Lisinopril

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

Composition:

Active substance: lisinopril;

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

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

Pharmaceutical form. Tablets.

Main physicochemical properties:

10 mg tablets: white, round, biconvex, homogeneous tablets with intact edges and a score line on one side;

20 mg tablets: white, round, biconvex, homogeneous tablets with intact edges.

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

ATC code C09A A03.

Pharmacological Properties

Pharmacodynamics

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

Since the primary mechanism by which lisinopril lowers blood pressure is believed to be suppression of the renin-angiotensin-aldosterone system (RAAS), lisinopril reduces blood pressure even in patients with low renin levels. ACE is identical to kininase II, the enzyme responsible for bradykinin degradation. It remains uncertain whether increased levels of bradykinin, a potent vasodilatory peptide, are important in the therapeutic effects of lisinopril.

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

It plays a positive role in restoring endothelial function in patients with hyperglycemia.

In a clinical study involving 115 children aged 6 to 16 years with arterial hypertension, patients with body weight less than 50 kg received 0.625 mg, 2.5 mg, or 20 mg of lisinopril once daily, while patients with body weight over 50 kg received 1.25 mg, 5 mg, or 40 mg of lisinopril once daily. By the end of the second week of the study, once-daily lisinopril reduced blood pressure in a dose-dependent manner, with progressively greater antihypertensive effects observed at doses above 1.25 mg.

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

Pharmacokinetics

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

Absorption

After oral administration of lisinopril, maximum serum concentration (C_max) is reached approximately 7 hours post-dose, although a slight delay in the time required to reach peak serum concentrations has been observed in patients with acute myocardial infarction. Based on urinary recovery, the mean absorption rate of lisinopril is approximately 25% following doses of 5–80 mg. Inter-patient variability ranges from 6% to 60%. Absolute bioavailability of lisinopril decreases to approximately 16% in patients with heart failure. Food intake does not affect the absorption of lisinopril.

Distribution

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

Elimination

Lisinopril is not metabolized and is excreted unchanged exclusively by the kidneys. With multiple dosing, the effective half-life of accumulation is 12.6 hours. The clearance of lisinopril is approximately 50 mL/min in healthy volunteers. The decline in serum concentration has a prolonged terminal phase, which does not favor drug accumulation. This terminal phase may represent saturable binding to ACE and is not proportional to dose.

Hepatic impairment

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

Renal impairment

Renal dysfunction reduces the renal excretion of lisinopril. This reduction is clinically significant only when the glomerular filtration rate is less than 30 mL/min. In mild to moderate renal impairment (creatinine clearance 30–80 mL/min), mean area under the curve (AUC) increases by only 13%. In severe renal impairment (creatinine clearance 5–30 mL/min), mean AUC increases by 4.5 times compared to normal. Lisinopril can be removed by dialysis. During 4 hours of hemodialysis, plasma lisinopril concentrations 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%), but due to urinary excretion, they exhibit approximately 16% lower absorption compared to healthy volunteers.

Children

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

Elderly patients

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

Clinical characteristics.

Indications.

Hypertension, heart failure (symptomatic treatment), acute myocardial infarction (short-term treatment (6 weeks) of patients with stable hemodynamics within 24 hours after acute myocardial infarction), initial diabetic nephropathy in patients with type II diabetes mellitus and arterial hypertension.

Contraindications.

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

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

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

− Concomitant use of Lisinopril with sacubitril/valsartan therapy. Lisinopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan.

− Hereditary or idiopathic angioedema.

− Second and third trimesters of pregnancy.

− Concomitant use of the medicinal product with aliskiren-containing products in patients with diabetes mellitus or renal impairment (GFR <60 mL/min/1.73 m²).

Interaction with other medicinal products and other forms of interaction.

Other antihypertensive agents.

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

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

Medicinal products increasing the risk of angioedema:

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

Concomitant treatment with ACE inhibitors and mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, sirolimus, everolimus), neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), vildagliptin, or tissue plasminogen activator may increase the risk of angioedema.

Diuretics.

Adding a diuretic to treatment in a patient receiving lisinopril usually enhances the hypotensive effect.

Patients receiving diuretics, particularly those just starting therapy, may experience excessive reduction in blood pressure after initiation of lisinopril treatment. The likelihood of symptomatic hypotension following lisinopril administration can be reduced by discontinuing the diuretic prior to starting lisinopril therapy.

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

Although serum potassium levels generally remained within normal limits in clinical studies, hyperkalemia was observed 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 supplements, or potassium-containing salt substitutes. Administration of potassium supplements, potassium-sparing diuretics, or potassium-containing salts, especially in patients with impaired renal function, may lead to a significant increase in serum potassium levels. When lisinopril is used concomitantly with potassium-wasting diuretics, diuretic-induced hypokalemia may be attenuated.

Cyclosporine:

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

Heparin:

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

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

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

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

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

Lithium-containing medicinal products.

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

Antidiabetic agents.

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

Sympathomimetics.

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Tricyclic antidepressants, neuroleptics, anesthetics.

Concomitant use of tricyclic antidepressants, neuroleptics, or anesthetics may enhance the hypotensive effect of Lisinopril.

Gold.

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

Special precautions.

Symptomatic hypotension.

Symptomatic hypotension is less common in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving lisinopril, arterial hypotension is more likely to occur in the presence of fluid volume depletion caused by diuretic therapy, salt-restricted diet, dialysis, diarrhea, or vomiting, as well as in cases of severe renin-dependent hypertension. Symptomatic hypotension may occur in patients with symptomatic heart failure, with or without renal impairment. Symptomatic hypotension is more likely in patients with more severe degrees of heart failure, those receiving high doses of loop diuretics, and in patients with hyponatremia or functional renal impairment. For patients at increased risk of symptomatic hypotension, initiation of therapy and dose adjustments should be closely monitored. This also applies to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or cerebral ischemia.

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

In some patients with heart failure and normal or low blood pressure, additional reduction in arterial pressure may occur during lisinopril therapy. This effect is expected and usually does not require discontinuation of treatment. However, if hypotension becomes symptomatic, dose reduction or discontinuation of lisinopril therapy may be necessary.

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

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy.

Like all ACE inhibitors, lisinopril should be administered with caution in patients with mitral valve stenosis or left ventricular outflow tract obstruction, such as 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 based on creatinine clearance (see table in the "Dosage and administration" section) and clinical response to treatment. Routine monitoring of serum potassium and creatinine levels is part of standard medical practice in managing such patients.

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

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

In some patients with arterial hypertension without concomitant renal vascular disease, increases in blood urea nitrogen and serum creatinine levels may occur, usually mild and transient, particularly when lisinopril is administered concomitantly with diuretics. This is more likely in patients with pre-existing renal dysfunction. Dose reduction and/or discontinuation of the diuretic and/or lisinopril may be required.

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

Hypersensitivity, angioedema.

Rare cases of angioedema involving the face, extremities, lips, tongue, pharynx, and/or larynx have been reported in patients receiving ACE inhibitors, including lisinopril. This may occur at any time during treatment. In such cases, the drug must be discontinued immediately, and the patient should receive appropriate treatment and remain under medical supervision until symptoms have completely resolved. In cases where swelling is localized to the tongue without respiratory compromise, prolonged observation may be required, as antihistamines and corticosteroids may be insufficient.

Very rarely, angioedema involving laryngeal or lingual swelling may be fatal. If swelling extends to the tongue, glottis, or larynx, airway obstruction may develop, particularly in patients with a history of airway surgery. In such cases, emergency interventions must be initiated immediately, including administration of epinephrine and/or securing airway patency. The patient must remain under close medical supervision until symptoms have completely and stably resolved.

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

Patients with a history of angioedema unrelated to ACE inhibitor use may have an increased risk of developing angioedema in response to drugs of this class.

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

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 tongue swelling, with or without respiratory compromise). Caution is advised when using lisinopril in patients receiving racecadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin.

Anaphylactoid reactions in patients undergoing hemodialysis. Anaphylactoid reactions have been reported in patients undergoing hemodialysis with high-flux membranes (e.g., AN 69) while receiving ACE inhibitors. In such cases, either the membrane type or the class of antihypertensive agent should be changed.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. In patients receiving ACE inhibitors, life-threatening anaphylactoid reactions have occasionally occurred during LDL apheresis with dextran sulfate. To prevent this, ACE inhibitors may be temporarily discontinued before apheresis.

Desensitization. In patients receiving ACE inhibitors, anaphylactoid reactions may occur during desensitization therapy (e.g., for hymenoptera venom). These reactions resolve upon temporary discontinuation of ACE inhibitors but may recur upon accidental re-exposure.

Hepatic impairment. In rare cases, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice, progressing to necrosis, and sometimes resulting in death. The mechanism of this syndrome is unknown. Patients receiving ACE inhibitors who develop jaundice or elevated liver enzymes should discontinue lisinopril and receive appropriate medical care.

Neutropenia/agranulocytosis.

Neutropenia/agranulocytosis, thrombocytopenia, and anemia may develop during ACE inhibitor therapy. Neutropenia has rarely been observed in patients with normal renal function and no other complicating factors. Neutropenia and agranulocytosis resolve after discontinuation of ACE inhibitor therapy. Lisinopril should be used with particular caution in patients with collagen vascular diseases (e.g., systemic lupus erythematosus or scleroderma), those receiving concomitant immunosuppressive therapy (e.g., corticosteroids, cytotoxic agents, antimetabolites), allopurinol, or procainamide, or in those with a combination of these risk factors, especially in the presence of renal impairment. Use of ACE inhibitors in such patients may be associated with particularly severe infections, which in some cases do not respond to intensive antibiotic therapy.

In such patients, periodic monitoring of white blood cell counts during lisinopril therapy is recommended, and patients should be advised to report any signs of infection.

Ethnic considerations (race).

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

Hepatic impairment.

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

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

Dual blockade of the RAAS.

Evidence indicates that concomitant use of ACE inhibitors, angiotensin II receptor blockers, and aliskiren increases the risk of arterial hypotension, hyperkalemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors, angiotensin II receptor blockers, and aliskiren is contraindicated.

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

Hyperkalemia.

Serum potassium levels may increase during treatment with ACE inhibitors, including lisinopril. Risk factors for hyperkalemia include renal impairment, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium supplements, or potassium-containing salt substitutes, and concomitant use of drugs that increase serum potassium (e.g., heparin).

If concomitant use of the above-mentioned drugs is unavoidable, regular monitoring of serum potassium levels is recommended.

Cough.

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

Surgery/anesthesia.

In patients undergoing surgery or receiving antihypertensive drugs during anesthesia, lisinopril may block the formation of angiotensin II due to compensatory renin release. If arterial hypotension occurs as a result of this mechanism, treatment with volume expansion may be effective.

Diabetes mellitus.

More careful monitoring of blood glucose levels is required during the first month of ACE inhibitor therapy, in addition to ongoing insulin or oral hypoglycemic therapy.

Lithium-containing drugs.

Combination of lithium and lisinopril is generally not recommended.

Use during pregnancy or breastfeeding.

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

It is known that prolonged exposure to ACE inhibitors during the second and third trimesters of pregnancy may cause fetal toxicity (renal dysfunction, 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.

Infants born to mothers who received lisinopril should be closely monitored for arterial hypotension.

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

Ability to affect reaction speed when driving or operating machinery.

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

Method of Administration and Dosage.

Dosage should be individualized according to the patient's condition and response of arterial pressure. Administer orally once daily, at the same time each day, independent of food intake.

Arterial Hypertension.

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

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

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

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

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

Patients with Renal Impairment.

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

Dosage Adjustment in Patients with Renal Impairment

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

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

Use in children with arterial hypertension aged 6 to 16 years.

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

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

Children with impaired renal function should receive a lower initial dose or have the dosing interval extended.

Heart failure.

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

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

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

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

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

Acute myocardial infarction.

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

Initial dose (first 3 days after myocardial infarction).

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

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

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

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

A 6-week course of therapy is recommended, followed by reassessment of the patient's condition. Patients with symptoms of heart failure should continue Lisinopril treatment.

Diabetic nephropathy.

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

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

Children

In children with arterial hypertension aged >6 years, the medicinal product has limited efficacy and safety data; however, there are no data for other indications (see section "Pharmacological properties"). Lisinopril is not recommended for treating children for indications other than arterial hypertension.

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

Use in elderly patients.

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

Use in patients with kidney transplant.

There is no experience with the use of lisinopril in patients with transplanted kidneys; therefore, treatment with Lisinopril is not recommended in such patients.

Children.

Lisinopril may be used in children only for arterial hypertension in those aged 6 years and older.

Overdose.

Data on Lisinopril overdose in humans are limited. Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include arterial hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, restlessness, and cough.

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

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

Adverse Reactions

When using this medicinal product and other ACE inhibitors, the following adverse effects may occur with the following frequencies: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); frequency not known (cannot be estimated due to lack of data).

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

Immune system disorders: frequency not known – anaphylactic/anaphylactoid reactions.

Metabolic and nutritional disorders: very rare – hypoglycemia.

Psychiatric and nervous system disorders: common – headache, dizziness; uncommon – mood changes, paresthesia, vertigo, taste disturbances, sleep disorders, hallucinations; rare – confusion, olfactory disturbances; frequency not known – depression, loss of consciousness.

Cardiovascular system disorders: common – orthostatic disturbances (including arterial hypotension); uncommon – myocardial infarction or stroke (as a consequence of significant reduction in blood pressure in high-risk patients), palpitations, tachycardia, Raynaud's phenomenon.

Respiratory system disorders: common – cough; uncommon – rhinitis; very rare – bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders: common – diarrhea, vomiting; uncommon – nausea, abdominal pain, dyspepsia; rare – dry mouth; very rare – pancreatitis, intestinal angioneurotic edema, cholestatic or hepatocellular hepatitis, jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus; rare – urticaria, alopecia, psoriasis, hypersensitivity reactions/angioedema of the face, lips, tongue, extremities, glottis and/or pharynx; very rare – increased sweating, bullous eruption, toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, exudative multiforme erythema, cutaneous lymphoid hyperplasia.

Skin reactions were accompanied by fever, myalgia, arthralgia/arthritis, vasculitis, eosinophilia, leukocytosis and/or positive antinuclear antibody test (ANA titer), elevated ESR, rash, photosensitivity, or other dermatological manifestations.

Renal disorders: common – renal dysfunction; rare – uremia, acute renal failure; very rare – oliguria/anuria.

Reproductive system disorders: uncommon – impotence; rare – gynecomastia.

Endocrine disorders: frequency not known – inappropriate antidiuretic hormone secretion.

General disorders: uncommon – increased fatigue, asthenia.

Biochemical laboratory findings: uncommon – increased serum urea, creatinine, liver enzymes and potassium concentrations, increased serum bilirubin, hyponatremia.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after medicinal product authorization is of great importance. It allows continuous monitoring of the benefit-risk ratio associated with the use of the medicinal product. Healthcare professionals are requested to report any suspected adverse reactions in accordance with local requirements.

Shelf life. 4 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets per blister, 1, 2, or 3 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

ANTIBIOTICE SA

ANTIBIOTICE SA

Manufacturer's name and address.

1, Valea Lupului Street, 707410, Iasi, Romania