopril can be reduced by discontinuing the diuretic prior to initiating lisinopril therapy.

Potassium supplements, potassium-sparing diuretics, or potassium-containing salt substitutes.

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving lisinopril. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Caution should also be exercised when lisinopril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim or co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of lisinopril with the above-mentioned agents is not recommended. If concomitant use of lisinopril with any of these agents is necessary, they should be used with caution and serum potassium levels should be monitored.

Cyclosporine.

Hyperkalemia may occur with concomitant use of ACE inhibitors and cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin.

Hyperkalemia may occur with concomitant use of ACE inhibitors and heparin. Monitoring of serum potassium levels is recommended.

Lithium.

Concomitant use of lithium and ACE inhibitors may lead to reversible increases in serum lithium levels and development of lithium toxicity. Use of thiazide diuretics may increase the risk of lithium intoxication and may exacerbate lithium toxicity already induced by concomitant use of ACE inhibitors. Concomitant use of lisinopril with lithium is not recommended; however, in cases where such combination is necessary, serum lithium levels should be closely monitored.

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

Prolonged use of NSAIDs may attenuate the antihypertensive effect of ACE inhibitors. The effects of NSAIDs and ACE inhibitors on increasing serum potassium levels are additive and may lead to renal dysfunction. These effects are usually reversible. In individual cases, acute renal failure may occur, particularly in patients with pre-existing renal impairment, such as elderly patients or those with dehydration.

Gold.

Nitritoid reactions (symptoms of vasodilation including flushing, nausea, dizziness, and arterial hypotension, which may be severe) following gold injection (e.g., sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitor therapy.

Other antihypertensive agents.

Concomitant use of lisinopril with other antihypertensive agents may result in enhanced hypotensive effects. Concomitant use of nitroglycerin and other organic nitrates or vasodilators may potentiate the hypotensive effect of lisinopril.

Tricyclic antidepressants, anesthetics, and antipsychotics.

Concomitant use of certain anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may enhance arterial hypotension.

Sympathomimetics.

May reduce the antihypertensive effect of ACE inhibitors.

Hypoglycemic agents.

Epidemiological studies have shown that concomitant use of ACE inhibitors and hypoglycemic agents (insulins and oral hypoglycemic agents) may potentiate the effect of the latter, up to the development of hypoglycemia. The likelihood of such events is particularly high during the first weeks of concomitant therapy and in patients with renal impairment.

Acetylsalicylic acid, thrombolytics, β-blockers, and nitrates.

Lisinopril may be administered concomitantly with acetylsalicylic acid (at cardiologically used doses), thrombolytic agents, β-blockers, and nitrates.

Agents that suppress bone marrow function.

Used concomitantly with lisinopril, may increase the risk of neutropenia and/or agranulocytosis. Allopurinol, cytostatics, immunosuppressants, corticosteroids, and procainamide, when used concomitantly with lisinopril, may lead to decreased white blood cell count and development of leukopenia.

Estrogens.

Due to fluid retention, estrogens may reduce the antihypertensive efficacy of lisinopril when used concomitantly.

Lisinopril should be used with caution in patients with acute myocardial infarction within 6–12 hours after administration of streptokinase (risk of arterial hypotension).

Lisinopril enhances the manifestations of alcohol intoxication. Narcotics, anesthetics, alcoholic beverages, and sedatives, when combined with lisinopril, may cause enhanced hypotensive effects.

Allopurinol, cytostatics, immunosuppressants, corticosteroids, procainamide.

Concomitant use with lisinopril may cause leukopenia.

Medicinal products that increase the risk of angioedema.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema.

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin increases the risk of angioedema.

Special precautions for use.

Symptomatic arterial hypotension.

Rarely observed in patients with uncomplicated arterial hypertension. In hypertensive patients receiving lisinopril, the likelihood of developing arterial hypotension increases with reduced circulating blood volume (e.g., due to diuretic therapy, dietary salt restriction, dialysis, diarrhea, or vomiting), as well as in severe forms of renin-dependent arterial hypertension.

Symptomatic arterial hypotension has been observed in patients with heart failure, regardless of whether it is associated with renal failure. This disorder is most commonly observed in patients with more severe heart failure who are required to take high doses of loop diuretics and who have hyponatremia or functional renal failure. Patients at increased risk of arterial hypotension require careful monitoring during the initial treatment period and dose titration.

This also applies to patients with ischemic heart disease or cerebrovascular disease, in whom a significant drop in arterial pressure may lead to myocardial infarction or impaired cerebral circulation.

In case of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of sodium chloride solution. A transient hypotensive reaction is not a contraindication for subsequent administration of the drug. After restoration of effective blood volume and arterial pressure, treatment with lisinopril may be continued.

In some patients with congestive heart failure who have normal or low arterial pressure, additional reduction in systemic arterial pressure may occur when lisinopril is initiated. This effect is expected and usually not a reason to discontinue therapy. However, if symptomatic arterial hypotension occurs, dose reduction or discontinuation of lisinopril may be necessary.

Arterial hypotension with acute myocardial infarction.

Initiation of lisinopril therapy is not recommended in acute myocardial infarction if prior treatment with vasodilating agents poses a risk of further serious deterioration in hemodynamic parameters. This applies to patients with systolic arterial pressure ≤ 100 mm Hg or cardiogenic shock. During the first 3 days after infarction, the dose of the drug should be reduced if systolic arterial pressure is ≤ 120 mm Hg. If systolic arterial pressure is ≤ 100 mm Hg, the maintenance dose should be reduced to 5 mg or temporarily to 2.5 mg. If sustained arterial hypotension occurs (systolic arterial pressure ≤ 90 mm Hg for more than 1 hour), lisinopril therapy should be discontinued.

Aortic and mitral stenosis / hypertrophic cardiomyopathy.

Like other ACE inhibitors, lisinopril should be administered with caution to patients with mitral stenosis or left ventricular outflow obstruction (e.g., aortic stenosis or hypertrophic cardiomyopathy).

Renal function impairment.

In patients with renal impairment (creatinine clearance < 80 mL/min), the initial dose of lisinopril should be determined based on the patient's creatinine clearance (see Table 1), and subsequently adjusted according to the patient's response to treatment. Routine monitoring of potassium and creatinine levels is part of standard medical practice in these patients.

In patients with heart failure, worsening renal function may occur at the beginning of ACE inhibitor therapy. Cases of acute renal failure, usually reversible, have been reported. In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, ACE inhibitors may increase blood urea nitrogen and serum creatinine levels; these changes are usually reversible upon discontinuation of the drug. The likelihood of this phenomenon is particularly high in patients with renal impairment.

In patients with renovascular hypertension, there is a high risk of developing severe arterial hypotension and renal failure. For such patients, treatment should be initiated under close medical supervision with low, carefully titrated doses. Since diuretics may contribute to the clinical scenario described above, their use should be discontinued during the first weeks of lisinopril therapy, and renal function should be closely monitored.

In some patients with arterial hypertension without evident renal vascular disease, lisinopril administration, especially when combined with diuretics, may lead to increased blood urea nitrogen and serum creatinine levels; these changes are generally mild and transient. The likelihood of such changes is higher in patients with impaired renal function. In such cases, dose reduction, discontinuation of diuretic, and/or discontinuation of lisinopril may be required.

Lisinopril treatment for acute myocardial infarction is not indicated in patients with signs of renal dysfunction characterized by serum creatinine levels ≥ 177 µmol/L and/or proteinuria ≥ 500 mg/day. If renal dysfunction develops during lisinopril therapy (serum creatinine concentration exceeds 265 µmol/L or serum creatinine levels double compared to baseline), the drug should be discontinued.

Increased sensitivity / angioedema.

Angioedema of the face, extremities, lips, tongue, vocal cords, and/or larynx rarely develops in patients receiving ACE inhibitors, including lisinopril. During treatment, angioedema may occur at any time. In such cases, lisinopril should be discontinued immediately, appropriate treatment initiated, and the patient placed under observation; the patient should not be discharged until all symptoms of swelling have completely resolved.

Even in cases where swelling is limited to the tongue and respiratory symptoms are absent, patients may require prolonged monitoring, as treatment with antihistamines and/or glucocorticosteroids may be insufficient.

Fatal cases of angioedema involving the larynx or tongue have been reported. If swelling extends to the tongue, vocal cords, or larynx, airway obstruction may occur, particularly in patients with a history of surgery on the respiratory organs. In such cases, emergency measures must be taken immediately (administration of adrenaline and/or airway support).

The patient should remain under close medical supervision until complete and sustained resolution of symptoms.

Patients with a history of angioedema unrelated to ACE inhibitor use have an increased risk of developing angioedema in response to ACE inhibitor therapy.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy should not be initiated earlier than 36 hours after the last dose of lisinopril. Lisinopril therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan.

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin increases the risk of angioedema (e.g., swelling of the airways or tongue, with or without respiratory compromise). Caution should be exercised when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving ACE inhibitors.

Hemodialysis.

When the drug is administered during dialysis with a polyacrylonitrile membrane, anaphylactoid reactions may occur. It is recommended to use membranes of a different type for dialysis or to use antihypertensive drugs from other classes in patients with arterial hypertension.

Anaphylactoid reactions during LDL-apheresis.

Since the use of ACE inhibitors during LDL-apheresis (low-density lipoprotein apheresis) with dextran sulfate may lead to life-threatening anaphylactoid reactions, ACE inhibitors should be temporarily discontinued before each apheresis procedure.

Desensitization.

Prolonged anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization therapy (e.g., for hymenoptera venom). If such patients discontinue ACE inhibitors during desensitization, no reactions are observed; however, accidental administration of an ACE inhibitor may provoke an anaphylactoid reaction.

Hepatic impairment.

ACE inhibitors have been associated with a rare syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unclear. If jaundice or markedly elevated liver enzyme activity develops in patients taking lisinopril, the drug should be discontinued, and the patient should remain under medical supervision until symptoms resolve.

Hyperkalemia.

ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. In patients with normal renal function, this effect is usually mild; however, in patients with impaired renal function, diabetes mellitus, and/or those taking potassium-containing dietary supplements (including potassium-containing salt substitutes), potassium-sparing diuretics, trimethoprim, or cotrimoxazole [trimethoprim + sulfamethoxazole], and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may occur. Potassium-sparing diuretics and angiotensin receptor blockers should be used with caution in patients receiving ACE inhibitors, and renal function and serum potassium levels should be monitored regularly.

Proteinuria.

Isolated cases of proteinuria have been reported in patients, particularly those with reduced renal function or after high-dose lisinopril administration. In cases of clinically significant proteinuria (exceeding 1 g/day), the drug should be used only after evaluating the therapeutic benefit versus potential risk and with continuous monitoring of clinical and biochemical parameters.

Primary hyperaldosteronism.

ACE inhibitors are ineffective in patients with primary hyperaldosteronism; therefore, lisinopril use is not recommended.

Diabetic patients.

In diabetic patients receiving hypoglycemic agents or insulin, blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy.

Lithium.

Concomitant use of lithium and lisinopril is generally not recommended.

Neutropenia/agranulocytosis.

Neutropenia/agranulocytosis, thrombocytopenia, and anemia may occur in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no complicating factors. Neutropenia and agranulocytosis are reversible and resolve after discontinuation of the ACE inhibitor.

Extreme caution should be exercised when prescribing lisinopril to patients with connective tissue disorders with vascular manifestations who are undergoing immunosuppressive therapy, taking allopurinol or procainamide, or a combination of these factors, especially in the presence of renal impairment.

Severe infections, not always responsive to intensive antibiotic therapy, may develop in some of these patients. If lisinopril is used in such patients, periodic monitoring of white blood cell count is recommended, and patients should be advised to report any signs of infection.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS).

Since concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased risk of arterial hypotension, hyperkalemia, and renal impairment (including acute renal failure), dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended. When such combination therapy (dual blockade) is considered absolutely necessary, it should be administered under specialist supervision with careful monitoring of renal function, fluid and electrolyte balance, and blood pressure. Patients with diabetic nephropathy should not receive concomitant treatment with ACE inhibitors and angiotensin II receptor blockers.

Racial factors.

ACE inhibitors are more frequently associated with angioedema in black patients compared to patients of other racial backgrounds. Like other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in black patients compared to individuals of other races, possibly due to a higher prevalence of low renin levels in the black population with arterial hypertension.

Cough.

A persistent, non-productive cough may occur during ACE inhibitor therapy and resolves after discontinuation of treatment. This ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Surgery / anesthesia.

In patients undergoing surgery or general anesthesia with agents that lower blood pressure, lisinopril may block the compensatory renin-mediated increase in angiotensin II formation. If arterial hypotension is suspected to occur via this mechanism, it may be corrected by increasing circulating blood volume (CBV).

Use during pregnancy or breastfeeding.

The drug is contraindicated in pregnant women or women planning to become pregnant.

When continued antihypertensive therapy is considered essential, women planning pregnancy should be switched to alternative antihypertensive agents with established safety during pregnancy. If pregnancy is confirmed during treatment, ACE inhibitor therapy should be discontinued immediately and, if necessary, replaced with a drug approved for use during pregnancy.

ACE inhibitors used during the second and third trimesters of pregnancy are known to have toxic effects on the fetus (renal dysfunction, oligohydramnios, delayed skull ossification) and on the newborn (renal failure, arterial hypotension, hyperkalemia).

If ACE inhibitors were used during the second or third trimester of pregnancy, ultrasound evaluation of renal function and skull structure in the newborn is recommended.

Newborns whose mothers took ACE inhibitors during pregnancy should be monitored for timely detection and correction of arterial hypotension.

The drug is contraindicated during breastfeeding.

Ability to affect reaction speed when driving or operating machinery.

Dizziness and increased fatigue may occur and may affect the ability to drive or operate machinery.

Dosage and Administration

Take tablets orally once daily, preferably at the same time each day, independent of food intake. The daily dose should be individually adjusted depending on the patient's response and blood pressure.

Arterial Hypertension

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

Initial Dose

For arterial hypertension, the recommended initial dose is 10 mg once daily. In patients with increased activity of the renin-angiotensin-aldosterone system (particularly in renovascular hypertension, excessive sodium chloride loss, dehydration, heart failure, or severe hypertension), excessive hypotension may occur after administration of the initial dose. For these patients, the recommended initial dose is 2.5–5 mg, and treatment should be initiated under medical supervision.

To achieve a 2.5 mg dose, use a preparation containing the corresponding amount of active substance.

Dosage must be reduced in patients with renal impairment (see Table 1).

Maintenance Dose

The usual effective maintenance dose is 20 mg once daily. If the desired therapeutic effect is not achieved within 2–4 weeks at this dose, the dose may be further increased. The maximum daily dose is 80 mg.

Patients Receiving Diuretics

In patients already receiving diuretic therapy, symptomatic hypotension may occur after the first dose of lisinopril. Diuretic treatment should be discontinued 2–3 days before initiating therapy with this medication. If discontinuation of diuretics is not possible, lisinopril should be initiated at a dose of 5 mg. Renal function and serum potassium levels should be monitored. Subsequent doses should be adjusted according to blood pressure. Diuretic therapy may be resumed if necessary.

Patients with Renal Impairment

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

Table 1

*The dose and dosing regimen should be determined according to blood pressure values. The dose may be increased up to a maximum of 40 mg daily, with monitoring of arterial pressure.

Chronic heart failure.

In patients with symptomatic heart failure, lisinopril may be administered as an adjunct to therapy with diuretics, digitalis preparations, or β-blockers. The drug should be initiated at a dose of 2.5 mg once daily under medical supervision to assess the initial effect on arterial pressure. The dose of lisinopril should be increased by no more than 10 mg at intervals of at least 2 weeks, up to a maximum dose of 35 mg daily.

Dose selection should be based on individual clinical monitoring of each patient.

In patients at high risk of developing symptomatic hypotension (due to excessive sodium chloride loss), with or without hyponatremia, and in patients with hypovolemia, as well as in those receiving high doses of diuretics, these conditions should be corrected prior to initiating therapy.

Acute myocardial infarction.

Patients should simultaneously receive standard conventional therapy including thrombolytic agents, acetylsalicylic acid, and β-blockers. Lisinopril is compatible with intravenous or transdermal nitroglycerin.

Initial dose (within the first 3 days after myocardial infarction).

Lisinopril therapy should be initiated within the first 24 hours after onset of symptoms. Therapy should not be initiated if systolic arterial pressure is below 100 mm Hg. The first dose of lisinopril is 5 mg; another 5 mg dose should be administered 24 hours later, followed by 10 mg once daily. The maintenance dose is 10 mg once daily.

In patients with systolic arterial pressure of 120 mm Hg or lower during the first 3 days after infarction, a reduced dose of lisinopril (2.5 mg) should be administered.

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

Maintenance dose.

The maintenance dose is 10 mg daily. In case of arterial hypotension (systolic arterial pressure ≤ 100 mm Hg), the maintenance dose of 5 mg should be temporarily reduced to 2.5 mg. In case of prolonged arterial hypotension (systolic arterial pressure < 90 mm Hg for more than 1 hour), treatment should be discontinued.

Treatment should continue for 6 weeks, after which the patient's condition should be reassessed. Patients who develop symptoms of heart failure should continue lisinopril therapy.

Diabetic nephropathy.

For treatment of arterial hypertension in patients with type II diabetes and early nephropathy, the dose of lisinopril is 10 mg daily. If necessary, the dose may be increased to 20 mg daily to achieve diastolic arterial pressure below 90 mm Hg in the sitting position.

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

Elderly patients.

Clinical studies have not revealed differences in efficacy or safety of the drug related to age. The initial dose of lisinopril in elderly patients with reduced renal function should be adjusted according to Table 1. Subsequently, dosing should be determined based on the blood pressure response.

Patients with transplanted kidney.

There is no experience with the use of the drug in patients after recent kidney transplantation. Therefore, lisinopril therapy is not recommended in these patients.

Children.

Use in children is not recommended, as efficacy and safety have not been established.

Overdose.

Symptoms: arterial hypotension, circulatory shock, acute circulatory failure, electrolyte disturbances, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, restlessness, and cough.

Treatment: intravenous administration of saline solutions. In case of arterial hypotension, the patient should be placed in a supine position with legs elevated. If possible, infuse angiotensin II and/or administer catecholamines intravenously. If the drug has been recently ingested, measures should be taken to remove lisinopril from the body (e.g., induce vomiting, gastric lavage, use of adsorbents and sodium sulfate). For persistent bradycardia, cardiac pacing is indicated. Continuous monitoring of vital functions and laboratory parameters (electrolytes and serum creatinine levels) is recommended. Lisinopril is removed from the blood by hemodialysis; however, the use of high-flux membranes made of polyacrylonitrile-sodium 2-methylsulfonate (e.g., AN 69) should be avoided.

In case of angioneurotic edema, administer antihistamine agents. If the clinical condition involves swelling of the tongue, glottis, or larynx, emergency treatment with transdermal administration of 0.3–0.5 mL of epinephrine solution (1:1000) should be initiated immediately. Intubation or tracheotomy may be required to ensure airway patency.

Adverse Reactions

Adverse reactions listed below are categorized by frequency: very common (> 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1000, < 1/100); rare (≥ 1/10000, < 1/1000); very rare (< 1/10000); unknown (cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare: decreased hemoglobin and hematocrit levels;
Very rare: bone marrow depression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia, lymphadenopathy, autoimmune disease.

Metabolism and nutrition disorders:

Very rare: hypoglycemia.

Nervous system disorders:

Common: dizziness, headache;
Uncommon: mood changes, paresthesia, dizziness, taste disturbances, sleep disturbances;
Rare: confusion, impaired balance, disorientation, subjective sensation of tinnitus and reduced visual acuity, olfactory disturbances;
Unknown: symptoms of depression, loss of consciousness.

Cardiac disorders:

Common: arterial hypotension (especially after the first dose in patients with sodium depletion, dehydration, or heart failure); orthostatic effects (including arterial hypotension);
Uncommon: myocardial infarction or cerebrovascular stroke, possibly secondary to excessive hypotension in high-risk patients, palpitations, tachycardia, Raynaud's phenomenon.

When lisinopril is used in patients with acute myocardial infarction, atrioventricular block of degree II–III, severe arterial hypotension, and/or renal dysfunction may occur, particularly within the first 24 hours; in isolated cases – cardiogenic shock.

Musculoskeletal and connective tissue disorders:

Unknown: muscle spasms.

Respiratory, thoracic and mediastinal disorders:

Common: dry cough, bronchitis;
Uncommon: rhinitis;
Rare: dyspnea, angioneurotic edema;
Very rare: bronchospasm, sinusitis, allergic alveolitis / eosinophilic pneumonia, glossitis. Upper respiratory tract infections have been reported.

Gastrointestinal disorders:

Common: diarrhea, vomiting;
Uncommon: nausea, abdominal pain, dyspepsia;
Rare: dry mouth, decreased appetite, taste alterations;
Very rare: pancreatitis, intestinal angioneurotic edema, constipation, hepatitis (hepatocellular or cholestatic), jaundice, and hepatic failure.

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus, hypersensitivity / angioneurotic edema of the face, limbs, lips, tongue, glottis, and/or pharynx;
Rare: urticaria, alopecia, psoriasis;
Very rare: increased sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, polymorphic erythema, cutaneous lymphoma.

A syndrome comprising one or more of the following symptoms has been reported: fever, vasculitis, myalgia, arthralgia/arthritis, presence of positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia, leukocytosis, rash, photosensitivity.

Renal and urinary disorders:

Common: renal dysfunction;
Rare: uremia, acute renal failure;
Very rare: oliguria/anuria.

Endocrine disorders:

Unknown: inappropriate antidiuretic hormone secretion.

Reproductive system and breast disorders:

Uncommon: impotence;
Rare: gynecomastia.

General disorders:

Uncommon: increased fatigue, weakness.

Investigations:

Uncommon: increased blood urea nitrogen, increased serum creatinine, elevated liver enzymes, hyperkalemia;
Rare: increased serum bilirubin, hyponatremia, proteinuria.

Shelf life.

4 years. Do not use after the expiry date stated on the packaging.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Packaging.

Tablets of 10 mg and 20 mg.

10 tablets per blister; 2 blisters or 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ALKALOID AD Skopje.

Manufacturer's address.

Boulevard of Alexander the Great, 12, Skopje, 1000, Republic of North Macedonia.