Lisinopril-teva

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

Composition:

Active substance: lisinopril;

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

Excipients: mannite (E 421), calcium hydrogen phosphate, pregelatinized maize starch, sodium croscarmellose, magnesium stearate; for 10 mg and 20 mg tablets: yellow iron oxide (E 172), black iron oxide (E 172), red iron oxide (E 172).

Pharmaceutical form. Tablets.

Main physicochemical properties:

5 mg tablets: white, round, biconvex, with a break line on one side;

10 mg tablets: light pink, unevenly colored, mottled, round, biconvex, with a break line on one side;

20 mg tablets: grey-red, unevenly colored, mottled, round, biconvex, with a break line on one side.

Pharmacotherapeutic group. Simple 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 to the vasoconstrictor peptide angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE leads to reduced concentrations of angiotensin II, resulting in decreased vasoconstrictor activity and aldosterone secretion. Reduced aldosterone secretion may lead to increased serum potassium concentration. Lisinopril reduces blood pressure primarily by inhibiting the renin-angiotensin-aldosterone system (RAAS). Nevertheless, lisinopril exerts antihypertensive effects even in patients with low renin levels. ACE is identical to kininase II, an enzyme responsible for bradykinin breakdown. The overall profile of adverse reactions in patients receiving lisinopril at high or low doses has been shown to be similar in nature and frequency. In patients treated with lisinopril, a more pronounced reduction in urinary albumin excretion has been observed compared to a calcium channel blocker producing a similar reduction in blood pressure. This indicates that the ACE-inhibiting action of lisinopril reduces microalbuminuria through a direct effect on renal tissues, in addition to its ability to lower blood pressure. Lisinopril therapy had no significant impact on blood glucose control, as evidenced by its minimal effect on glycosylated hemoglobin (HbA1c) levels.

Pharmacokinetics.

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

Absorption. After oral administration of lisinopril, maximum serum concentration (Cmax) is reached within 7 hours, although in patients with acute myocardial infarction there is a tendency toward a slight delay in reaching peak concentrations. Based on urinary excretion, the average extent of lisinopril absorption is approximately 25%, with interpatient variability ranging from 6% to 60% within the studied dose range (5–80 mg). In patients with heart failure, absolute bioavailability is reduced by approximately 16%. Food intake does not affect drug absorption.

Distribution. Lisinopril does not bind to serum proteins except for circulating ACE. Studies in rats have shown that lisinopril poorly penetrates the blood-brain barrier.

Elimination. Lisinopril is not metabolized and is excreted unchanged in urine. The elimination half-life in patients receiving multiple doses is 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 mL/min. The decline in serum concentration demonstrates a prolonged terminal phase, which is not related to drug accumulation. This terminal phase likely reflects saturable binding to ACE and is not dose-proportional.

Patients with hepatic impairment. In patients with cirrhosis, hepatic dysfunction leads to reduced absorption of lisinopril (by approximately 30%), but due to decreased clearance, exposure increases (by approximately 50%) compared to healthy volunteers.

Renal impairment. Renal dysfunction reduces the elimination of lisinopril, which is excreted by the kidneys; however, this reduction is clinically significant only when glomerular filtration rate (GFR) is below 30 mL/min. In mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the mean area under the concentration-time curve (AUC) increases by only 13%, whereas in severe renal impairment (creatinine clearance 5–30 mL/min), the mean AUC increases by 4.5-fold. Lisinopril can be removed by dialysis. During 4 hours of hemodialysis, plasma lisinopril concentration decreases on average by 60%, with a dialysis clearance of 40–55 mL/min.

Heart failure. Patients with heart failure have greater lisinopril exposure compared to healthy volunteers (mean AUC increase of 125%), but, as indicated by the amount of lisinopril measured in urine, absorption is reduced by approximately 16% compared to healthy volunteers.

Elderly patients. Elderly patients have higher plasma drug levels and higher AUC values (increase of approximately 60%) 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, excipients of the medicinal product, or to other ACE inhibitors.
• History of angioedema associated with administration of ACE inhibitors.
• Concomitant use with sacubitril/valsartan. Treatment with Lisinopril-Teva may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other types of interactions" and "Special precautions for use").
• Hereditary or idiopathic angioedema.
• Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy or lactation").
• Concomitant use with medicinal products containing aliskiren in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²).

Interaction with other medicinal products and other types of interactions.

Antihypertensive agents. Concomitant use with other antihypertensive medicinal products (e.g., nitroglycerin, other nitrates, or other vasodilators) may additionally reduce arterial blood pressure.

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

Medicinal products that increase the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special precautions for use"). Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, sirolimus, everolimus), neutral endopeptidase (NEP) inhibitors (e.g., racecadotril), vildagliptin, or tissue plasminogen activator may increase the risk of angioedema (see section "Special precautions for use").

Diuretics. The antihypertensive effect is usually enhanced when diuretics are added to lisinopril therapy. In patients already receiving diuretics, particularly those recently initiated on diuretic therapy, excessive reduction in arterial blood pressure may sometimes occur after adding lisinopril. The likelihood of symptomatic arterial hypotension with lisinopril may be reduced by discontinuing diuretic therapy prior to starting lisinopril.

Potassium-containing dietary supplements, potassium-sparing diuretics, potassium-containing salt substitutes, and other medicinal products that may increase serum potassium levels. Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving this medicinal product. Use of potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels, especially in patients with impaired renal function. Caution should also be exercised when lisinopril is used 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 with the above-mentioned medicinal products is not recommended. If concomitant use of these agents is indicated, treatment should be administered with caution and serum potassium levels should be monitored frequently. When lisinopril is used concomitantly with potassium-wasting diuretics, diuretic-induced hypokalemia may be attenuated.

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 preparations. 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 further increase the risk of lithium toxicity and exacerbate existing intoxication. Concomitant use of lisinopril and lithium is not recommended; however, if such combination is necessary, serum lithium levels should be closely monitored.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses ≥3 g/day. When ACE inhibitors are used concomitantly with NSAIDs (acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 [COX-2] inhibitors, and nonselective NSAIDs), attenuation of the antihypertensive effect may occur. Concomitant use of NSAIDs and ACE inhibitors may increase the risk of renal dysfunction, including possible acute renal failure, and elevated serum potassium levels, particularly in patients with pre-existing renal impairment. These effects are usually reversible. The combination should be used with caution, especially in elderly patients. Patients should receive adequate hydration, and renal function should be monitored after initiation of concomitant therapy and periodically thereafter.

Gold preparations. Nitritoid reactions (vasodilatory symptoms including flushing, nausea, dizziness, and arterial hypotension, which may be severe) have been observed more frequently in patients receiving ACE inhibitors who are administered gold injections (e.g., sodium aurothiomalate).

Tricyclic antidepressants/antipsychotics/anesthetics. Concomitant use of certain anesthetic agents, tricyclic antidepressants, and neuroleptic drugs with ACE inhibitors may lead to further reduction in arterial blood pressure.

Sympathomimetic agents. Sympathomimetic drugs may reduce the antihypertensive effect of ACE inhibitors.

Antidiabetic medicinal products. Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance glucose-lowering effects with an increased risk of hypoglycemia. This effect usually occurs during the first weeks of combination therapy and in patients with renal insufficiency.

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

Special precautions for use.

Symptomatic arterial hypotension. Symptomatic arterial hypotension was rarely observed in patients with uncomplicated arterial hypertension. In patients with arterial hypertension receiving lisinopril, symptomatic arterial hypotension is more likely to occur in the presence of disturbances in water and electrolyte balance, such as those caused by diuretic therapy, dialysis, dietary salt restriction, diarrhoea, or vomiting, or in cases of severe renin-dependent hypertension. Symptomatic arterial hypotension has been observed in patients with heart failure (with or without renal insufficiency). The likelihood of developing arterial hypotension is higher in patients with severe heart failure who are receiving high doses of loop diuretics, have hyponatremia, or functional renal impairment. In patients at increased risk of symptomatic arterial hypotension, initiation of therapy and subsequent dose escalation should be performed under close medical supervision. The same precautions apply to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In the event of arterial hypotension, the patient should be placed in a supine position; if necessary, intravenous infusion of physiological saline should be administered. Transient hypotension is not a contraindication to continued use of the drug, which can usually be resumed without complications after blood pressure has increased following expansion of fluid volume.

In some patients with heart failure who have normal or low blood pressure, further reduction in systemic arterial pressure may occur during lisinopril therapy. This effect is predictable and usually does not require discontinuation of lisinopril therapy. If arterial hypotension becomes symptomatic, dose reduction or discontinuation of lisinopril may be necessary.

Arterial hypotension in acute myocardial infarction. Treatment with lisinopril 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 and to patients who have developed cardiogenic shock. During the first 3 days after myocardial infarction, the dose of the drug should be reduced if systolic blood pressure is 120 mm Hg or lower. If systolic blood pressure is 100 mm Hg or lower, maintenance doses 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 should be discontinued.

Stenosis of aortic or mitral valve/hypertrophic cardiomyopathy. As with other ACE inhibitors, caution should be exercised when administering lisinopril to patients with mitral valve stenosis or outflow obstruction from the left ventricle (e.g., aortic stenosis or hypertrophic cardiomyopathy).

Renal function impairment. For patients with impaired renal function (creatinine clearance <80 mL/min), the initial dose of lisinopril should be adjusted based on creatinine clearance (see table in section "Dosage and administration"), and subsequently according to the patient's response to treatment. In such patients, serum creatinine and potassium levels should be monitored regularly.

In patients with heart failure, arterial hypotension occurring at the beginning of ACE inhibitor therapy may lead to deterioration of renal function. In such cases, acute renal failure, usually reversible, has been reported.

In some patients with bilateral renal artery stenosis or stenosis of the renal artery of a solitary kidney, ACE inhibitors increase blood urea nitrogen and serum creatinine levels; these effects usually resolve after discontinuation of the drug. The likelihood of such events is particularly high in patients with pre-existing renal impairment. The presence of renovascular hypertension increases the risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under medical supervision with low doses carefully titrated. Since diuretics may promote 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 without evident renal vascular disease, administration of lisinopril, particularly in combination with diuretics, may lead to increases in blood urea nitrogen and serum creatinine; 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 and/or discontinuation of diuretics and/or lisinopril may be necessary.

In acute myocardial infarction, lisinopril therapy should not be initiated in patients with impaired renal function (serum creatinine >177 µmol/L and/or proteinuria >500 mg/day). If renal impairment develops during lisinopril therapy (serum creatinine >265 µmol/L or doubling of baseline levels), discontinuation of the drug should be considered.

Hypersensitivity/angioedema. Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been 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 symptoms completely resolve. Even in cases where swelling is localized only to the tongue and does not impair breathing, prolonged observation may be required, as 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, glottis, or larynx, obstructive airway compromise may develop, particularly in patients with prior surgical procedures on the airways. In such cases, immediate emergency measures should be taken, including administration of adrenaline and/or securing airway patency. The patient must remain under close medical supervision until symptoms have completely and stably resolved.

ACE inhibitors cause angioedema more frequently in Black patients than in others.

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. 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 (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

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

Anaphylactoid reactions in patients undergoing hemodialysis. Anaphylactoid reactions have been reported in patients undergoing hemodialysis with high-flux membranes (e.g., AN69) while concurrently receiving an ACE inhibitor. These patients should be advised to switch to dialysis membranes of another type or to use antihypertensive drugs from another class.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactoid reactions have occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These reactions may be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Desensitization. In patients receiving ACE inhibitors, persistent anaphylactoid reactions may occur during desensitization therapy (e.g., to hymenoptera venom). These reactions may be avoided by temporarily discontinuing ACE inhibitors in such patients, but may recur after inadvertent re-exposure to the drug.

Hepatic impairment. Very rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis and (sometimes) fatal outcome. The mechanism of this syndrome is unknown. If jaundice develops or marked elevations in liver enzymes occur in patients receiving lisinopril, lisinopril should be discontinued and appropriate medical care provided.

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 used with extreme caution in patients with collagen vascular disease, those receiving immunosuppressive therapy, treatment with allopurinol or procainamide, or in the presence of a combination of these risk factors, especially with impaired renal function. Severe infections, not always responsive to intensive antibiotic therapy, may develop in some such patients. Periodic monitoring of white blood cell counts is recommended in these patients, and they should be instructed to report any signs of infection.

Dual blockade of the RAAS. Concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren has been associated with an 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 antagonists, 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 antagonists is not recommended in patients with diabetic nephropathy.

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

Cough. Cough has been reported with ACE inhibitor use. The cough is typically non-productive and persistent, and resolves after discontinuation of therapy. When performing differential diagnosis of cough, it should be considered that ACE inhibitor therapy may be the cause.

Surgery/anesthesia. In patients undergoing major surgery or receiving anesthetics that cause arterial hypotension, lisinopril may block the formation of angiotensin II secondary to compensatory renin release. Hypotension resulting from this mechanism can be corrected by increasing circulating blood volume.

Hyperkalemia. ACE inhibitors may cause hyperkalemia due to suppression of aldosterone release. This effect is usually mild in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function, diabetes mellitus, and/or in patients taking potassium-containing supplements (including salt substitutes), potassium-sparing diuretics (e.g., spironolactone, triamterene, amiloride), 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. 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").

Patients with diabetes mellitus. Close monitoring of blood glucose levels is required during the first month of ACE inhibitor therapy in patients with diabetes mellitus who are receiving oral antidiabetic agents or insulin.

Lithium. Concomitant use of lithium and lisinopril is generally not recommended.

Pregnancy. Initiation of ACE inhibitor therapy during pregnancy is not recommended (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Excipients

Sodium. This medicinal product contains less than 1 mmol of sodium (23 mg) per tablet, i.e., essentially "sodium-free."

Use during pregnancy or breastfeeding.

Pregnancy. Use of ACE inhibitors is not recommended during the first trimester of pregnancy (see section "Special precautions for use"). ACE inhibitors are contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on teratogenic risk following exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded. If continuation of ACE inhibitor therapy is not considered essential, women planning pregnancy should be switched to alternative antihypertensive agents with a well-established safety profile in pregnancy. Upon confirmation of pregnancy, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative therapy initiated. Exposure to ACE inhibitors during the second and third trimesters of pregnancy is known to induce 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 function and skull ossification should be monitored by ultrasound. Newborns of mothers who took ACE inhibitors should be closely monitored for arterial hypotension.

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

Ability to influence the speed of reactions when driving or operating machinery.

When driving vehicles or operating machinery, it should be considered that dizziness or fatigue may occasionally occur.

Method of Administration and Dosage

Lisinopril should be taken orally once daily. As with other medicinal products taken once daily, lisinopril should be taken every day at approximately the same time. Food intake does not affect the absorption of lisinopril tablets. The dosage should be individually adjusted according to the patient's clinical condition and blood pressure levels.

Arterial Hypertension

Lisinopril can be used both as monotherapy and in combination with other classes of antihypertensive medicinal products.

Initial Dose

The recommended initial dose for patients with hypertension is usually 10 mg. Patients with a highly active RAAS (particularly those with renovascular hypertension, increased salt (sodium chloride) excretion, and/or reduced extracellular fluid volume, heart failure, or severe arterial hypertension) may experience excessive hypotension after the initial dose. For such patients, the recommended initial dose is 2.5–5 mg, and treatment initiation should occur under direct medical supervision. A reduced initial dose is also recommended in the presence of renal impairment (see table below).

Maintenance Dose

The usual effective maintenance dose is 20 mg once daily. If this dose does not provide sufficient therapeutic effect within 2–4 weeks, it may be increased. The maximum dose used in long-term controlled clinical trials was 80 mg per day.

Patients Taking Diuretics

Symptomatic arterial hypotension may occur after initiation of lisinopril therapy. This is more likely in patients receiving diuretics during lisinopril treatment. Therefore, such patients should be treated with caution due to the potential for increased salt (sodium chloride) excretion and/or reduced extracellular fluid volume. If possible, diuretic therapy should be discontinued 2–3 days before starting lisinopril. For patients with arterial hypertension who cannot discontinue diuretics, lisinopril therapy should be initiated at a starting dose of 5 mg. Renal function and serum potassium levels should be monitored. Subsequent lisinopril doses should be adjusted according to the blood pressure response. If necessary, diuretic therapy may be resumed.

Dose Adjustment in Patients with Renal Impairment

Dosing in patients with impaired renal function should be based on creatinine clearance, as shown in the table below.

Dose Adjustment in Patients with Renal Impairment

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

The dose may be gradually increased until blood pressure is controlled or until the maximum dose of 40 mg per day is reached.

Use in children with hypertension aged 6 to 16 years

The recommended initial dose is 2.5 mg/day for patients with body weight from 20 to <50 kg and 5 mg/day for patients with body weight ≥50 kg. The dose should be individually adjusted up to a maximum of 20 mg/day for patients with body weight from 20 to <50 kg and up to 40 mg/day for patients with body weight ≥50 kg. Doses exceeding 0.61 mg/kg (or exceeding 40 mg) have not been studied in children.

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

Heart failure

Patients with heart failure should take lisinopril as an adjunctive therapy to diuretics, digitalis preparations, or β-blockers. Lisinopril therapy may be initiated at a dose of 2.5 mg once daily. The drug should be administered under medical supervision to monitor its initial effect on arterial pressure.

The dose of lisinopril should be increased:

• by increasing the dose by no more than 10 mg;
• with intervals between dose increases of at least 2 weeks;
• up to the highest dose tolerated by the patient, with a maximum of 35 mg once daily.

Dosage titration should be based on the individual clinical response of each patient. Patients at high risk of symptomatic hypotension, such as those with increased sodium chloride excretion (with or without hyponatremia), hypovolemia, or those receiving intensive diuretic therapy, should have these conditions corrected, if possible, prior to initiating lisinopril therapy. Renal function and serum potassium levels should be monitored.

Acute myocardial infarction

Patients should receive standard recommended therapies as clinically indicated, such as thrombolytic agents, acetylsalicylic acid, and β-blockers. Intravenous or transdermal nitroglycerin may be used concomitantly with lisinopril.

Initial dose (first 3 days after infarction)

Lisinopril treatment may be initiated within the first 24 hours after symptom onset. Treatment should not be initiated if systolic blood pressure is less than 100 mm Hg. The initial dose of lisinopril is 5 mg orally, followed by a second 5 mg dose after 24 hours, then 10 mg after 48 hours, and thereafter 10 mg once daily. Patients with low systolic blood pressure (≤120 mm Hg) at the start of treatment or during the first 3 days after infarction should receive a lower dose of 2.5 mg orally.

In cases of renal impairment (creatinine clearance below 80 mL/min), the initial dose of lisinopril should be adjusted according to the patient's creatinine clearance (see table above).

Maintenance dose

The maintenance dose is 10 mg once daily. If arterial hypotension occurs (systolic pressure ≤100 mm Hg), the maintenance dose may be reduced to 5 mg daily, temporarily decreased to 2.5 mg if necessary. If prolonged arterial hypotension occurs (systolic pressure <90 mm Hg for more than 1 hour), lisinopril should be discontinued.

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

Renal complications in diabetes mellitus

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

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

Elderly patients

Clinical studies have not demonstrated differences in efficacy and safety of the drug related to age. However, in patients of advanced age associated with reduced renal function, the initial dose of lisinopril should be selected according to the table above. Thereafter, the dose should be adjusted based on the blood pressure response.

Use in patients with transplanted kidney

There is no experience with the use of lisinopril in patients with recently transplanted kidneys. Therefore, lisinopril therapy is not recommended in such patients.

Children.

There is limited experience regarding the efficacy and safety of lisinopril use in children aged 6 years and older with hypertension; however, there is no experience for other indications. Lisinopril is not recommended for use in children for indications other than 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/1.73 m²).

Overdose.

Data on overdose in humans are limited. Symptoms associated with ACE inhibitor overdose may include arterial hypotension, circulatory shock, electrolyte imbalances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Recommended treatment of overdose includes intravenous infusion of normal saline. In cases of arterial hypotension, the patient should be placed in a supine position with legs elevated. If available, infusion of angiotensin II and/or intravenous administration of catecholamines may be considered. If the drug was recently ingested, measures should be taken to remove lisinopril from the body (e.g., induction of emesis, gastric lavage, administration of adsorbents and sodium sulfate). Lisinopril may be removed from systemic circulation by hemodialysis (see section "Special precautions"). A cardiac pacemaker is indicated in cases of therapy-resistant bradycardia. Vital signs, serum electrolyte concentrations, and creatinine levels should be monitored frequently.

Adverse reactions.

Adverse reactions reported during treatment with lisinopril and other ACE inhibitors are listed below by frequency of occurrence: 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 from available data).

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

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

Metabolism and nutrition disorders: very rare – hypoglycemia.

Nervous system and psychiatric disorders: common – dizziness, headache; uncommon – mood changes, paresthesia, vertigo, taste disturbances, sleep disorders, hallucinations; rare – confusion, smell disturbances; frequency not known – depressive symptoms, syncope.

Cardiovascular system disorders: common – orthostatic effects (including arterial hypotension); uncommon – myocardial infarction or stroke (possibly as a complication of excessive arterial hypotension in high-risk patients), palpitations, tachycardia, Raynaud's syndrome.

Respiratory, thoracic and mediastinal 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 angioedema, hepatitis (hepatocellular or cholestatic), jaundice, hepatic failure.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus; rare – urticaria, alopecia, psoriasis, hypersensitivity/angioedema (angioedema of the face, extremities, lips, tongue, glottis and/or larynx); very rare – excessive sweating, pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pseudolymphoma of the skin.

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

Renal and urinary disorders: common – renal function impairment; rare – uremia, acute renal failure; very rare – oliguria/anuria.

Endocrine disorders: rare – syndrome of inappropriate antidiuretic hormone secretion (SIADH).

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

General disorders: uncommon – increased fatigue, asthenia.

Laboratory investigations: uncommon – increased blood urea nitrogen, increased serum creatinine, increased liver enzymes, hyperkalemia; rare – increased serum bilirubin, hyponatremia.

Safety data obtained from clinical trials indicate that lisinopril is generally well tolerated in pediatric patients with arterial hypertension and that the safety profile in this age group is comparable to that observed in adults.

Reporting suspected adverse reactions. All suspected adverse reactions and lack of drug efficacy should be reported via the following link: https://aisf.dec.gov.ua/.

Shelf life. 4 years.

Storage conditions.
The medicinal product does not require special storage conditions. Keep out of reach of children.

Packaging. 10 tablets per blister, 3 or 6 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Merckle GmbH.

Manufacturer's address and location of operations. Ludwig-Merckle-Strasse 3, 89143, Blaubeuren, Germany.