Lisinopril-astrafarm

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LIZINOPRIL-ASTRAPHARM (LISINOPRIL-ASTRAPHARM)

Composition:

Active substance: lisinopril;

1 tablet contains 5 mg, 10 mg, or 20 mg of lisinopril;

Excipients: calcium hydrogen phosphate, mannitol (E 421), maize starch, magnesium stearate, colloidal anhydrous silicon dioxide.

Pharmaceutical form. Tablets.

Main physicochemical properties: white, flat cylindrical tablets with bevelled edges and a score line.

Pharmacotherapeutic group.

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

Pharmacological Properties

Pharmacodynamics

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

Since the antihypertensive mechanism of action 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 elevated bradykinin levels (which has potent 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 considerable interindividual variability (6–60%). Concomitant food intake does not affect absorption. Maximum plasma concentration is reached approximately within 6–8 hours.

Distribution. Steady-state serum concentrations are achieved within 2–3 days after initiation of therapy. Apart from binding to ACE, lisinopril does not bind to plasma proteins.

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 is reduced proportionally to the degree of functional impairment (this reduction becomes clinically significant when glomerular filtration rate is below 30 mL/min).

In patients with heart failure, renal clearance of lisinopril is reduced.

Elderly patients have higher plasma concentrations of lisinopril and higher area under the concentration-time curve (AUC) values (approximately 60% higher) compared to younger patients.

Clinical characteristics.

Indications.

Arterial hypertension.

Heart failure (symptomatic treatment).

Acute myocardial infarction (short-term treatment (6 weeks) of hemodynamically stable patients no later than 24 hours after acute myocardial infarction).

Renal complications in diabetes mellitus (treatment of kidney disease in hypertensive patients with type 2 diabetes mellitus and initial nephropathy).

Contraindications.

Hypersensitivity to lisinopril, to other components of the drug or to other angiotensin-converting enzyme (ACE) inhibitors.

History of angioedema (including after use of ACE inhibitors, idiopathic or hereditary angioedema, Quincke's edema).

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

Bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; acute myocardial infarction with unstable hemodynamics; cardiogenic shock; concomitant use of the drug and high-flux membranes made of polyacrylonitrile-sodium 2-methylallylsulfonate (e.g., AN 96) during emergency dialysis; patients with serum creatinine level ≥ 220 μmol/L.

Concomitant use of aliskiren-containing drugs in patients with diabetes mellitus or renal function impairment (GFR < 60 mL/min/1.73 m²).

Primary hyperaldosteronism.

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

Concomitant use with sacubitril/valsartan. Treatment with Lisinopril-Astrafarm may be initiated only 36 hours after the last dose of sacubitril/valsartan (see 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.

Diuretics. The antihypertensive effect is usually enhanced when diuretics are used concomitantly in patients already taking lisinopril. At the beginning of combination therapy with lisinopril and diuretics, patients may experience excessive reduction in blood pressure. The possibility of symptomatic arterial hypotension with lisinopril may be reduced by discontinuing diuretic therapy prior to starting lisinopril, increasing fluid or salt volume, and initiating therapy with low doses of ACE inhibitors.

MEDICINAL PRODUCTS THAT INCREASE THE RISK OF ANGIOEDEMA. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Concomitant use of ACE inhibitors with racecadotril, mammalian target of rapamycin (mTOR) inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (see section "Special precautions for use").

Potassium-sparing diuretics, potassium-containing dietary supplements or salt substitutes. Although serum potassium levels usually remained within normal limits in clinical trials of ACE inhibitors, hyperkalemia did occur in some patients. Risk factors for hyperkalemia include renal impairment, diabetes mellitus, and concomitant use of potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes.

The use of potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels, particularly in patients with impaired renal function. Hypokalemia caused by potassium-wasting diuretics may be attenuated during lisinopril therapy.

Caution should also be exercised when using Lisinopril-Astrafarm concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of Lisinopril-Astrafarm with the above-mentioned medicinal products is not recommended. If concomitant use of these drugs is indicated, treatment should be carried out with caution and serum potassium levels should be monitored frequently.

Cyclosporine. Hyperkalemia may occur when ACE inhibitors are used concomitantly with cyclosporine. Monitoring of serum potassium levels is recommended.

Heparin. Hyperkalemia may occur when ACE inhibitors are used concomitantly with 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 toxic effects. The use of thiazide diuretics may increase the risk of lithium intoxication and may exacerbate it if already induced by concomitant use of ACE inhibitors. Concomitant use of lisinopril with lithium is not recommended, but in cases where such combination is necessary, careful monitoring of serum lithium levels should be performed.

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, which may lead to renal dysfunction. These effects are usually reversible. In individual cases, acute renal failure may occur, particularly in patients with impaired renal function, e.g., elderly patients or those with dehydration.

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

Other antihypertensive agents (β-blockers, α-blockers, calcium antagonists). When lisinopril is used concomitantly with other antihypertensive agents, an enhanced hypotensive effect is observed. Concomitant use of nitroglycerin and other organic nitrates or vasodilators may enhance the hypotensive effect of lisinopril.

Tricyclic antidepressants, anesthetics, and antipsychotics. Administration of certain anesthetics, tricyclic antidepressants, and antipsychotics during ACE inhibitor therapy may enhance arterial hypotension.

Sympathomimetic agents. Sympathomimetic drugs may reduce the antihypertensive effect of ACE inhibitors. Therefore, blood pressure should be monitored more carefully to determine whether the desired therapeutic effect has been achieved.

Hypoglycemic agents. Epidemiological studies have shown that concomitant use of ACE inhibitors and hypoglycemic agents (insulins and oral hypoglycemic agents) may enhance 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 impaired renal function.

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Dual blockade of RAAS with concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren has been shown to be associated with a higher incidence of adverse reactions such as arterial hypotension, hyperglycemia, and renal impairment (including acute renal failure), compared to monotherapy.

Allopurinol, cytostatics, immunosuppressants, corticosteroids, procainamide. Concomitant use with lisinopril may cause leukopenia.

MEDICINAL PRODUCTS THAT SUPPRESS BONE MARROW FUNCTION. Concomitant use with lisinopril increases the risk of neutropenia and/or agranulocytosis.

Estrogens. Concomitant use of estrogens with lisinopril may reduce the antihypertensive effect of lisinopril due to fluid retention.

Other

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

Narcotics, anesthetics, alcohol, and sedatives in combination with lisinopril may enhance the hypotensive effect.

Special precautions for use.

Symptomatic arterial hypotension.

Rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving lisinopril, the risk 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 is most commonly seen in patients with severe heart failure who require high doses of loop diuretics and who have hyponatremia or functional renal impairment. 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 blood pressure may lead to myocardial infarction or impaired cerebral circulation.

In the event of arterial hypotension, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of sodium chloride solution. Transient hypotensive response is not a contraindication for subsequent administration of the drug. After restoration of effective blood volume and resolution of transient hypotension, lisinopril therapy may be continued.

In some patients with chronic heart failure who have normal or low blood pressure, additional reduction in systemic arterial pressure may occur upon initiation of lisinopril. This effect is expected and usually not a reason to discontinue therapy. However, if symptomatic arterial hypotension develops, dose reduction or discontinuation of lisinopril may be required.

Arterial hypotension in acute myocardial infarction. In patients with acute myocardial infarction and stable hemodynamics, lisinopril therapy should be initiated within the first 24 hours to prevent left ventricular dysfunction and heart failure, as well as to reduce mortality. Lisinopril therapy should not be initiated in acute myocardial infarction if there is a risk of further serious hemodynamic disturbances following vasodilator treatment. This applies to patients with systolic blood pressure ≤100 mm Hg or those who have developed cardiogenic shock. During the first 3 days after myocardial infarction, the dose of the drug should be reduced if systolic pressure does not exceed 120 mm Hg. If systolic arterial pressure is ≤100 mm Hg, the dose should be reduced to 5 mg or temporarily to 2.5 mg. If prolonged arterial hypotension occurs after lisinopril administration (systolic pressure remains below 90 mm Hg for more than 1 hour), lisinopril therapy must be discontinued.

In patients with hypovolemia and sodium deficiency due to diuretic use, salt-free diet, vomiting, diarrhea, or after dialysis, sudden severe arterial hypotension and acute renal failure may occur. In such cases, fluid and electrolyte losses should be corrected before starting lisinopril therapy, and adequate medical supervision should be ensured. The drug should be prescribed with particular caution (considering benefit-risk ratio) to patients after kidney transplantation, as well as to patients with renal or hepatic dysfunction, hematological disorders, or autoimmune diseases. All these pathological conditions during lisinopril use require appropriate medical monitoring and laboratory control.

Aortic and mitral stenosis/hypertrophic cardiomyopathy.

Like other ACE inhibitors, lisinopril should be used with caution in patients with mitral stenosis or impaired left ventricular ejection (e.g., in 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 according to the patient's creatinine clearance (see Table 1), and subsequently adjusted based on 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, initiation of ACE inhibitors may lead to worsening renal function. Acute renal failure, usually reversible, has been reported in such cases. In some patients with bilateral renal artery stenosis or stenosis of the artery of a single kidney, ACE inhibitors may increase blood urea and serum creatinine levels; these changes are usually reversible upon discontinuation of the drug. The likelihood of such changes is particularly high in patients with pre-existing renal impairment.

In patients with renovascular hypertension, there is a high risk of developing severe arterial hypotension and renal failure. In such patients, treatment should be initiated under close medical supervision with low, carefully titrated doses. Since diuretics may contribute to the clinical course 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 but no apparent renal vascular disease, lisinopril administration—especially in combination with diuretics—may lead to increased blood urea and serum creatinine levels. These changes are usually mild and transient. The likelihood of such changes is higher in patients with impaired renal function. In such cases, dose reduction, discontinuation of diuretics, or discontinuation of lisinopril may be necessary.

Lisinopril is not indicated for the treatment of acute myocardial infarction 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 doubles compared to baseline levels), the drug should be discontinued.

Hypersensitivity/angioedema. Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been very rarely reported in patients receiving ACE inhibitors, including lisinopril. Angioedema may occur at any time during treatment. In such cases, the drug must be discontinued immediately, appropriate therapy initiated, and the patient monitored until complete resolution of symptoms. Even 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.

Fatal cases due to laryngeal or lingual angioedema have been reported. If swelling involves the tongue, glottis, or larynx, obstructive airway compromise may develop, particularly in patients with prior surgical procedures on the airways. In such cases, emergency measures must be initiated immediately, including administration of adrenaline and/or securing airway patency. The patient must remain under close medical supervision until symptoms have completely and stably resolved.

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.

ACE inhibitors may cause more frequent angioedema in patients of Black race compared to patients of Caucasian race.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy may be initiated only 36 hours after the last dose of lisinopril. Lisinopril therapy may be initiated only 36 hours after the last dose of sacubitril/valsartan.

Concomitant use of ACE inhibitors with racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., airway or lingual swelling with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Caution is advised when initiating racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already receiving an ACE inhibitor.

Hemodialysis.

Anaphylactoid reactions may occur when the drug is administered during dialysis with a polyacrylonitrile membrane. It is recommended to use alternative dialysis membranes or alternative antihypertensive drugs in patients undergoing dialysis.

Anaphylactoid reactions during LDL apheresis.

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

Desensitization.

Prolonged anaphylactoid reactions have been reported in patients receiving ACE inhibitors during desensitization therapy (e.g., for hymenoptera venom). When such patients discontinued ACE inhibitors during desensitization, no reactions occurred; however, accidental administration of an ACE inhibitor triggered an anaphylactoid reaction.

Hepatic impairment.

Rare cases of a syndrome associated with cholestatic jaundice or hepatitis progressing to fulminant hepatic necrosis, sometimes fatal, have been reported with ACE inhibitors. The mechanism of this syndrome is unclear. If jaundice or markedly elevated liver enzymes develop in patients receiving lisinopril, the drug should be discontinued, and the patient should remain 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 no other complicating factors. Neutropenia and agranulocytosis are reversible upon discontinuation of the ACE inhibitor. Lisinopril should be prescribed with extreme caution in patients with collagen vascular diseases, those receiving immunosuppressive therapy, or those treated with allopurinol or procainamide, or in combination of these risk factors, especially in the presence of renal impairment. Severe infections, not always responsive to intensive antibiotic therapy, have occurred in some such patients. Periodic monitoring of white blood cell counts and patient instruction to report any signs of infection are recommended when using the drug in these patients.

Cough. Cough may occur after administration of ACE inhibitors. This cough is usually non-productive and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of chronic cough.

Surgery/anesthesia. In patients undergoing surgery or anesthesia with agents that may cause arterial hypotension, lisinopril may block angiotensin II formation following compensatory renin secretion. If hypotension occurs due to this mechanism, circulating blood volume should be restored.

Serum potassium levels. Several cases of elevated serum potassium levels have been reported in patients receiving ACE inhibitors, including lisinopril. Patients at high risk of hyperkalemia include those with renal impairment, diabetes mellitus, or hypoaldosteronism. ACE inhibitors may cause hyperkalemia due to inhibition of aldosterone release. This effect is usually mild in patients with normal renal function. However, in patients with renal impairment and/or those taking potassium-containing supplements (including salt substitutes), potassium-sparing diuretics, or other drugs that increase serum potassium (e.g., heparin, trimethoprim or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and particularly aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may occur. Caution is required when using potassium-sparing diuretics and angiotensin receptor blockers in patients receiving ACE inhibitors. Serum potassium and renal function should be monitored in such patients (see section "Interaction with other medicinal products and other forms of interaction").

If concomitant use of the above-mentioned drugs with lisinopril is considered necessary, regular monitoring of serum potassium levels is recommended.

Hyperkalemia.

Elevated serum potassium levels have been observed in some patients receiving ACE inhibitors, including lisinopril. Patients at risk of hyperkalemia include those with renal impairment or diabetes mellitus who are taking potassium-sparing diuretics, potassium-containing salt substitutes, or other drugs that increase serum potassium (e.g., heparin).

If use of the above-mentioned drugs during ACE inhibitor therapy is deemed necessary, regular monitoring of serum potassium levels is recommended.

Patients with diabetes mellitus.

Patients with diabetes mellitus receiving antidiabetic agents or insulin should have their blood glucose levels closely monitored during the first month of ACE inhibitor therapy.

Lithium.

Concomitant use of lithium and lisinopril is generally not recommended.

Racial factors.

ACE inhibitors more frequently cause angioedema in patients of Black race compared to other racial groups. Like other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in Black patients compared to other racial groups, possibly due to a higher prevalence of low-renin hypertension in this population.

Primary hyperaldosteronism.

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

Dual blockade of the RAAS.

Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been associated with increased risk of arterial hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

If dual blockade therapy is absolutely necessary, it should be administered under specialist supervision with regular monitoring of renal function, electrolyte levels, and blood pressure. Concomitant use of ACE inhibitors and angiotensin II receptor blockers is not recommended in patients with diabetic nephropathy.

Proteinuria. Isolated cases of proteinuria have been reported in patients, particularly those with reduced renal function or after high doses of lisinopril. In cases of clinically significant proteinuria (>1 g/day), lisinopril should be used only after careful assessment of therapeutic benefit versus potential risk, and with continuous monitoring of clinical and biochemical parameters.

The product contains mannitol, which may cause a mild laxative effect.

Use during pregnancy or breastfeeding.

Pregnancy. The medicinal product is contraindicated during pregnancy and in women planning pregnancy. If pregnancy is confirmed during treatment with this medicinal product, administration should be discontinued immediately and, if necessary, replaced with another medicinal product approved for use during pregnancy.

It is known that prolonged exposure to ACE inhibitors during the second and third trimesters of pregnancy causes fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia). If exposure to ACE inhibitors occurs during the second trimester of pregnancy, renal and skull bone function should be monitored by ultrasound.

Newborns whose mothers received lisinopril should be carefully monitored for arterial hypotension, oliguria, and hyperkalemia.

Breastfeeding. Since information on the use of lisinopril during breastfeeding is lacking, lisinopril is not recommended during lactation. An alternative treatment with a better-established safety profile should be considered during this period, especially when nursing a newborn or premature infant.

Ability to influence reaction speed when driving or operating machinery.

Due to the possibility of dizziness and fatigue, lisinopril may affect the ability to drive or operate machinery, especially at the beginning of treatment. Therefore, patients should refrain from driving or operating machinery until their individual response to the drug has been established.

Method of administration and dosage.

Tablets are taken 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 levels.

Arterial hypertension.

The drug may 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, cardiac decompensation, or severe arterial hypertension), excessive reduction in blood pressure may occur after the initial dose. In such 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 the formulation containing the corresponding amount of active ingredient.

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 with this dose within 2–4 weeks, the dose may be further increased. The maximum daily dose is 80 mg.

Patients receiving diuretics.

In patients already receiving diuretic therapy, symptomatic arterial hypotension may occur after the first dose of lisinopril. Diuretic treatment should be discontinued 2–3 days before starting the drug. If discontinuation of diuretics is not feasible, lisinopril should be initiated at a dose of 5 mg once daily. Renal function and serum potassium levels should be monitored. Subsequent dosing should be adjusted according to blood pressure response. If necessary, diuretic therapy may be resumed.

Patients with renal impairment.

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

Table 1

Creatinine clearance (mg/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, with monitoring of blood pressure.

The maintenance dose depends on the clinical response and should be individualized with regular monitoring of renal function, and serum potassium and sodium concentrations.

Chronic heart failure.

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

Dose selection should be based on individual clinical monitoring.

In patients at high risk of developing symptomatic arterial hypotension (e.g., due to excessive sodium chloride depletion, with or without hyponatremia), hypovolemia, or those receiving high-dose diuretic therapy, these conditions should be corrected prior to initiating treatment.

Acute myocardial infarction.

Patients should simultaneously receive standard 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.

Treatment should not be initiated if systolic blood pressure is below 100 mm Hg. The first dose of lisinopril is 5 mg, followed by another 5 mg dose after 24 hours, then 10 mg once daily. The maintenance dose is 10 mg once daily.

In patients with systolic blood pressure ≤120 mm Hg during the first 3 days after myocardial 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 once daily. If arterial hypotension occurs (systolic blood pressure ≤100 mm Hg), the maintenance dose should be temporarily reduced from 5 mg to 2.5 mg. In case of prolonged arterial hypotension (systolic blood 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. In patients who develop symptoms of heart failure, lisinopril therapy should be continued.

Diabetic nephropathy.

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

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. Subsequent dosing should be based on individual response and blood pressure.

Patients with kidney transplantation.

There is no experience with the use of lisinopril in patients with recent kidney transplantation; therefore, treatment with lisinopril is not recommended in these patients.

Children.

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

Overdose.

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

Treatment: intravenous administration of saline solutions. In case of arterial hypotension, the patient should be placed in a supine position with legs slightly elevated. If available, infusion of angiotensin II and/or intravenous catecholamines may be administered. If ingestion was recent, gastric lavage, administration of adsorbents, and sodium sulfate are indicated. For persistent bradycardia, cardiac pacing is indicated.

Continuous monitoring of vital functions and laboratory parameters (serum electrolytes and creatinine) is recommended.

Lisinopril can be removed from the body by hemodialysis; however, polyacrylonitrile metal sulfonate high-flux membranes (e.g., AN69) should be avoided.

In case of angioneurotic edema, antihistamines should be administered. 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, and intubation or tracheotomy should be performed to ensure airway patency.

Adverse reactions.

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

Metabolic disorders: hypoglycemia.

Central nervous system and psychiatric disorders: dizziness, headache, mood changes, paresthesia, vertigo, taste disturbances, sleep disturbances, loss of balance, disorientation, confusion, olfactory disturbances, symptoms of depression, loss of consciousness, subjective sensation of tinnitus, and decreased visual acuity.

Cardiovascular system disorders: arterial hypotension (especially after the first dose in patients with sodium depletion, dehydration, or heart failure); orthostatic effects (including arterial hypotension); myocardial infarction and stroke (as possible secondary events due to excessive hypotension in high-risk patients); palpitations, tachycardia, Raynaud's syndrome, syncope. 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, especially within the first 24 hours; in rare cases, cardiogenic shock.

Musculoskeletal system disorders: muscle spasms have been reported.

Respiratory system disorders: cough, bronchitis, rhinitis, dyspnea, dyspnoea, angioneurotic edema, bronchospasm, glossitis, sinusitis, allergic alveolitis/eosinophilic pneumonia. Upper respiratory tract infections have been reported.

Gastrointestinal disorders: diarrhea, vomiting, nausea, abdominal pain, dyspepsia, dry mouth, decreased appetite, taste disturbances, pancreatitis, intestinal angioneurotic edema, constipation, hepatitis (hepatocellular or cholestatic), jaundice, and hepatic failure.

Skin disorders: rash, pruritus; hypersensitivity reactions, including angioneurotic edema of the face, extremities, lips, tongue, glottis, and/or pharynx; sensation of warmth, skin hyperemia, urticaria, alopecia, psoriasis, 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, increased erythrocyte sedimentation rate, eosinophilia, leukocytosis, rash, photosensitivity, or other skin manifestations, elevated body temperature.

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

Endocrine system disorders: inappropriate antidiuretic hormone secretion.

Reproductive system disorders: impotence, gynecomastia.

General disorders: increased fatigue, weakness.

Laboratory findings: increased blood urea nitrogen, serum creatinine, liver enzymes, hyperkalemia, elevated serum bilirubin, hyponatremia, proteinuria.

Reporting suspected adverse reactions

Reporting of suspected adverse reactions after drug registration is important. It allows continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 3 or 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

ASTRAFARM LLC.

Manufacturer's address and location of business activity.

6 Kyivska St., Vyshneve, Kyiv-Sviatoshyn District, Kyiv Region, 08132, Ukraine.