Linotor

Instructions for Medical Use of the Medicinal Product LİNOTOR® (Linotor®)

Composition:

Active substance: lisinopril;

One tablet contains lisinopril (as dihydrate) 5 mg, or

One tablet contains lisinopril (as dihydrate) 10 mg, or

One tablet contains lisinopril (as dihydrate) 20 mg;

Excipients: mannite (E 421), calcium hydrogen phosphate, corn starch, pregelatinized starch, iron oxide red (E 172), magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics:

Linotor® 5 mg – round tablets, 6.0 mm in diameter, biconvex surface, light pink in color, with a score on one side and imprint "PhI" on the other;

Linotor® 10 mg – round tablets, 6.0 mm in diameter, biconvex surface, pink-brown in color, with a score on one side and imprint "PhI" on the other;

Linotor® 20 mg – round tablets, 8.0 mm in diameter, biconvex surface, light pink-brown in color, with imprint "PhI" on one side.

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

ATC code C09A A03.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

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

Pharmacodynamic Effects

Although the antihypertensive effect of lisinopril is primarily attributed to inhibition of the renin-angiotensin-aldosterone system, lisinopril exerts its antihypertensive effect even in patients with low-renin hypertension. ACE is identical to kininase II, the enzyme responsible for bradykinin breakdown. The role of increased levels of the potent vasodilatory peptide bradykinin in the therapeutic effect of lisinopril has not yet been fully elucidated.

Blood pressure begins to decrease within 1 hour after oral administration, with maximum antihypertensive effect achieved within 6 hours. The duration of action of lisinopril is approximately 24 hours and is dose-dependent.

In some cases, optimal blood pressure reduction is achieved after 2–4 weeks of therapy. During long-term treatment, the antihypertensive effect of the drug does not diminish. Upon abrupt discontinuation of therapy, there is no rapid or significant rebound increase in blood pressure to pre-treatment levels.

Pediatric Population

In a clinical study involving 115 children aged 6 to 16 years with hypertension, patients with body weight below 50 kg received 0.625 mg, 2.5 mg, or 20 mg of lisinopril once daily, while patients with body weight above 50 kg received 1.25 mg, 5 mg, or 40 mg of lisinopril once daily. At the end of the second week of the study, once-daily lisinopril produced dose-dependent reductions in blood pressure, with sustained antihypertensive effects observed at doses exceeding 1.25 mg.

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

Pharmacokinetics

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

Absorption

After oral administration of lisinopril, peak serum concentrations are reached within 7 hours, although in patients with acute myocardial infarction, a slight tendency toward a prolonged time to peak concentration has been observed. The mean absorption of lisinopril is approximately 25%, with individual variation depending on the administered dose (5–80 mg) ranging from 6% to 60%. These data are based on the amount of drug recovered in urine. In patients with heart failure, absolute bioavailability is reduced by approximately 16%. Food intake does not affect the absorption of lisinopril.

Distribution

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

Elimination

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

Hepatic Impairment

In patients with cirrhosis, impaired liver function leads to reduced absorption of lisinopril (approximately 30% lower based on urinary recovery) and increased exposure (approximately 50% higher) compared to healthy volunteers due to reduced clearance.

Renal Impairment

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

Lisinopril can be removed by dialysis. During a 4-hour hemodialysis session, plasma lisinopril concentration is reduced by an average of 60%, with dialysis clearance ranging between 40 and 55 ml/min.

Heart Failure

Patients with heart failure have significantly higher exposure to lisinopril compared to healthy volunteers (mean AUC increased by 125%). However, based on the amount of lisinopril recovered in urine, there is a reduction in absorption of approximately 16% compared to healthy volunteers.

Children

The pharmacokinetic profile of lisinopril was studied in 29 pediatric patients aged 6 to 16 years with arterial hypertension and glomerular filtration rate (GFR) < 30 ml/min/1.73 m². After administration of doses ranging from 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 are similar to those previously observed in adults.

AUC and Cmax values in children in this study were comparable to those obtained in adults.

Elderly Patients

Elderly patients have higher plasma drug levels and higher AUC values (increased by approximately 60%) compared to younger patients.

Clinical characteristics.

Indications.

• Arterial hypertension.
• Symptomatic heart failure.
• Acute myocardial infarction (short-term (6 weeks) treatment of acute myocardial infarction within the first 24 hours in patients with stable hemodynamics).
• Renal complications in patients with diabetes mellitus (treatment of kidney disease in patients with arterial hypertension, type 2 diabetes mellitus, and initial nephropathy).

Contraindications.

• Hypersensitivity to lisinopril, to any excipient of the medicinal product, or to other ACE inhibitors.
• History of angioedema associated with previous ACE inhibitor therapy.
• Concomitant use of lisinopril and sacubitril/valsartan. Lisinopril should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Special precautions for use" and "Interaction with other medicinal products and other forms of interaction").
• Hereditary or idiopathic angioedema.
• Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
• Concomitant use of lisinopril and aliskiren-containing medicinal products in patients with diabetes mellitus or renal function impairment (eGFR < 60 ml/min/1.73 m²) (see section "Interaction with other medicinal products and other forms of interaction").

Interaction with other medicinal products and other forms of interaction.

Antihypertensive agents

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

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 increased incidence of adverse reactions such as hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to use of a single agent acting on the RAAS (see sections "Contraindications" and "Special precautions for use").

Agents increasing the risk of angioedema

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated, as it increases the risk of angioedema (see sections "Contraindications" and "Special precautions for use").

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 (see section "Special precautions for use").

Diuretics

When a diuretic is added to the treatment regimen of a patient receiving lisinopril, the antihypertensive effect is usually additive.

In patients receiving diuretics, particularly those recently initiated on diuretic therapy, a marked decrease in blood pressure may occasionally occur after adding lisinopril. The likelihood of symptomatic hypotension during lisinopril therapy can be reduced by discontinuing the diuretic prior to starting lisinopril (see sections "Special precautions for use" and "Method of administration and dosage").

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

Although serum potassium levels generally remain within normal limits, hyperkalemia has been observed in some patients receiving lisinopril. Administration of potassium-containing dietary supplements, potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), or potassium-containing salt substitutes may lead to significant increases in serum potassium levels, particularly in patients with impaired renal function. Caution should also be exercised when using Linotor® together with other agents that may increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combining Linotor® with the above-mentioned agents is not recommended. If concomitant use is required, they should be used with caution and under continuous monitoring of serum potassium levels. When lisinopril is administered together with potassium-wasting diuretics, hypokalemia induced by the diuretic may be reduced.

Cyclosporines

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

Heparin

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

Lithium

Increased serum lithium concentrations and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Concomitant use of thiazide diuretics with ACE inhibitors increases the risk of lithium toxicity and exacerbates already elevated lithium toxicity. Concomitant use of lithium and lisinopril is not recommended; however, if combined use is necessary, careful monitoring of serum lithium levels is required (see section "Special precautions for use").

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

Concomitant use of ACE inhibitors with NSAIDs (e.g., acetylsalicylic acid at anti-inflammatory doses, cyclooxygenase-2 (COX-2) inhibitors, and nonselective NSAIDs) may result in reduced antihypertensive effect. Additionally, concomitant use of ACE inhibitors and NSAIDs may increase the risk of worsening renal function, including development of acute renal failure, and increased serum potassium levels, particularly in patients with reduced renal function. These effects are usually reversible. Caution should be exercised when using combination therapy, especially in elderly patients. Patients should receive adequate hydration, and renal function should be closely monitored at the start of combination therapy and throughout treatment.

Gold

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

Tricyclic antidepressants/neuroleptics/anesthetics

Concomitant use of certain anesthetics, tricyclic antidepressants, and antipsychotics with ACE inhibitors may lead to further reduction in blood pressure (see section "Special precautions for use").

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors.

Antidiabetic agents

Epidemiological studies suggest that concomitant use of ACE inhibitors and antidiabetic agents (insulins, oral hypoglycemic agents) may potentiate glucose lowering, increasing the risk of hypoglycemia. This effect is more commonly observed during the first weeks of combination therapy and in patients with impaired renal function.

Acetylsalicylic acid, thrombolytics, beta-blockers, nitrates

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

Special precautions for use.

The medicinal product contains mannitol (E 421) as an excipient, which may have a mild laxative effect.

Symptomatic hypotension.

Clinical manifestations of arterial hypotension rarely occur in patients with uncomplicated arterial hypertension. In hypertensive patients receiving lisinopril, the likelihood of hypotension is higher if dehydration is present, for example, due to diuretic therapy, diarrhea or vomiting, salt-free diet, dialysis, or in those with severe forms of renin-dependent hypertension. Symptomatic hypotension has been observed in patients with heart failure, with or without renal impairment. The likelihood of its occurrence is higher in patients with more severe forms of heart failure, as evidenced by the use of high doses of loop diuretics, hyponatremia, or functional renal impairment. Initiation of therapy and dose adjustment in patients at increased risk of symptomatic hypotension should be performed under careful medical supervision. Similar precautions should be applied to patients with ischemic heart disease or cerebrovascular disorders, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

If arterial hypotension occurs, the patient should be placed in a supine position and, if necessary, physiological saline should be administered intravenously. Transient lowering of blood pressure is not a contraindication for continued use of the drug. Once blood pressure increases after fluid volume restoration, the drug may be used as usual.

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

Arterial hypotension in acute myocardial infarction.

Lisinopril therapy should not be initiated in patients with acute myocardial infarction who are at risk of further hemodynamic complications following vasodilator therapy. This group includes patients with systolic blood pressure of 100 mm Hg or lower, or those who have developed cardiogenic shock. If systolic blood pressure is 120 mm Hg or lower during the first 3 days after infarction, the dose should be reduced. If systolic blood pressure is 100 mm Hg or lower, the maintenance dose should be reduced to 5 mg or temporarily to 2.5 mg. Lisinopril therapy should be discontinued if arterial hypotension persists (systolic blood pressure below 90 mm Hg for more than 1 hour).

Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy.

Like other ACE inhibitors, lisinopril should be used with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction, such as aortic stenourosis or hypertrophic cardiomyopathy.

Renal function impairment.

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 1), and subsequently based on the patient's response to treatment. Regular monitoring of potassium and creatinine levels in such patients is part of standard medical practice.

In patients with heart failure, arterial hypotension occurring at the beginning of ACE inhibitor therapy may lead to further 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 artery of a solitary kidney receiving ACE inhibitors, increased blood urea nitrogen and serum creatinine levels have been observed, usually reversible upon discontinuation of therapy. This is particularly characteristic in patients with pre-existing renal impairment. If renovascular hypertension is also present, the risk of severe hypotension and renal failure increases. Treatment of such patients should be initiated under close medical supervision with low doses and careful dose titration. Since diuretic therapy may be a contributing factor to the above-mentioned effects, diuretics should be discontinued prior to lisinopril administration, and renal function should be monitored during the first weeks of lisinopril therapy.

In some patients with arterial hypertension without obvious signs of renal vascular disorders, increased blood urea and serum creatinine levels have been observed, usually mild and reversible, particularly when lisinopril is used concomitantly with diuretics. The likelihood of such effects is higher in patients with pre-existing renal impairment. In such cases, dose reduction and/or discontinuation of diuretics and/or lisinopril may be necessary.

Lisinopril therapy should not be initiated in patients with acute myocardial infarction who have signs of renal dysfunction (serum creatinine concentration above 177 µmol/L and/or proteinuria above 500 mg/day). If renal disorders develop during lisinopril therapy (serum creatinine concentration above 265 µmol/L or double the level observed before treatment initiation), the physician should consider discontinuing lisinopril therapy.

Hypersensitivity/angioedema.

Angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has occasionally been reported in patients receiving ACE inhibitors, including lisinopril. These events may occur at any time during treatment. In such cases, lisinopril should be discontinued immediately, appropriate treatment initiated, and continuous monitoring performed until complete resolution of symptoms.

Even in cases where swelling is localized to the tongue without respiratory difficulties, prolonged observation may be required, as treatment with antihistamines and corticosteroids may be insufficient.

Very rarely, fatal outcomes due to angioedema associated with laryngeal or tongue swelling have been reported. In patients with swelling of the tongue, glottis, or larynx, airway obstruction is possible, especially in those who have undergone airway surgery. In such cases, immediate emergency measures are required, including administration of adrenaline and/or maintaining airway patency. The patient should remain under close medical supervision until symptoms have completely and stably resolved.

ACE inhibitors cause angioedema more frequently in individuals of African descent compared to other racial groups.

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

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Sacubitril/valsartan therapy should not be initiated earlier than 36 hours after the last dose of Linotor®. Linotor® therapy should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Patients who concomitantly use ACE inhibitors with racecadotril, mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus), or vildagliptin have an increased risk of developing angioedema (e.g., swelling of the airways or tongue with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction"). Caution should be exercised when initiating racecadotril, mTOR inhibitors (e.g., temsirolimus, sirolimus, everolimus), or vildagliptin in patients receiving ACE inhibitors.

Anaphylactic reactions in patients undergoing hemodialysis.

Anaphylactic reactions have been reported in patients undergoing hemodialysis using high-flux membranes (e.g., AN 69) while concomitantly receiving ACE inhibitors. In such cases, either a different type of dialysis membrane or a different class of antihypertensive agents should be used.

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

Rarely, life-threatening anaphylactic reactions have occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis procedure.

Desensitization.

Anaphylactic reactions have been observed in patients receiving ACE inhibitors during desensitizing therapy (e.g., Hymenoptera venom). These reactions were avoided by temporarily discontinuing ACE inhibitors, but reappeared upon inadvertent re-administration of 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 liver enzyme levels increase in patients taking lisinopril, the drug 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 complications. Neutropenia and agranulocytosis resolve after discontinuation of ACE inhibitor therapy. Lisinopril should be used with extreme caution in patients with collagen vascular disease, those receiving immunosuppressive therapy, allopurinol, or procainamide, or those with multiple complicating factors, especially if renal function is already impaired. Serious infections may develop in some of these patients, and intensive antibiotic therapy may not always be effective. If lisinopril is prescribed to such patients, periodic monitoring of white blood cell count is recommended, and patients should be informed to report any signs of infection.

Dual blockade of the RAAS.

Evidence indicates that concomitant use of ACE inhibitors, angiotensin receptor blockers (ARBs), or aliskiren increases the risk of arterial hypotension, hyperkalemia, and reduced renal function (including acute renal failure). Therefore, dual blockade of the RAAS by combining ACE inhibitors with ARBs or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

If dual RAAS blockade is considered absolutely necessary, treatment should only be conducted under careful specialist supervision with continuous, close monitoring of renal function, blood electrolyte levels, and blood pressure.

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

Race.

ACE inhibitors cause angioedema more frequently in individuals of African descent compared to other racial groups.

Like other ACE inhibitors, lisinopril may be less effective in lowering blood pressure in individuals of African descent compared to other racial groups, possibly due to the higher prevalence of low-renin status among African descent patients with arterial hypertension.

Cough.

Cases of cough have been reported during ACE inhibitor therapy. In typical cases, this is a non-productive, persistent cough that resolves after discontinuation of treatment. When performing differential diagnosis of cough, it should be considered that cough may be caused by ACE inhibitor therapy.

Surgical procedures/anesthesia.

During major surgical procedures or anesthesia with agents causing arterial hypotension, lisinopril may block angiotensin II formation following compensatory renin secretion. If arterial hypotension results from this mechanism, fluid volume should be restored.

Hyperkalemia.

ACE inhibitors may cause hyperkalemia because they inhibit aldosterone release. This effect is usually mild in patients with normal renal function. However, in patients with impaired renal function, diabetes mellitus, and/or those taking potassium-containing supplements (including salt substitutes), potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), other drugs associated with increased serum potassium (e.g., heparin, trimethoprim, or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers, hyperkalemia may occur. Patients receiving ACE inhibitors should use potassium-sparing diuretics and angiotensin receptor blockers cautiously, and serum potassium levels and renal function parameters should be monitored (see "Interaction with other medicinal products and other forms of interaction").

Patients with diabetes mellitus.

During the first month of ACE inhibitor therapy, close glycemic monitoring is required for diabetic patients receiving oral antidiabetic agents or insulin.

Lithium.

Combination of lithium and lisinopril is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Pregnancy.

Initiation of ACE inhibitor therapy during pregnancy is not recommended. If continuation of ACE inhibitor therapy is not considered mandatory, women planning pregnancy should be switched to alternative antihypertensive agents with a well-established safety profile during pregnancy. If pregnancy is diagnosed, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative therapy initiated (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

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 associated with ACE inhibitor use during the first trimester of pregnancy are inconclusive, but a slight increase in risk cannot be excluded. If continuation of ACE inhibitor therapy is not considered mandatory, women planning pregnancy should be switched to alternative antihypertensive agents with a well-established safety profile during pregnancy. Upon confirmation of pregnancy, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative treatment initiated.

It is known that ACE inhibitors, when used during the second and third trimesters of pregnancy, exhibit fetotoxic effects (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If ACE inhibitors were used from the second trimester of pregnancy, ultrasound assessment of renal and skull function is recommended.

Newborns whose mothers received ACE inhibitors should be carefully monitored for arterial hypotension (see sections "Contraindications" and "Special precautions for use").

Lactation. Since information on the use of lisinopril during breastfeeding is lacking, lisinopril is not recommended. Alternative treatment methods with better-established safety profiles during breastfeeding are recommended, especially when breastfeeding a newborn or premature infant.

Ability to affect reaction speed when driving or operating machinery.

When driving or operating machinery, the possibility of dizziness or fatigue should be considered.

Method of administration and dosage.

Lisinopril is recommended to be administered orally once daily, at approximately the same time each day. Food intake does not affect the absorption of lisinopril. The dosage should be individually adjusted according to the patient's response and blood pressure.

Arterial hypertension

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

Initial dose

The recommended initial dose for patients with arterial hypertension is 10 mg. Patients with highly active RAAS (particularly those with renovascular hypertension, increased salt depletion, 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. Reduction of the initial dose is also recommended in cases of renal impairment (see Table 1 below).

Maintenance dose

The usual recommended maintenance dose is 20 mg once daily. If this dose does not provide adequate therapeutic effect within 2–4 weeks, it may be increased. The maximum daily dose used in 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 who are receiving diuretics during treatment with lisinopril. Therefore, such patients should be treated with caution due to the potential for increased salt depletion and/or reduced extracellular fluid volume. If possible, diuretic therapy should be discontinued 2–3 days prior to starting lisinopril. For patients with arterial hypertension who cannot discontinue diuretic therapy, treatment with lisinopril should be initiated at a 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. Diuretic therapy may be reintroduced as needed.

Dose adjustment for patients with renal impairment

Dosing for patients with renal impairment should be based on creatinine clearance, as shown in Table 1 below.

Table 1. Dose adjustment for patients with renal impairment.

Creatinine clearance (mL/min)	Initial dose (mg/day)
<10 mL/min (including patients on dialysis)	2.5 mg*
10–30 mL/min	2.5–5 mg
31–80 mL/min	5–10 mg

* – dosage and/or frequency of administration must be calculated based on blood pressure response.

Dosage may be gradually increased until blood pressure normalizes or until reaching the maximum daily dose of 40 mg.

Use in children with hypertension aged 6–16 years.

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

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

Heart failure

Patients with symptomatic heart failure should take lisinopril as adjunctive therapy to diuretics and, if necessary, digitalis preparations or beta-blockers. Lisinopril therapy may be initiated at a dose of 2.5 mg once daily, administered under medical supervision to monitor the initial effect of the drug on blood pressure.

Lisinopril dosage should be increased:

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

Dosage selection should be based on the clinical response of each individual patient. Patients at high risk of symptomatic hypotension, such as those with elevated salt depletion with or without hyponatremia, hypovolemia, or those receiving intensive diuretic therapy, should have their condition optimized, if possible, prior to initiating lisinopril therapy. Renal function and serum potassium levels should be monitored.

Acute myocardial infarction

Depending on the clinical situation, the patient should receive standard recommended therapy, such as thrombolytics, aspirin, and beta-blockers. Intravenous or transdermal nitroglycerin may be used concomitantly with lisinopril.

Initial dose (first 3 days after myocardial infarction)

Lisinopril therapy may be initiated within the first 24 hours after onset of symptoms. Therapy should not be initiated if systolic blood 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 thereafter 10 mg once daily. For patients with low systolic pressure not exceeding 120 mm Hg at the beginning of therapy or during therapy within the first 3 days after infarction, treatment should be initiated at a lower dose of 2.5 mg.

In case 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 1).

Maintenance dose

The recommended maintenance dose is 10 mg once daily. In case of arterial hypotension (systolic pressure ≤ 100 mm Hg), a daily maintenance dose of 5 mg may be prescribed; 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 with the drug should be discontinued. Therapy is recommended for 6 weeks, after which the patient's condition should be reassessed. Patients with symptoms of heart failure should continue lisinopril treatment.

Renal complications in patients with diabetes

For patients with type 2 diabetes, hypertension, and early-stage nephropathy, the lisinopril dose is 10 mg once daily, which may be increased, if necessary, to 20 mg once daily to achieve a sustained diastolic blood pressure below 90 mm Hg.

In case 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 1).

Elderly patients

Clinical trials have not revealed changes in efficacy or safety of the drug related to age. However, as advancing age is associated with reduced renal function, the initial dose of lisinopril should be selected according to the recommendations in Table 1. Thereafter, dosage should be adjusted based on 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.

Children.

Lisinopril may be used in children with hypertension aged 6 to 16 years.

There is limited experience regarding the safety and efficacy of the drug in children with hypertension under 6 years of age, and no experience with lisinopril for other indications. Therefore, lisinopril is not recommended for use in children for indications other than hypertension.

Lisinopril is also 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 hypotension, circulatory shock, electrolyte disturbances, renal failure, pulmonary hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Recommended treatment of overdose is intravenous infusion of physiological saline. If hypotension occurs, the patient should be placed in a supine position. If available, treatment with angiotensin II infusion and/or intravenous catecholamines may be considered. If drug intake was recent, measures aimed at eliminating lisinopril should be taken (e.g., emesis, gastric lavage, use of adsorbents and sodium sulfate). Lisinopril may be removed from systemic circulation by hemodialysis (see section "Special precautions"). A cardiac pacemaker is indicated in case of therapy-resistant bradycardia. Vital signs, serum electrolyte concentrations, and creatinine levels should be continuously monitored.

Adverse reactions.

The following adverse reactions may occur during the use of this medicinal product and other ACE inhibitors, with the following frequencies: very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); very rare (<1/10,000); frequency not known (cannot be estimated from the available 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 disorders.

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

Metabolism and nutrition disorders: very rare – hypoglycemia.

Nervous system disorders: common – dizziness, headache; uncommon – sudden mood changes, paresthesia, vertigo, taste disturbances, sleep disturbances, hallucinations; rare – confusion, olfactory disturbances; frequency not known – depressive symptoms, loss of consciousness.

Cardiac and vascular disorders: common – orthostatic effects (including arterial hypotension); uncommon – myocardial infarction and stroke, possibly as complications of excessive hypotension in patients at risk, palpitations, tachycardia, Raynaud's syndrome.

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, hepatocellular or cholestatic hepatitis, jaundice, hepatic failure.

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

A syndrome complex has been reported, which may include: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity, or other dermatological manifestations.

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

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

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

General disorders: uncommon – fatigue, asthenia.

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

Clinical safety data indicate that lisinopril is generally well tolerated in pediatric patients with arterial hypertension, and its safety profile in this age group is similar to that in adults.

Shelf life. 4 years.

Storage conditions.

Keep out of the reach of children.

Store at a temperature not exceeding 30 °C.

Packaging.

14 tablets in a blister pack, 2 blisters in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Pharma International Company.

Manufacturer's address.

Al Kastal area, Airport road, P.O. Box 334, Jubaiha 11941, Amman – Jordan.

Marketing Authorization Holder.

Pharma International Company.

Address of the Marketing Authorization Holder.

P.O. Box 334, Al-Jubaiha 11941, Amman, Jordan.