Lipril

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

Composition:

Active substance: lisinopril;

1 tablet contains lisinopril (calculated as 100 % anhydrous lisinopril) − 5.0 mg, corresponding to lisinopril dihydrate − 5.44 mg; 10 mg, corresponding to lisinopril dihydrate − 10.89 mg; 20 mg, corresponding to lisinopril dihydrate − 21.78 mg;

Excipients: mannitol (E 421), calcium hydrogen phosphate dihydrate, maize starch, magnesium stearate; for 10 mg dosage – iron oxide yellow (E 172); for 20 mg dosage – iron oxide red (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

Lipril 5 mg per tablet − white, round, flat tablets with bevelled edges and a score line.

Lipril 10 mg per tablet − cream-colored, flat cylindrical tablets with bevelled edges and a score line. Marbling and specks on the tablet surface are permissible.

Lipril 20 mg per tablet − pink-colored, flat cylindrical tablets with bevelled edges and a score line. Marbling and specks on the tablet surface are permissible.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors. Lisinopril. ATC code C09A A03.

Pharmacological Properties

Pharmacodynamics

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

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

Pharmacokinetics

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

Absorption

After oral administration of lisinopril, maximum plasma concentration is reached within 7 hours. In patients with acute myocardial infarction, there is a tendency toward a slightly prolonged time to reach peak plasma concentration. The mean absorption of lisinopril is approximately 25% and varies among individual patients depending on the administered dose (5–80 mg), ranging from 6% to 60%. These data are based on the amount of drug recovered in urine. In patients with heart failure, absolute bioavailability is reduced by approximately 16%. The presence of food in the gastrointestinal tract does not affect lisinopril absorption.

Distribution

Lisinopril does not bind to other plasma proteins except circulating ACE. Studies in rats indicate that lisinopril poorly penetrates the blood-brain barrier.

Elimination

Lisinopril is not metabolized and is excreted unchanged entirely in urine. With repeated dosing, the effective cumulative half-life of lisinopril is 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 mL/min. Plasma concentration decline has a prolonged terminal phase, which does not affect drug accumulation. This final phase likely reflects strong binding to ACE and is not dose-proportional.

Pharmacokinetics in Special Patient Populations

Hepatic Impairment

Impaired liver function in patients with cirrhosis leads to reduced absorption of lisinopril (by approximately 30%) and increased exposure (by approximately 50%) compared to healthy volunteers, due to reduced clearance.

Renal Impairment

Renal impairment reduces the elimination of lisinopril, which is excreted by the kidneys, but this reduction is clinically significant only when glomerular filtration rate is below 30 mL/min. In mild to moderate renal impairment (creatinine clearance 30–80 mL/min), mean AUC increased by only 13%, whereas in severe renal impairment (creatinine clearance 5–30 mL/min), mean AUC increased 4.5-fold.

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 volunteers (mean AUC increased by 125%). However, based on the amount of lisinopril recovered in urine, absorption is reduced by approximately 16% compared to healthy volunteers.

Elderly Patients

In elderly patients, plasma concentrations of lisinopril and AUC values are higher (increased by approximately 60%) compared to younger patients.

Clinical characteristics.

Indications.

• Essential hypertension;
• heart failure (symptomatic treatment);
• acute myocardial infarction (short-term treatment (6 weeks) of patients with stable hemodynamic parameters no later than 24 hours after acute myocardial infarction);
• treatment of early nephropathy in patients with type 2 diabetes mellitus and arterial hypertension.

Contraindications.

• Hypersensitivity to lisinopril, to other components of the drug or to other ACE inhibitors;
• history of angioedema after ACE inhibitor therapy;
• idiopathic or hereditary angioedema;
• bilateral renal artery stenosis or stenosis of the artery of a solitary kidney;
• post-renal transplantation state;
• mitral or aortic stenosis, hypertrophic cardiomyopathy with pronounced hemodynamic disturbances;
• acute myocardial infarction with unstable hemodynamics;
• cardiogenic shock;
• use of high-flux membranes made of polyacrylonitrile-sodium-2-methylallylsulfonate (e.g., AN 69) during dialysis;
• concomitant use with drugs containing aliskiren in patients with diabetes mellitus or impaired renal function (eGFR < 60 mL/min/1.73 m²);
• serum creatinine level > 220 µmol/L;
• primary hyperaldosteronism;
• pregnancy or women planning to become pregnant (see "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive drugs: the hypotensive effect of lisinopril may be enhanced. Concomitant use with nitroglycerin and other organic nitrates or vasodilators may further reduce arterial pressure. Ganglion blockers or adrenergic neuron blockers may be used in combination with lisinopril only under strict monitoring.

Combination of lisinopril with aliskiren-containing drugs should be avoided.

Dual blockade of the RAAS by combined use of ACE inhibitors (including lisinopril), angiotensin receptor blockers (ARBs), or aliskiren is associated with a higher incidence of adverse effects such as arterial hypotension, hyperkalemia, and decreased renal function (including acute renal failure), compared to use of a single RAAS-blocking agent (see sections "Contraindications", "Special precautions").

Diuretics: additive antihypertensive effect is observed. In patients already receiving diuretics, especially those recently initiated on diuretic therapy, administration of lisinopril may occasionally cause excessive reduction in arterial pressure. The risk of symptomatic arterial hypotension can be minimized by discontinuing the diuretic prior to starting lisinopril therapy.

Potassium-sparing diuretics, potassium-containing dietary supplements, or potassium-containing salt substitutes: although serum potassium levels usually remained within normal limits in clinical trials of ACE inhibitors, hyperkalemia developed in some patients.

Risk factors for hyperkalemia include renal impairment, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), potassium-containing dietary supplements, or salt substitutes containing potassium.

Concomitant use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels, particularly in patients with impaired renal function.

During concomitant use of lisinopril with potassium-wasting diuretics, diuretic-induced hypokalemia may be attenuated.

Cyclosporine, heparin, trimethoprim/co-trimoxazole, lovastatin: increased risk of hyperkalemia when used in combination with ACE inhibitors.

Lithium preparations: reversible increase in serum lithium concentration and its toxic effects may occur when used concomitantly with ACE inhibitors. Concomitant use of thiazide diuretics may increase the risk of lithium intoxication and may potentiate toxicity already caused by simultaneous use of ACE inhibitors. Concomitant use of lisinopril with lithium is not recommended; however, if such combination is necessary, careful monitoring of serum lithium levels is required.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses ≥ 3 g per day, selective COX-2 inhibitors, and non-selective NSAIDs: reduced antihypertensive effect of ACE inhibitors. Concomitant use of NSAIDs and ACE inhibitors may lead to deterioration of renal function, including acute renal failure, particularly in elderly patients and in dehydrated patients (including those on diuretic therapy), and may cause additive effects on increasing serum potassium levels, especially in patients with pre-existing renal impairment. These effects are usually reversible. Such combinations should be used cautiously, particularly in patients with renal impairment, with periodic monitoring of renal function.

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

Tricyclic antidepressants, antipsychotic agents, and anesthetics: possible potentiation of arterial hypotension.

Sympathomimetics: may reduce the antihypertensive effect of ACE inhibitors.

Hypoglycemic agents (insulins, oral hypoglycemic agents): possible potentiation of blood glucose-lowering effect with increased risk of hypoglycemia. The likelihood of this effect is particularly high during the first weeks of combination therapy and in patients with impaired renal function.

Estrogens, corticosteroids: possible reduction in antihypertensive effect of ACE inhibitors due to fluid retention.

Interleukin-2 (aldesleukin): enhanced hypotensive effect of ACE inhibitors.

Myelosuppressive agents: increased risk of neutropenia and/or agranulocytosis.

Cytostatics, immunosuppressants, corticosteroids, procainamide: concomitant use with lisinopril may lead to development of leukopenia.

Allopurinol: increased risk of leukopenia and hypersensitivity reactions, especially in patients with impaired renal function.

Tissue plasminogen activators, immunosuppressants such as mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus): possible increased risk of angioedema.

Antacids: may reduce the bioavailability of lisinopril; therefore, Lipril should be taken 1–2 hours before or 1–2 hours after antacid administration.

Lisinopril may be administered concomitantly with acetylsalicylic acid (at cardiologically recommended doses), thrombolytics, β-blockers, and/or nitrates.

Alcohol potentiates the hypotensive effect of ACE inhibitors.

Special precautions for use.

Symptomatic arterial hypotension.

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated hypertension. In patients with arterial hypertension receiving lisinopril, hypotension occurs more frequently in the presence of hypovolemia, for example, during diuretic therapy, salt restriction in diet, dialysis, diarrhea, or vomiting, or in severe forms of renin-dependent hypertension. Cases of symptomatic hypotension have been observed in patients with heart failure, with or without associated renal insufficiency. It occurs more frequently in patients with more severe degrees of heart failure who require high doses of loop diuretics, have hyponatremia, or functional renal impairment.

Initiation of therapy and dose adjustment in patients at increased risk of symptomatic hypotension should be performed under close medical supervision. Such monitoring is also necessary for patients with ischemic heart disease or cerebrovascular disease, in whom excessive blood pressure reduction may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position, and if necessary, receive intravenous infusion of sodium chloride physiological solution. Transient arterial hypotension during treatment with the drug is not a contraindication for its continued use after normalization of blood pressure and restoration of circulating blood volume.

In some patients with heart failure and normal or low blood pressure, the drug may further reduce systemic arterial pressure. This effect is expected and usually not a reason to discontinue treatment. However, if hypotension becomes symptomatic, dose reduction or discontinuation of lisinopril may be required.

Arterial hypotension in acute myocardial infarction.

Lisinopril therapy should not be initiated in patients with acute myocardial infarction if there is a risk of further serious hemodynamic disturbances following vasodilator therapy. This applies to patients with systolic blood pressure of 100 mm Hg or lower, or those in cardiogenic shock. If systolic blood pressure is 120 mm Hg or lower, the dose of the drug should be reduced during the first 3 days after infarction. If systolic blood pressure is 100 mm Hg or lower, the maintenance dose should be reduced to 5 mg or temporarily to 2.5 mg. If arterial hypotension persists (systolic blood pressure < 90 mm Hg for over 1 hour), lisinopril should be discontinued.

Valvular stenosis of aortic and/or mitral valve / hypertrophic cardiomyopathy.

Like other ACE inhibitors, lisinopril is not recommended for patients with mitral valve stenosis or outflow obstruction from the left ventricle (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 adjusted according to creatinine clearance (see Table 1), and subsequently according to blood pressure levels. Such patients require periodic monitoring of serum potassium and creatinine levels.

In patients with heart failure, arterial hypotension caused by ACE inhibitors may lead to further deterioration of renal function, potentially resulting in reversible (after discontinuation of the drug) acute renal failure.

In some patients with arterial hypertension without evident signs of renovascular disease, a slight transient increase in serum urea and creatinine levels may occur, especially when lisinopril is used concomitantly with diuretics. This is more likely in patients with pre-existing renal impairment. This condition may require dose reduction and/or discontinuation of the diuretic and/or lisinopril.

In acute myocardial infarction, lisinopril therapy is not indicated in patients with signs of renal dysfunction (serum creatinine concentration (SCr) > 177 µmol/L and/or proteinuria > 500 mg/day). If renal dysfunction develops during lisinopril therapy (SCr > 265 µmol/L or doubling of baseline levels), the physician should consider discontinuing the drug.

Patients after kidney transplantation.

There is no experience with the use of the drug in patients with recently transplanted kidneys; therefore, the drug should not be used in this patient group.

Hypersensitivity / angioedema.

Angioedema of the face, extremities, lips, tongue, vocal cords, and/or larynx has been observed in individual cases in patients treated with ACE inhibitors, including lisinopril. Angioedema may develop at any time during treatment. In such cases, lisinopril should be discontinued immediately, appropriate treatment initiated, and the patient observed until symptoms completely resolve.

Even in cases where swelling is limited to the tongue and without respiratory symptoms, patients may require prolonged monitoring, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal cases due to angioedema of the larynx or tongue have been very rarely reported. If swelling involves the tongue, vocal cords, or larynx, airway obstruction may occur, particularly in patients who have previously undergone surgery on the respiratory tract. In such cases, immediate emergency measures should be taken (administration of adrenaline (epinephrine) and/or airway support). The patient should remain under close medical supervision until symptoms have completely and stably resolved.

Patients with a history of angioedema unrelated to ACE inhibitor therapy may have an increased risk of developing angioedema during ACE inhibitor treatment.

Anaphylactoid reactions during hemodialysis.

Patients undergoing dialysis with high-flux membranes (e.g., AN 69) while receiving concomitant ACE inhibitor therapy are at risk of anaphylactoid reactions. These patients are advised to use a different type of dialysis membrane or another class of antihypertensive agents.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis.

Rarely, life-threatening anaphylactoid reactions may occur in patients receiving ACE inhibitors during dextran sulfate LDL apheresis. These reactions can be avoided by temporarily withholding ACE inhibitor therapy before each apheresis session.

Anaphylactoid reactions during desensitization therapy.

In patients receiving ACE inhibitors, prolonged anaphylactoid reactions have occurred during allergen desensitization therapy (e.g., with Hymenoptera venom). Avoiding ACE inhibitors during desensitization may prevent such reactions, but accidental re-administration of ACE inhibitors may trigger anaphylactoid reactions.

Hepatic function impairment.

Very rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice or hepatitis and progressing to fulminant hepatic necrosis, sometimes with fatal outcome. The mechanism of this syndrome is unknown. If patients receiving ACE inhibitors develop jaundice or marked elevation of hepatic enzymes in serum, the drug should be discontinued and the patient kept under medical supervision until symptoms resolve.

Neutropenia/agranulocytosis.

Cases of neutropenia/agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and without other complicating factors. Neutropenia and agranulocytosis are reversible upon discontinuation of ACE inhibitors.

Lisinopril should be used with particular caution in patients with connective tissue diseases, those receiving immunosuppressants, allopurinol, or procainamide, and especially in combination with these risk factors, particularly if renal impairment already exists.

In some of these patients, severe infections have developed, sometimes unresponsive to intensive antibiotic therapy. Periodic monitoring of white blood cell counts is recommended in such patients receiving lisinopril, and patients should be advised to inform their physician of any signs of infection.

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

Concomitant use of ACE inhibitors (including lisinopril), angiotensin II receptor blockers (ARBs), or aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal function deterioration (including acute renal failure). Therefore, dual RAAS blockade by combining ACE inhibitors with ARBs or aliskiren is not recommended.

If dual RAAS blockade is considered absolutely necessary, it should occur only under close specialist supervision with frequent and careful monitoring of renal function, serum electrolytes (especially potassium), and blood pressure.

ACE inhibitors and ARBs should not be used concomitantly in patients with diabetic nephropathy.

Ethnic characteristics.

Angioedema occurs more frequently in patients of Black race receiving ACE inhibitors compared to patients of other races. As with other ACE inhibitors, the antihypertensive effect of lisinopril is less pronounced in patients of Black race than in patients of other races, possibly due to a higher prevalence of low-renin hypertension in Black patients.

Cough.

Treatment with ACE inhibitors may cause a non-productive, persistent cough that resolves after discontinuation of the drug. ACE inhibitor-induced cough should be differentiated from cough due to other diseases.

Surgical procedures/anesthesia.

During major surgical procedures or anesthesia with agents causing arterial hypotension, lisinopril may block angiotensin II formation due to compensatory renin release. If arterial hypotension occurs due to this mechanism, it should be managed by increasing circulating blood volume.

Hyperkalemia.

Increased serum potassium concentration has been observed in some patients receiving ACE inhibitors, including lisinopril. Risk factors for hyperkalemia include renal impairment, diabetes mellitus, concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing dietary supplements or potassium salt substitutes, or other drugs that increase serum potassium (e.g., heparin, trimethoprim/sulfamethoxazole combination, also known as co-trimoxazole). If concomitant use of these agents with ACE inhibitors is considered necessary, regular monitoring of serum potassium and renal function is recommended.

Monitoring of serum electrolytes is particularly important in patients receiving potassium-sparing diuretics and ACE inhibitors or ARBs for heart failure. In such cases, the lowest effective doses of potassium-sparing diuretics and ACE inhibitors/ARBs should be used. In case of hyperkalemia, consideration should be given to suspending or discontinuing treatment.

Diabetes mellitus.

Patients receiving oral antidiabetic agents or insulin require careful glycemic monitoring, especially during the first month of ACE inhibitor therapy.

Primary hyperaldosteronism.

ACE inhibitors are ineffective in patients with primary hyperaldosteronism; therefore, the drug should not be used in this patient group.

Lithium.

Concomitant use of lithium and lisinopril is generally not recommended.

Use during pregnancy or breastfeeding.

ACE inhibitors are contraindicated in pregnant women or women planning to become pregnant.

Epidemiological data on teratogenic risk during ACE inhibitor use in the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. Data on the use of ACE inhibitors in the second and third trimesters indicate fetotoxicity (impaired renal function, oligohydramnios, cranial hypoplasia) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

When planning pregnancy, alternative antihypertensive therapy with a well-established safety profile during pregnancy should be selected.

If pregnancy is detected during ACE inhibitor therapy, treatment should be discontinued immediately and replaced, if necessary, with medications approved for use during pregnancy. In such cases, ultrasound monitoring of fetal renal and cranial development is recommended.

Newborns whose mothers received ACE inhibitors during pregnancy require careful monitoring due to the potential risk of developing arterial hypotension, oliguria, and hyperkalemia.

Since information on the use of lisinopril during breastfeeding is lacking, the drug is contraindicated in breastfeeding women. An alternative antihypertensive therapy with a better-established safety profile during breastfeeding should be selected, especially when nursing a newborn or preterm infant.

Ability to influence reaction speed when driving or operating machinery.

Neurological adverse reactions (dizziness, confusion, drowsiness) may occur during treatment, especially at the beginning of therapy. Therefore, patients should refrain from driving or operating machinery until individual response to the drug is established.

Dosage and Administration.

The drug should be taken once daily in the morning, preferably at the same time each day, with a sufficient amount of water. Lisinopril may be taken independently of food intake.

The dosage and duration of treatment are determined individually by a physician, depending on the severity of the disease, renal function, and concomitant therapy.

Essential hypertension.

Lisinopril may be used as monotherapy or in combination with other antihypertensive agents.

Initial dose. The recommended initial dose is 10 mg once daily. In patients with increased activity of the renin-angiotensin-aldosterone system (e.g., in renovascular hypertension, excessive electrolyte loss and/or dehydration, cardiac decompensation, or severe arterial hypertension), an excessive reduction in arterial pressure may occur after the initial dose. Therefore, such patients should be under medical supervision at the beginning of treatment, and the recommended initial dose should be 2.5–5 mg.

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.

Patients taking diuretics.

In patients receiving diuretic therapy, symptomatic arterial hypotension may occur after the first dose of the drug. Diuretic therapy should be discontinued 2–3 days prior to initiating lisinopril. If discontinuation of diuretics is not feasible, the initial dose of lisinopril should not exceed 5 mg daily. Renal function and serum potassium levels should be monitored. The subsequent dosing regimen should be adjusted according to blood pressure readings. If necessary, diuretic therapy may be resumed.

Patients with renal impairment.

For patients with renal impairment, the initial dose should be determined based on creatinine clearance values (see Table 1).

Table 1

Dosage adjustment in renal impairment

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

*The dose and/or dosing regimen should be adjusted according to blood pressure values.

The dose may be increased up to a maximum of 40 mg daily under blood pressure monitoring.

Heart failure.

In patients with symptomatic heart failure, lisinopril may be used as an adjunct to therapy with diuretics, digitalis preparations, or β-adrenergic blockers.

The initial dose, which must be administered under medical supervision to assess the initial effect on blood pressure, is 2.5 mg once daily. The dose may be increased in increments of no more than 10 mg at intervals of at least 2 weeks, up to a maximum dose of 35 mg once daily.

Dose adjustments should take into account the individual patient's clinical response.

In patients at high risk of developing symptomatic hypotension (e.g., those with or without electrolyte depletion and hyponatremia, hypovolemia, or those receiving intensive diuretic therapy), these conditions should be corrected prior to initiating therapy. Lisinopril treatment should be administered under monitoring of renal function and serum potassium levels.

Acute myocardial infarction.

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

Lisinopril therapy should be initiated within the first 24 hours after onset of symptoms of myocardial infarction according to the following regimen: initial dose of 5 mg, the next dose (after 24 hours) – 5 mg, then (after 48 hours) – 10 mg. Thereafter, the maintenance dose is 10 mg once daily. For patients with low systolic blood pressure (≤120 mm Hg) at the start of treatment or within the first 3 days after myocardial infarction, initiate treatment with 2.5 mg.

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).

The maintenance dose is 10 mg once daily. If arterial hypotension occurs (systolic blood pressure ≤100 mm Hg), temporarily reduce the maintenance dose from 5 mg to 2.5 mg. If prolonged arterial hypotension occurs (systolic blood pressure <90 mm Hg for more than 1 hour), treatment should be discontinued.

The duration of treatment is 6 weeks; thereafter, the patient's condition should be re-evaluated. The development of symptoms of heart failure does not preclude continued use of the drug.

Diabetic nephropathy.

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

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

Elderly patients.

No differences in efficacy or safety of the drug have been observed depending on patient age. For initiating lisinopril therapy in elderly patients with impaired renal function, refer to Table 1. Thereafter, the dose should be adjusted according to blood pressure values.

Children.

The efficacy and safety of lisinopril in children have not been established; therefore, the drug should not be used in this age group.

Overdose.

Symptoms: arterial hypotension, circulatory shock, disturbances in water-electrolyte balance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, restlessness, and cough.

Treatment: symptomatic. Intravenous administration of normal saline is recommended. In case of arterial hypotension, the patient should be placed in a supine position with legs elevated. Infusion of angiotensin II and/or intravenous administration of catecholamines may be considered. If drug ingestion was recent, induction of emesis, gastric lavage, administration of enterosorbents, and sodium sulfate are recommended for drug elimination. Lisinopril may be removed from the body by hemodialysis; however, the use of high-flux polysulfone metalloacrylonitrile membranes (e.g., AN 69) should be avoided.

For treatment of persistent bradycardia, cardiac pacing is indicated. Continuous monitoring of vital functions, serum electrolyte concentrations, and creatinine levels is required.

In case of angioedema development, appropriate emergency therapy is required (administration of adrenaline (0.3–0.5 mL of a 1:1000 adrenaline solution) subcutaneously, glucocorticoids, antihistamines, and securing airway patency via intubation or tracheotomy).

Adverse reactions.

Blood and lymphatic system: decreased hemoglobin and hematocrit levels, bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia, lymphadenopathy, autoimmune disorders.

Nervous system: dizziness, headache, mood changes, paresthesia, vertigo, taste disturbances, sleep disorders, confusion, olfactory disturbances, loss of balance, disorientation, tinnitus, decreased visual acuity, symptoms of depression, syncope, hallucinations.

Cardiovascular system: arterial hypotension (especially after the first dose in patients with sodium deficiency, dehydration, or heart failure), orthostatic effects (including hypotension), myocardial infarction or cerebrovascular stroke, possibly secondary to excessive arterial hypotension in high-risk patients; palpitations, tachycardia, Raynaud's phenomenon. When lisinopril is administered to patients with acute myocardial infarction, second- or third-degree AV block, severe arterial hypotension and/or renal dysfunction may occur, particularly within the first 24 hours; in isolated cases, cardiogenic shock.

Musculoskeletal system: muscle spasms have been reported.

Respiratory system, thoracic organs and mediastinum: cough, rhinitis, bronchitis, dyspnea, bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia. Upper respiratory tract infections have been reported.

Gastrointestinal tract and hepatobiliary system: diarrhea, constipation, vomiting, nausea, abdominal pain, dyspepsia, dry mouth, glossitis, decreased appetite, pancreatitis, intestinal angioedema, hepatocellular or cholestatic hepatitis, jaundice, hepatic failure.

Skin and subcutaneous tissues: rash, pruritus, urticaria, alopecia, psoriasis, hypersensitivity reactions/angioedema: angioedema of the face, extremities, lips, tongue, vocal cords and/or larynx, hyperhidrosis, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma.

A complex reaction involving one or more of the following symptoms has been reported: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibody test, elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity reactions or other dermatological manifestations.

Urinary system: renal dysfunction, uremia, acute renal failure, oliguria/anuria.

Endocrine system: inadequate secretion of antidiuretic hormone.

Reproductive system and mammary glands: impotence, gynecomastia.

Metabolic disorders: hypoglycemia, gout.

General disorders and administration site conditions: increased fatigue, asthenia.

Laboratory test results: increased levels of urea, creatinine, bilirubin and liver enzymes in blood serum, hyperkalemia, hyponatremia, proteinuria.

Shelf life. 3 years.

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

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 3 blisters per carton; 60 tablets in a container, 1 container per carton; 90 tablets in a container, 1 container per carton.

Prescription category. Prescription only.

Manufacturer.

Public Joint-Stock Company "Scientific and Production Center "Borshchahivskiy Chemical and Pharmaceutical Plant".

Limited Liability Company "AGROFARM".

Manufacturer's address and place of business.

Ukraine, 03134, Kyiv, Miru St., 17.

Ukraine, 08200, Kyiv Oblast, Irpin, Centralna St., 113-A.