Lisinopril-SZ (Tablets) Instructions for Use

Marketing Authorization Holder

Severnaya Zvezda NAO (Russia)

Contact Information

SEVERNAYA ZVEZDA NAO (Russia)

ATC Code

C09AA03 (Lisinopril)

Active Substance

Lisinopril (Rec.INN registered by WHO)

Dosage Forms

	Lisinopril-SZ	Tablets 5 mg: 20, 30, 50, 60 or 100 pcs.
		Tablets 10 mg: 20, 30, 50, 60 or 100 pcs.
		Tablets 20 mg: 20, 30, 50, 60 or 100 pcs.

Dosage Form, Packaging, and Composition

Tablets white or almost white, flat-cylindrical in shape, with a bevel.

Excipients: lactose monohydrate (milk sugar) – 74.25 mg, calcium stearate – 0.75 mg.

10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
100 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.
100 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, flat-cylindrical in shape, with a bevel.

Excipients: lactose monohydrate (milk sugar) – 148.5 mg, calcium stearate – 1.5 mg.

10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
100 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.
100 pcs. – polymer bottles (1) – cardboard packs.

Tablets white or almost white, flat-cylindrical in shape, with a bevel.

Excipients: lactose monohydrate (milk sugar) – 178.2 mg, calcium stearate – 1.8 mg.

10 pcs. – contour cell packs (2) – cardboard packs.
10 pcs. – contour cell packs (3) – cardboard packs.
10 pcs. – contour cell packs (5) – cardboard packs.
10 pcs. – contour cell packs (6) – cardboard packs.
30 pcs. – polymer jars (1) – cardboard packs.
100 pcs. – polymer jars (1) – cardboard packs.
30 pcs. – polymer bottles (1) – cardboard packs.
100 pcs. – polymer bottles (1) – cardboard packs.

Clinical-Pharmacological Group

ACE inhibitor

Pharmacotherapeutic Group

ACE inhibitor

Pharmacological Action

An ACE inhibitor, it reduces the formation of angiotensin II from angiotensin I. The decrease in angiotensin II content leads to a direct reduction in aldosterone secretion. It reduces the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces total peripheral vascular resistance, blood pressure, preload, pressure in the pulmonary capillaries, causes an increase in cardiac output and increases myocardial tolerance to stress in patients with chronic heart failure. It dilates arteries to a greater extent than veins. Some effects are explained by the impact on the tissue renin-angiotensin system. With long-term use, it reduces hypertrophy of the myocardium and walls of resistive arteries. It improves blood supply to the ischemic myocardium.

The onset of the antihypertensive effect is within 1 hour. The maximum effect is observed after 6-7 hours and persists for 24 hours. The duration of the effect also depends on the dose. In arterial hypertension, the effect is noted in the first days after the start of treatment, a stable effect develops after 1-2 months. Upon abrupt withdrawal of lisinopril, no pronounced increase in blood pressure is observed.

ACE inhibitors prolong the life expectancy of patients with chronic heart failure (CHF) and slow the progression of left ventricular dysfunction in patients who have had a myocardial infarction without clinical manifestations of heart failure.

The efficacy and safety of lisinopril (up to 10 mg/day) were evaluated in patients with acute myocardial infarction (AMI). Lisinopril, prescribed within the first 24 hours after AMI for 6 weeks, led to a statistically significant reduction in overall mortality by 11%.

In addition to lowering blood pressure, Lisinopril reduces albuminuria. Taking 10-20 mg of lisinopril once a day for 12 months in patients with arterial hypertension and type 2 diabetes mellitus with an initial stage of nephropathy, manifested as microalbuminuria, reduced systolic/diastolic blood pressure by 13/10 mm Hg and urinary albumin excretion by 40%. In patients with hyperglycemia, it contributes to the normalization of the function of damaged glomerular endothelium. Lisinopril does not affect blood glucose concentration in patients with diabetes mellitus and does not lead to an increased incidence of hypoglycemia.

Pharmacokinetics

Absorption

The absorption of lisinopril averages 25-30% with significant interindividual variability (6-60%). Food intake does not affect the absorption of lisinopril. T_max in blood plasma is approximately 7 hours; in patients with acute myocardial infarction, T_max is 8-10 hours.

Distribution

It enters the systemic circulation unchanged. Lisinopril does not bind to plasma proteins (except for circulating ACE). Permeability through the blood-brain barrier and placental barrier is low.

Metabolism

Lisinopril is not metabolized.

Excretion

Lisinopril is excreted by the kidneys unchanged. The fraction bound to ACE is excreted slowly. The clearance of lisinopril in healthy volunteers is approximately 50 ml/min. After multiple doses, the effective T_1/2 of lisinopril is 12.6 hours.

Pharmacokinetics in special patient groups

In patients with CHF, absorption and creatinine clearance are reduced. In this category of patients, the absolute bioavailability of lisinopril decreases by approximately 16%; however, AUC increases by an average of 125% compared to healthy volunteers.

In patients with renal failure, an increased concentration of lisinopril in blood plasma is observed, an increase in the time to reach C_max and an increase in T_1/2 are noted.

Impaired renal function leads to an increase in the AUC and T_1/2 of lisinopril, but these changes become clinically significant only when the glomerular filtration rate (GFR) falls below 30 ml/min. In mild and moderate renal failure (creatinine clearance from 31 to 80 ml/min), the mean AUC increases by 13%, while in severe renal failure (creatinine clearance from 5 to 30 ml/min), an increase in the mean AUC by 4.5 times is observed.

In patients with liver cirrhosis, the bioavailability of lisinopril is reduced by approximately 30%, but the drug exposure (AUC) increases by 50% compared to healthy volunteers due to reduced clearance.

In elderly patients (over 65 years), the plasma concentration and AUC of lisinopril are 2 times higher than in young patients.

Indications

• Essential and renovascular arterial hypertension (as monotherapy or in combination with other antihypertensive agents);
• Chronic heart failure (as part of combination therapy);
• Early treatment of acute myocardial infarction (in patients with stable hemodynamic parameters within the first 24 hours to prevent left ventricular dysfunction and heart failure);
• Diabetic nephropathy (reduction of albuminuria in patients with type 1 diabetes mellitus with normal blood pressure, and in patients with type 2 diabetes mellitus with arterial hypertension).

ICD codes

Dosage Regimen

The drug is taken orally, once a day in the morning, regardless of meals, preferably at the same time.

To ensure the dosage regimens indicated below, if it is necessary to use lisinopril at a dose of 2.5 mg, lisinopril preparations from other manufacturers in the dosage form of 2.5 mg tablets or 5 mg tablets with a score should be prescribed.

Essential arterial hypertension

The recommended initial dose of lisinopril for patients not taking antihypertensive agents is 10 mg once a day. If there is no therapeutic effect, the dose is increased every 2-3 days by 5 mg/day to an average therapeutic dose of 20-40 mg/day. The usual maintenance dose is 20 mg once a day. The maximum daily dose of lisinopril is 40 mg once a day (in clinical studies, the maximum dose of lisinopril was 80 mg/day, but increasing the dose above 40 mg/day usually does not lead to a further decrease in blood pressure). The therapeutic effect develops after 2-4 weeks from the start of treatment, which should be taken into account when increasing the dose. If the therapeutic effect is insufficient, it is possible to combine Lisinopril with other antihypertensive agents.

If the patient was previously treated with diuretics, their use should be discontinued 2-3 days before starting lisinopril. If this is not possible, the initial dose of the drug should not exceed 5 mg/day. After taking the first dose, medical supervision is necessary for several hours, as a pronounced decrease in blood pressure may occur.

Renovascular hypertension or other conditions with increased activity of the renin-angiotensin-aldosterone system (RAAS)

The initial dose of lisinopril is 2.5-5 mg/day under the control of blood pressure, renal function, and plasma potassium concentration. The maintenance dose is established depending on the blood pressure level.

Since Lisinopril is excreted by the kidneys, in renal failure the initial dose is determined depending on creatinine clearance (CC). With CC 31-80 ml/min, the initial dose of lisinopril is 5-10 mg/day; with CC 10-30 ml/min – 2.5-5 mg/day; with CC less than 10 ml/min, including in patients on hemodialysis – 2.5 mg/day. The maintenance dose is determined depending on blood pressure (with regular monitoring of renal function, blood potassium and sodium concentrations).

Recommendations regarding the dosing regimen in patients with mild and moderate hepatic impairment have not been developed, so dose selection in such patients should be carried out with caution, starting with the lowest possible dose.

In elderly patients, the drug should be used with caution, starting with the lowest possible dose.

Chronic heart failure

In CHF, the initial dose of lisinopril is 2.5 mg once a day. The first dose of lisinopril must be started under close medical supervision to assess the effect of the drug on blood pressure. Subsequently, the dose of lisinopril should be gradually increased by 2.5 mg at intervals of 3-5 days to 5-10-20 mg/day. It is not recommended to exceed the maximum daily dose of lisinopril of 20 mg (in clinical studies, the maximum dose of lisinopril in patients with CHF was 35 mg once a day).

If possible, the dose of the diuretic should be reduced before starting lisinopril. Before starting treatment with lisinopril and further during treatment, blood pressure, renal function, and serum potassium and sodium levels should be regularly monitored to avoid the development of arterial hypotension and associated renal dysfunction.

Early treatment of acute myocardial infarction

Initial therapy (first 3 days of acute myocardial infarction). Within the first 24 hours after acute myocardial infarction, 5 mg of lisinopril is prescribed as a single dose. After 24 hours (1 day), 5 mg of lisinopril is prescribed as a single dose; after 48 hours (two days) – 10 mg of lisinopril as a single dose. Treatment should not be started if systolic blood pressure is less than 100 mm Hg. Patients with low systolic blood pressure (≤120 mm Hg) at the start of treatment and during the first 3 days after acute myocardial infarction are prescribed a lower dose of lisinopril – 2.5 mg once a day.

Maintenance therapy. The maintenance dose of lisinopril is 10 mg once a day. The course of treatment is at least 6 weeks. Subsequently, the advisability of continuing therapy should be assessed. Patients with symptoms of heart failure are recommended to continue taking lisinopril. In case of development of arterial hypotension (systolic blood pressure ≤100 mm Hg), the daily dose of lisinopril is temporarily reduced to 5 mg, if necessary, to 2.5 mg. In case of a prolonged pronounced decrease in blood pressure (systolic blood pressure below 90 mm Hg for more than 1 hour), the use of lisinopril must be discontinued.

Diabetic nephropathy (reduction of albuminuria in patients with type 1 diabetes mellitus with normal blood pressure, and in patients with type 2 diabetes mellitus with arterial hypertension)

The initial dose of lisinopril is 10 mg/day, which, if necessary, is increased to 20 mg/day until target diastolic blood pressure values are achieved (diastolic blood pressure below 75 mm Hg in a sitting position in patients with type 1 diabetes mellitus and below 90 mm Hg in a sitting position in patients with type 2 diabetes mellitus).

In case of impaired renal function (creatinine clearance less than 80 ml/min), the initial dose is determined depending on creatinine clearance (see above).

Adverse Reactions

The frequency of adverse reactions is given in accordance with the WHO classification: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10000, <1/1000), very rare (<1/10000), including isolated reports, frequency not known (frequency cannot be estimated from the available data).

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

Endocrine system disorders rare – syndrome of inappropriate ADH secretion.

Nervous system disorders common – dizziness, headache; uncommon – emotional lability, paresthesia, vertigo, sleep disorder, taste perversion, hallucinations; rare – depression of consciousness, impaired sense of smell; frequency not known – depression, syncope, confusion, drowsiness, convulsive twitching of the muscles of the limbs and lips.

Cardiac and vascular disorders common – orthostatic hypotension; uncommon – myocardial infarction, palpitations, tachycardia, cerebrovascular accident (due to a pronounced decrease in blood pressure in high-risk patients), Raynaud’s syndrome; frequency not known – chest pain, bradycardia, worsening of heart failure symptoms, AV conduction disorder, pronounced decrease in blood pressure.

Respiratory, thoracic and mediastinal disorders common – dry cough; uncommon – rhinitis; very rare – sinusitis, dyspnea, bronchospasm, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders common – diarrhea, vomiting; uncommon – nausea, dyspepsia, abdominal pain; rare – dry oral mucosa; very rare – pancreatitis, intestinal angioedema, hepatitis, hepatocellular or cholestatic jaundice, liver failure.

Skin and subcutaneous tissue disorders uncommon – skin rash, skin itching; rare – urticaria, alopecia, psoriasis, photosensitivity, hypersensitivity reactions, angioedema of the face, extremities, lips, tongue, pharynx and/or larynx; very rare – increased sweating, pemphigus, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome), exudative multiforme erythema, cutaneous pseudolymphoma.

Renal and urinary disorders common – impaired renal function; rare – uremia, acute renal failure; very rare – oliguria, anuria; frequency not known – proteinuria.

Reproductive system and breast disorders uncommon – decreased potency; rare – gynecomastia.

Laboratory and instrumental data uncommon – increased plasma urea concentration, increased plasma creatinine concentration, increased activity of liver transaminases, hyperkalemia; rare – increased plasma bilirubin concentration, hyponatremia; very rare – decreased blood glucose concentration (hypoglycemia), increased titer of antinuclear antibodies in plasma, increased ESR.

General disorders and administration site conditions uncommon – asthenia, increased fatigue; frequency not known – anorexia, fever.

A symptom complex has been described that may include fever, vasculitis, myalgia, arthralgia/arthritis, increased titer of antinuclear antibodies in plasma, increased ESR, eosinophilia, leukocytosis, and possibly also the development of skin rash, photosensitivity reaction or other skin manifestations.

With simultaneous use of ACE inhibitors and gold preparations for intravenous administration (sodium aurothiomalate), a symptom complex has been described, including facial flushing, nausea, vomiting, and decreased blood pressure.

Contraindications

• Hypersensitivity to lisinopril, any other component of the drug, or other ACE inhibitors;
• History of angioedema, including against the background of ACE inhibitor use;
• Hereditary or idiopathic angioedema;
• Pregnancy;
• Breastfeeding period;
• Age under 18 years (efficacy and safety not established);
• Simultaneous use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus or moderate or severe renal impairment (GFR <60 ml/min/1.73 m² body surface area);
• Simultaneous use with angiotensin II receptor antagonists (ARAs) in patients with diabetic nephropathy;
• Simultaneous use with neutral endopeptidase inhibitors (such as sacubitril) due to the high risk of developing angioedema;
• Rare hereditary galactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome (the preparation contains lactose monohydrate).

With caution

• Arterial hypotension;
• Bilateral renal artery stenosis or stenosis of the artery of a solitary kidney;
• Renovascular hypertension;
• Renal failure (creatinine clearance less than 30 ml/min);
• Status after kidney transplantation;
• Primary hyperaldosteronism;
• Aortic or mitral stenosis;
• Hypertrophic obstructive cardiomyopathy;
• Chronic heart failure;
• Coronary artery disease or cerebrovascular diseases;
• Systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma);
• Bone marrow hematopoiesis depression, immunosuppressive therapy, simultaneous use of allopurinol or procainamide, or a combination of these complicating factors (risk of neutropenia and agranulocytosis);
• Diabetes mellitus;
• Hyperkalemia;
• Simultaneous use with potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes;
• Simultaneous use with lithium preparations;
• Burdened allergic history;
• Simultaneous desensitization with hymenoptera venom allergen;
• Simultaneous LDL apheresis procedure using dextran sulfate;
• Hemodialysis using high-flux membranes (such as AN69^®);
• Gout, hyperuricemia;
• Hyponatremia (increased risk of arterial hypotension in patients on a salt-free or low-salt diet);
• Conditions accompanied by a decrease in circulating blood volume (including during diuretic therapy, adherence to a diet with limited table salt, dialysis, diarrhea or vomiting);
• Use during major surgical interventions or during general anesthesia;
• Use in patients of Black race;
• Use in elderly patients (over 65 years).

Use in Pregnancy and Lactation

Use of lisinopril during pregnancy is contraindicated. If pregnancy is established, administration of the drug Lisinopril-SZ should be discontinued as soon as possible. Use of ACE inhibitors in the II and III trimesters of pregnancy has an adverse effect on the fetus (possible marked decrease in blood pressure, renal failure, hyperkalemia, skull hypoplasia, intrauterine death). There are no data on the negative effect of the drug on the fetus in case of use during the first trimester. Newborns and infants who were exposed to ACE inhibitors in utero should be closely monitored for timely detection of marked decrease in blood pressure, oliguria, hyperkalemia.

Lisinopril penetrates the placental barrier. There are no data on the excretion of lisinopril with breast milk. Breastfeeding should be discontinued during treatment with the drug.

Use in Hepatic Impairment

Recommendations regarding the dosing regimen in patients with mild and moderate hepatic insufficiency have not been developed, therefore dose selection in such patients should be carried out with caution, starting with the lowest possible dose.

Use in Renal Impairment

The drug should be prescribed with caution in renal failure (creatinine clearance less than 30 ml/min), bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, status after kidney transplantation.

Pediatric Use

Use of the drug is contraindicated under 18 years of age.

Geriatric Use

The drug should be prescribed with caution in elderly patients.

Special Precautions

Symptomatic arterial hypotension

Marked decrease in blood pressure most often occurs with a decrease in circulating blood volume, for example, due to diuretic therapy, a diet with limited table salt intake, dialysis, diarrhea or vomiting.

In patients with CHF and with or without renal impairment, a marked decrease in blood pressure is possible. It is more often detected in patients with severe stage CHF, as a result of the use of high doses of diuretics, hyponatremia or impaired renal function. In such patients, treatment should be started under strict medical supervision (carefully titrate the dose of the drug and diuretics).

The same recommendations apply to patients with coronary artery disease, cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke.

Before starting treatment with lisinopril, circulating blood volume should be replenished and/or serum sodium levels normalized if possible, and careful monitoring of patients at increased risk of developing symptomatic arterial hypotension should be carried out at the beginning of treatment and during dose adjustment.

In case of arterial hypotension, the patient should be placed on their back and, if necessary, intravenous infusion of physiological saline should be performed.

Transient arterial hypotension is not a contraindication to subsequent administration of the drug, which can usually be used immediately after blood pressure increases and circulating blood volume increases.

Arterial hypotension in acute myocardial infarction

In acute myocardial infarction, use of lisinopril is contraindicated in cardiogenic shock and severe arterial hypotension (systolic blood pressure less than 100 mm Hg), because in such patients the use of a vasodilator can significantly worsen hemodynamic parameters. In patients with low systolic blood pressure (>100 mm Hg and ≤120 mm Hg) during the first 3 days after acute myocardial infarction, low doses of lisinopril (2.5 mg once daily) should be used. In case of development of arterial hypotension (systolic blood pressure ≤100 mm Hg), the maintenance dose of lisinopril is temporarily reduced to 5 mg/day, if necessary – to 2.5 mg/day. In case of prolonged marked decrease in blood pressure (systolic blood pressure below 90 mm Hg for more than 1 hour), use of lisinopril should be discontinued.

In acute myocardial infarction, treatment with lisinopril should not be started in patients with signs of renal dysfunction, which were defined as serum creatinine concentration exceeding 177 µmol/l, and/or proteinuria exceeding 500 mg/24 hours. If renal function impairment develops during therapy with lisinopril (serum creatinine concentration exceeding 265 µmol/l or twice the corresponding value before starting treatment), the physician should consider the advisability of discontinuing lisinopril.

Mitral stenosis/aortic stenosis/hypertrophic obstructive cardiomyopathy

Lisinopril, like other ACE inhibitors, should be used with caution in patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic obstructive cardiomyopathy), as well as in patients with mitral stenosis.

Renal function impairment

In patients with impaired renal function (creatinine clearance less than 80 ml/min), the initial dose of lisinopril should be adjusted according to creatinine clearance (see section “Dosage regimen”). Regular monitoring of potassium levels and plasma creatinine concentration is a mandatory treatment tactic for such patients.

In patients with CHF, arterial hypotension can lead to worsening of renal function. Cases of acute renal failure, usually reversible, have been observed in such patients.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney who received ACE inhibitors, an increase in serum urea and creatinine concentrations was observed, usually reversible upon discontinuation of treatment. This is especially likely in patients with renal failure. In case of concomitant renovascular arterial hypertension, there is an increased risk of developing severe arterial hypotension and renal failure. In such patients, treatment should be started under careful medical supervision with low doses and the dose should be carefully titrated.

Since diuretic treatment may contribute to the development of the above conditions, the diuretic should be discontinued, and renal function should be monitored during the first weeks of lisinopril therapy.

In some patients with arterial hypertension without significant pre-existing renovascular hypertension, an increase in serum urea and creatinine concentrations was noted, usually minor and transient, especially in cases where Lisinopril was used simultaneously with a diuretic. This is especially likely in patients with pre-existing renal failure. Dose reduction and/or discontinuation of the diuretic and/or lisinopril may be required.

Kidney transplantation

There is no experience with the use of lisinopril in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

In patients with primary hyperaldosteronism, ACE inhibitors are ineffective, therefore the use of lisinopril is not recommended.

Hypersensitivity reactions/angioedema

Angioedema of the face, extremities, lips, tongue, epiglottis and/or larynx has been rarely observed in patients receiving treatment with ACE inhibitors, including Lisinopril. Angioedema can occur at any time during treatment. In such cases, the drug should be immediately discontinued, appropriate treatment should be prescribed and medical supervision should be provided until symptoms completely resolve. Even in cases of tongue edema not accompanied by respiratory failure, patients may require prolonged observation, since treatment with antihistamines and corticosteroids may be insufficient.

Angioedema accompanied by laryngeal edema can be fatal. Swelling of the tongue, vocal folds, or larynx can lead to airway obstruction. If such symptoms appear, emergency therapy is required: administration of epinephrine (0.3-0.5 ml of epinephrine (adrenaline) solution 1:1000 subcutaneously, administration of corticosteroids, antihistamines) and/or ensuring airway patency. The patient should be under medical supervision until symptoms completely and permanently disappear.

In rare cases, intestinal edema (angioedema of the intestine) develops during therapy with ACE inhibitors. In this case, patients experience abdominal pain as an isolated symptom or in combination with nausea and vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis is established using abdominal CT, ultrasound, or during surgery. Symptoms disappeared after discontinuation of ACE inhibitors. The possibility of intestinal edema should be considered when conducting differential diagnosis of abdominal pain in patients taking ACE inhibitors.

Patients with a history of angioedema not associated with ACE inhibitor use may be at greater risk of developing angioedema during ACE inhibitor therapy.

In Black patients taking ACE inhibitors, angioedema was observed more often than in other races.

An increased risk of angioedema was observed in patients simultaneously taking ACE inhibitors and drugs such as mTOR inhibitors (temsirolimus, sirolimus, everolimus), dipeptidyl peptidase type IV inhibitors (sitagliptin, saxagliptin, vildagliptin, linagliptin), estramustine, neutral endopeptidase inhibitors (racecadotril, sacubitril) and tissue plasminogen activators.

Anaphylactoid reactions during desensitization with hymenoptera venom allergen

In patients taking ACE inhibitors during desensitization with hymenoptera venom, life-threatening anaphylactoid reactions may occur extremely rarely. ACE inhibitor treatment should be temporarily discontinued before starting the desensitization course.

Anaphylactoid reactions during LDL apheresis

In patients taking ACE inhibitors, anaphylactoid reactions may develop during LDL apheresis using dextran sulfate. The development of these reactions can be prevented by temporarily discontinuing the ACE inhibitor before each LDL apheresis procedure.

Hemodialysis using high-flux membranes

Anaphylactoid reactions may occur during simultaneous hemodialysis using high-flux membranes (including AN69^®). The possibility of using another type of dialysis membrane or another antihypertensive agent should be considered.

Hepatic function impairment

In rare cases, a syndrome of cholestatic jaundice progressing to fulminant liver necrosis, sometimes fatal, has been observed during ACE inhibitor use. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in liver enzyme activity occurs during ACE inhibitor use, the drug should be discontinued, and the patient should be under appropriate medical supervision.

Neutropenia/agranulocytosis, thrombocytopenia, anemia

Neutropenia/agranulocytosis, thrombocytopenia and anemia may occur during ACE inhibitor use. In patients with normal renal function and without other complicating factors, neutropenia rarely develops. Neutropenia and agranulocytosis are reversible and disappear after discontinuation of the ACE inhibitor. Lisinopril should be used with particular caution in patients with systemic connective tissue diseases, during treatment with immunosuppressants, allopurinol or procainamide, especially in patients with impaired renal function. Some patients developed severe infections, in some cases resistant to intensive antibiotic therapy. When using lisinopril in such patients, periodic monitoring of white blood cell count (blood test with leukocyte count) is recommended. Patients should be warned to report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Ethnic differences

It should be taken into account that Black patients have a higher risk of developing angioedema. Like other ACE inhibitors, Lisinopril is less effective in reducing blood pressure in Black patients. This effect is possibly associated with a pronounced predominance of low-renin status in Black patients with arterial hypertension.

Surgical interventions/general anesthesia

Before surgical intervention (including dental surgery), the physician/anesthesiologist should be informed about the use of an ACE inhibitor. During extensive surgical interventions, as well as when using other agents that cause a decrease in blood pressure, Lisinopril, by blocking the formation of angiotensin II, can cause a pronounced unpredictable decrease in blood pressure. In case of arterial hypotension, it should be corrected by increasing circulating blood volume.

Elderly age

In elderly patients, use of standard doses of lisinopril leads to a higher plasma concentration of lisinopril. Therefore, special caution is required when determining the dose, although no differences in the antihypertensive effect of lisinopril between elderly and young patients have been identified.

Cough

A dry prolonged cough has been observed with the use of ACE inhibitors, which disappears after discontinuation of ACE inhibitor treatment. When making a differential diagnosis of cough, cough caused by ACE inhibitor use should be taken into account.

Hyperkalemia

Hyperkalemia may develop during therapy with ACE inhibitors, including Lisinopril. Risk factors for hyperkalemia are renal failure, elderly age (over 65 years), diabetes mellitus, some concomitant conditions (dehydration, decreased circulating blood volume, acute decompensated heart failure, metabolic acidosis), simultaneous use of potassium-sparing diuretics (such as spironolactone, eplerenone, triamterene or amiloride), as well as potassium preparations, potassium-containing salt substitutes and other drugs that contribute to an increase in plasma potassium levels (e.g., heparin).

Use of potassium supplements/preparations, potassium-sparing diuretics, potassium-containing salt substitutes can lead to a significant increase in blood potassium levels, especially in patients with reduced renal function. Hyperkalemia can lead to serious, sometimes fatal, cardiac arrhythmias.

If simultaneous use of lisinopril and the above-mentioned potassium-containing or potassium-elevating drugs is necessary, caution should be exercised and serum potassium levels should be regularly monitored.

Diabetes mellitus

When using lisinopril in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be regularly monitored during the first month of therapy.

Lithium preparations

As a rule, simultaneous use of lithium preparations and lisinopril is not recommended.

Ethanol (alcohol)

It is not recommended to consume alcoholic beverages during treatment, because ethanol enhances the antihypertensive effect of ACE inhibitors.

Combination therapy

In acute myocardial infarction, standard therapy (thrombolytics, acetylsalicylic acid as an antiplatelet agent, beta-blockers) is indicated. Lisinopril can be used in combination with intravenous administration or with the use of therapeutic transdermal systems of nitroglycerin.

Dual blockade of the RAAS

Cases of arterial hypotension, syncope, stroke, hyperkalemia and renal function impairment (including acute renal failure) have been reported in susceptible patients, especially with simultaneous use of several drugs that affect the RAAS.

Simultaneous use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal failure (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Simultaneous use of ACE inhibitors with ARBs is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

In cases where simultaneous prescription of two drugs affecting the RAAS is necessary, their use should be carried out under medical supervision with particular caution and with regular monitoring of renal function, blood pressure parameters and plasma electrolyte levels.

Effect on ability to drive vehicles and mechanisms

There are no data on the effect of lisinopril on the ability to drive vehicles and mechanisms when used in therapeutic doses, however, it must be taken into account that dizziness may occur, so caution should be exercised.

Overdose

Symptoms

Data on overdose in humans are limited. Symptoms associated with ACE inhibitor overdose may include arterial hypotension, circulatory collapse, dry oral mucosa, drowsiness, urinary retention, constipation, water-electrolyte balance disorders, renal failure, increased respiration, tachycardia, palpitations, bradycardia, dizziness, anxiety and cough.

Treatment

Gastric lavage, use of enterosorbents (activated charcoal), symptomatic therapy. If arterial hypotension develops, the patient should be placed on their back and legs raised. Intravenous administration of 0.9% sodium chloride is indicated for the treatment of overdose. Monitoring of blood pressure, water-electrolyte balance parameters is necessary. Bradycardia can be reduced by intravenous administration of atropine. If bradycardia resistant to treatment develops, the possibility of installing a pacemaker should be considered. Lisinopril can be removed from the systemic circulation by hemodialysis. During dialysis, the use of high-flux polyacrylonitrile membranes should be avoided (risk of anaphylactoid reactions).

Drug Interactions

Dual blockade of the RAAS

In patients with atherosclerotic disease, heart failure, or diabetes mellitus with target organ damage, simultaneous therapy with an ACE inhibitor and an ARB is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening of renal function (including acute renal failure) compared to the use of only one drug affecting the RAAS.

Dual blockade (for example, when combining an ACE inhibitor with an ARB) should be limited to individual cases with careful monitoring of renal function, potassium levels, and regular blood pressure control. Simultaneous use of ACE inhibitors with medicines containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Simultaneous use of ACE inhibitors with ARBs is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes, and other drugs that can increase serum potassium levels

When lisinopril is used concomitantly with potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations or potassium-containing salt substitutes, and other drugs that can increase serum potassium levels (including ARBs, heparin, tacrolimus, cyclosporine; drugs containing co-trimoxazole [trimethoprim + sulfamethoxazole]), the risk of hyperkalemia increases (especially in patients with impaired renal function). Therefore, these combinations should be prescribed with caution, under the control of plasma potassium levels and renal function. In elderly patients and patients with impaired renal function, the simultaneous use of ACE inhibitors with sulfamethoxazole/trimethoprim was accompanied by severe hyperkalemia, which is believed to have been caused by trimethoprim, so Lisinopril should be used with caution with drugs containing trimethoprim, regularly monitoring plasma potassium levels.

Other antihypertensive drugs

When used concomitantly with vasodilators, beta-blockers, slow calcium channel blockers, diuretics, and other antihypertensive drugs, the antihypertensive effect of lisinopril is enhanced.

Lithium preparations

When lisinopril is used concomitantly with lithium preparations, the elimination of lithium from the body may decrease. Therefore, the plasma lithium concentration should be regularly monitored.

NSAIDs, including selective COX-2 inhibitors and high doses of acetylsalicylic acid (≥3 g/day)

NSAIDs (including selective COX-2 inhibitors) and acetylsalicylic acid in doses greater than 3 g/day reduce the antihypertensive effect of lisinopril.

In some patients with impaired renal function (for example, elderly patients or dehydrated patients, including those taking diuretics) receiving therapy with NSAIDs (including selective COX-2 inhibitors), the simultaneous use of ACE inhibitors or ARBs may cause further deterioration of renal function, including the development of acute renal failure, and hyperkalemia. These effects are usually reversible. Simultaneous use of ACE inhibitors and NSAIDs should be done with caution (especially in elderly patients and in patients with impaired renal function). Patients should receive an adequate amount of fluid. It is recommended to carefully monitor renal function, both at the beginning and during treatment.

The use of lisinopril in combination with acetylsalicylic acid as an antiplatelet agent is not contraindicated.

Hypoglycemic drugs

Concomitant use of lisinopril and insulin, as well as oral hypoglycemic agents, may lead to the development of hypoglycemia. The greatest risk of development is observed during the first weeks of concomitant use, as well as in patients with impaired renal function.

Tricyclic antidepressants, antipsychotics, general anesthetics, narcotic drugs

When used concomitantly with tricyclic antidepressants, antipsychotics, general anesthetics, barbiturates, and muscle relaxants, the antihypertensive effect of lisinopril is enhanced.

Alpha- and beta-adrenergic agonists

Alpha- and beta-adrenergic agonists (sympathomimetics), such as epinephrine (adrenaline), isoproterenol, dobutamine, dopamine, may reduce the antihypertensive effect of lisinopril.

Baclofen

Enhances the antihypertensive effect of ACE inhibitors. Blood pressure should be carefully monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.

Ethanol

Concomitant use of ethanol enhances the antihypertensive effect of lisinopril.

Estrogens

Estrogens weaken the antihypertensive effect of lisinopril due to fluid retention.

Allopurinol, procainamide, cytostatics, immunosuppressants, corticosteroids (for systemic use)

Concomitant use of ACE inhibitors with allopurinol, procainamide, and cytostatics increases the risk of developing neutropenia/agranulocytosis.

Gold preparations

When lisinopril and intravenous gold preparations (sodium aurothiomalate) are used concomitantly, a symptom complex including facial flushing, nausea, vomiting, and decreased blood pressure has been described.

Selective serotonin reuptake inhibitors

Concomitant use of lisinopril with selective serotonin reuptake inhibitors may lead to severe hyponatremia.

mTOR inhibitors (mammalian Target of Rapamycin) (for example, temsirolimus, sirolimus, everolimus)

In patients taking ACE inhibitors and mTOR inhibitors (temsirolimus, sirolimus, everolimus) simultaneously, an increased frequency of angioedema was observed.

Dipeptidyl peptidase-4 (DPP-IV) inhibitors (gliptins), for example, sitagliptin, saxagliptin, vildagliptin, linagliptin

In patients taking ACE inhibitors and dipeptidyl peptidase-4 inhibitors (gliptins) simultaneously, an increased frequency of angioedema was observed.

Estramustine

Increased frequency of angioedema when used concomitantly with ACE inhibitors.

Neutral endopeptidase (NEP) inhibitors

An increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor).

When ACE inhibitors are used concomitantly with drugs containing sacubitril (a neprilysin inhibitor), the risk of angioedema increases, therefore the simultaneous use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. The administration of drugs containing sacubitril is contraindicated in patients receiving ACE inhibitors, as well as within 36 hours after discontinuation of ACE inhibitors.

Tissue plasminogen activators

Observational studies have revealed an increased frequency of angioedema in patients taking ACE inhibitors after the use of alteplase for thrombolytic therapy of ischemic stroke.

Pharmacokinetic interactions

Antacids and cholestyramine reduce the absorption of lisinopril from the gastrointestinal tract.

Storage Conditions

The drug should be stored out of the reach of children, protected from light, at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the packaging.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.