Aurolyza

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT AURORIZA (AUROLIZA)

Composition:

Active substance: lisinopril;

1 tablet contains lisinopril dihydrate equivalent to 5 mg or 10 mg or 20 mg of lisinopril;

Excipients: calcium hydrogen phosphate anhydrous, maize starch, iron oxide yellow (or iron oxide red for 5 mg tablets) (E 172), mannite (E 421), pregelatinized starch, magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical characteristics:

5 mg tablets: light red, round, biconvex, uncoated tablets, marked with "L" on one side and "5" on the other side, located on one side of the break line;

10 mg tablets: light yellow, round, biconvex, uncoated tablets, marked with "L" on one side and "10" on the other side;

20 mg tablets: light yellow, capsule-shaped, biconvex, uncoated tablets, marked with "L" on one side and "20" on the other 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 reduced plasma concentrations of angiotensin II, resulting in decreased vasoconstriction and reduced aldosterone secretion, which may also lead to increased serum potassium levels.

Pharmacodynamic effects

Although the mechanism by which lisinopril lowers blood pressure is presumed to be primarily through inhibition of the renin-angiotensin-aldosterone system, lisinopril exerts antihypertensive effects even in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. It remains unclear whether increased levels of the potent vasodilatory peptide bradykinin play a role in the therapeutic effect of lisinopril.

Children

In a clinical study involving 115 pediatric patients aged 6–16 years with arterial 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 of 50 kg or more received 1.25 mg, 5 mg, or 40 mg of lisinopril once daily. At the end of the 2-week treatment period, once-daily lisinopril produced dose-dependent blood pressure reduction, with stable antihypertensive efficacy demonstrated at doses exceeding 1.25 mg.

This effect was confirmed during the withdrawal phase. Diastolic blood pressure increased by approximately 9 mm Hg in patients receiving placebo compared to those receiving medium and high doses of lisinopril. The dose-dependent antihypertensive effect of lisinopril was consistent across several 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, peak serum concentration (Cmax) of lisinopril is reached within 7 hours, although in patients with acute myocardial infarction a slight tendency toward prolonged time to reach Cmax has been observed. The average absorption of lisinopril is approximately 25%, varying among individual patients depending on the administered dose (5–80 mg) within the range of 6% to 60%. These data are based on the amount of drug recovered in urine. Absolute bioavailability is reduced by approximately 16% in patients with heart failure. Food intake does not affect the absorption of lisinopril.

Distribution

Lisinopril does not bind to other serum proteins except 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 after multiple dosing is 12.6 hours. The clearance of lisinopril in healthy volunteers is 50 ml/min. In cases of impaired renal function, elimination of lisinopril is reduced proportionally to the degree of functional impairment. The decline in serum concentration shows a prolonged terminal phase and is not related to drug accumulation. This final phase likely reflects strong binding to ACE and is not dose-proportional.

Patients with hepatic impairment

In patients with cirrhosis, hepatic dysfunction 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

Renal dysfunction reduces the elimination of lisinopril, which is excreted by the kidneys, but this reduction is clinically significant only when glomerular filtration rate (GFR) is below 30 ml/min.

With mild to moderate renal impairment (creatinine clearance 30–80 ml/min), the mean area under the plasma 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 a 4-hour hemodialysis session, plasma lisinopril concentration decreases by an average of 60%, with dialysis clearance ranging between 40 ml/min and 55 ml/min.

Heart failure

Patients with heart failure have substantially greater exposure to lisinopril compared to healthy volunteers (mean AUC increase of 125%). However, based on the amount of lisinopril recovered 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 (approximately 60% higher) compared to younger patients.

Children

The pharmacokinetic profile of lisinopril was studied in 29 children with arterial hypertension aged 6 to 16 years and GFR above 30 ml/min/1.73 m². After administration of lisinopril at doses of 0.1–0.2 mg/kg, steady-state plasma concentrations were achieved within 6 hours, and the extent of absorption based on urinary excretion was 28%. These findings were similar to those previously observed in adults.

AUC and Cmax values in children were comparable to those observed in adults.

Clinical characteristics.

Indications.

• Essential 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).
• Diabetic renal complications (treatment of kidney disease in hypertensive patients with type 2 diabetes and initial nephropathy).

Contraindications.

• Hypersensitivity to lisinopril, other components of the medicinal product, or to other ACE inhibitors.
• History of angioedema associated with previous use of ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Concomitant use of aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (eGFR <60 mL/min/1.73 m²).
• Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breastfeeding").
• Concomitant use with sacubitril/valsartan. Treatment with Aurolyza may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Antihypertensive agents

Concomitant use of Aurolyza with other antihypertensive agents (e.g., glyceryl trinitrate, other nitrates, or other vasodilators) may result in additional lowering of blood pressure.

Clinical trial data have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combining ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with a higher incidence of adverse events such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to using a single agent acting on the RAAS (see sections "Contraindications" and "Special precautions for use").

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

Diuretics. The antihypertensive effect is generally more pronounced when diuretics are added to lisinopril therapy. In patients receiving diuretics, particularly those recently initiated on diuretic therapy, a significant drop in blood pressure may occasionally occur after adding lisinopril. The possibility of symptomatic arterial hypotension with lisinopril may be reduced by discontinuing diuretic therapy prior to starting lisinopril (see section "Special precautions for use").

Potassium-containing supplements, potassium-sparing diuretics, or potassium-containing salt substitutes. Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients receiving this medicinal product. Potassium-sparing diuretics (such as spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to a significant increase in serum potassium levels. Caution should also be exercised when using Aurolyza concomitantly with other medicinal products that 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, combination of Aurolyza with the above-mentioned medicinal products is not recommended. If concomitant use is indicated, treatment should be administered with caution and serum potassium levels should be monitored frequently.

When Aurolyza is used concomitantly with potassium-wasting diuretics, diuretic-induced hypokalemia may be corrected.

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. Increased serum lithium concentrations and toxicity have been reported with concomitant use of lithium and ACE inhibitors. The concomitant use of thiazide diuretics with ACE inhibitors increases the risk of lithium toxicity and further enhances the already elevated risk of 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.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid at doses ≥3 g per day. When ACE inhibitors are used concomitantly with NSAIDs (acetylsalicylic acid at doses exerting anti-inflammatory effects, COX-2 inhibitors, and non-selective NSAIDs), attenuation of the antihypertensive effect may occur.

Concomitant use of ACE inhibitors and NSAIDs may lead to an increased risk of impaired renal function, 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 administered with caution, especially in elderly patients. Adequate hydration should be ensured, and renal function should be monitored after initiation of combination therapy and periodically thereafter.

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

Sympathomimetic agents. Sympathomimetic agents 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 enhance glucose-lowering effects, 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.

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

Special precautions for use.

Symptomatic arterial hypotension has rarely been 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-electrolyte balance, for example due to diuretic therapy, salt restriction, diarrhoea or vomiting, or in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Undesirable effects"). Symptomatic arterial hypotension has been observed in patients with heart failure (with or without renal impairment).

The likelihood of developing arterial hypotension is higher in patients with severe heart failure who are receiving high doses of loop diuretics, have hyponatraemia, or have functionally impaired renal function. In patients at increased risk of developing arterial hypotension, initiation of therapy and subsequent dose escalation should be performed under close medical supervision. The same precautions apply to patients with ischaemic heart disease or cerebrovascular disease, in whom excessive reduction in blood pressure may lead to myocardial infarction or stroke.

In case of arterial hypotension, the patient should be placed in a supine position; if necessary, intravenous administration of physiological saline solution should be performed.

Transient hypotension is not a contraindication to continued use of the drug, which can usually be re-administered without complications after blood pressure has increased following an increase in fluid volume.

In some patients with heart failure who have normal or low blood pressure, additional reduction in systemic arterial pressure may occur during treatment with lisinopril. 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 acute myocardial infarction if there is a risk of further serious haemodynamic disturbances following vasodilator therapy. This applies to patients with systolic blood pressure of 100 mm Hg or lower or patients who have developed cardiogenic shock. During the first 3 days after myocardial infarction, the dose of the drug should be reduced if systolic pressure does not exceed 120 mm Hg. If systolic blood pressure is 100 mm Hg or lower, the dose should be reduced to 5 mg or temporarily to 2.5 mg. If prolonged arterial hypotension occurs after lisinopril administration (systolic pressure remains below 90 mm Hg for more than 1 hour), lisinopril treatment should be discontinued.

Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy. As with other ACE inhibitors, lisinopril is not recommended for use in patients with mitral valve stenosis or impaired outflow from the left ventricle (in aortic stenosis or hypertrophic cardiomyopathy).

Renal function impairment. In patients with impaired renal function (creatinine clearance < 80 mL/min), the initial dose of lisinopril should be adjusted based on creatinine clearance 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 impaired 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 single kidney, ACE inhibitors increase blood urea and serum creatinine levels; these effects usually resolve after discontinuation of the drug. The likelihood of such events is particularly high in patients with renal impairment.

Renovascular hypertension increases the risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated under medical supervision, starting with low doses carefully titrated. Since diuretics may promote the development of the clinical course described above, their use should be discontinued during the first weeks of lisinopril treatment, and renal function should be closely monitored.

In some patients with arterial hypertension without evident renal vascular disease, lisinopril use, particularly in combination with diuretics, may lead to increased blood urea and serum creatinine levels; these changes are usually mild and transient. The likelihood of such changes is higher in patients with impaired renal function. In such cases, dose reduction and/or discontinuation of diuretics and/or lisinopril may be necessary.

In acute myocardial infarction, lisinopril should not be used in patients with impaired renal function (serum creatinine level >177 µmol/L and/or proteinuria >500 mg/day). If renal impairment develops during lisinopril treatment (serum creatinine level >265 µmol/L or doubles compared to baseline), 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 should be discontinued immediately, appropriate therapy initiated, and the patient monitored until complete resolution of symptoms. Even in cases where swelling is localized only to the tongue and does not lead to respiratory impairment, prolonged observation may be required, as therapy with antihistamines and corticosteroids may be insufficient.

Very rare fatal cases of laryngeal or lingual angioedema have been reported. If swelling extends to the tongue, glottis, or larynx, obstructive respiratory distress may develop, particularly in patients who have previously undergone surgery on the airways. In such cases, immediate emergency measures should be taken, including administration of adrenaline and/or securing airway patency. The patient should remain under close medical supervision until symptoms have completely and stably resolved.

ACE inhibitors may cause more cases of angioedema in patients of non-Caucasian race compared to patients of Caucasian race.

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 (see section "Contraindications").

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan may be initiated only 36 hours after the last dose of the medicinal product Auroraise. The medicinal product Auroraise 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), or vildagliptin may increase the risk of angioedema (e.g., airway or tongue swelling with or without respiratory distress) (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 haemodialysis. Anaphylactoid reactions have been reported in patients undergoing haemodialysis using 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 an antihypertensive medicinal product of another class.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. During dextran sulphate apheresis, use of ACE inhibitors may lead to life-threatening anaphylactoid reactions. These symptoms can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis.

Desensitization. Anaphylactic reactions may occur in patients receiving ACE inhibitors during desensitization therapy (e.g., hymenoptera venom). These reactions resolve during temporary discontinuation of ACE inhibitors but may reappear upon inadvertent re-administration.

Hepatic impairment. Very rarely, use of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice or hepatitis 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 anaemia 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 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 several of these complicating factors, especially if renal function is already impaired. Serious infections may develop in some of these patients, in which intensive antibiotic therapy may not be effective. If lisinopril is prescribed to such patients, periodic monitoring of white blood cell count is recommended, and patients should be informed of the need to report any signs of infection.

Dual blockade of the RAAS. Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been reported to increase the risk of arterial hypotension, hyperkalaemia, and renal impairment (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see sections "Pharmacodynamics" and "Interaction with other medicinal products and other forms of interaction").

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

Race. ACE inhibitors cause angioedema more frequently in patients of non-Caucasian race compared to other racial groups. As with other ACE inhibitors, lisinopril may be less effective in reducing blood pressure in patients of non-Caucasian race compared to other racial groups, possibly due to the higher prevalence of low-renin status among non-Caucasian patients with arterial hypertension.

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

Surgery/anaesthesia. In patients undergoing major surgery or anaesthesia with agents causing arterial hypotension, lisinopril may block angiotensin II formation following compensatory renin secretion. If arterial hypotension occurs due to this mechanism, fluid volume should be restored.

Serum potassium levels. ACE inhibitors may cause hyperkalaemia as they suppress aldosterone release. This effect is usually minor in patients with normal renal function. However, in patients with impaired renal function and/or those taking potassium-containing supplements (including salt substitutes), potassium-sparing diuretics, or other agents that increase serum potassium levels (e.g., heparin, trimethoprim, or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), particularly aldosterone antagonists or angiotensin receptor blockers, hyperkalaemia may occur. Caution is required when using potassium-sparing diuretics and angiotensin receptor blockers in patients receiving ACE inhibitors. In such patients, serum potassium levels and renal function should be monitored (see section "Interaction with other medicinal products and other forms of interaction").

Patients with diabetes mellitus. In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, careful glycaemic monitoring is required during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

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

Pregnancy. ACE inhibitors should not be taken during pregnancy. If continued therapy with ACE inhibitors is not considered necessary, patients planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile for use during pregnancy. Upon diagnosis of pregnancy, 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 during the first trimester of pregnancy is not recommended (see section "Special precautions for use"). Use of ACE inhibitors is contraindicated during the second and third trimesters of pregnancy (see sections "Contraindications" and "Special precautions for use").

Epidemiological data on teratogenic risk following ACE inhibitor exposure during the first trimester of pregnancy are inconclusive, although a small increased risk cannot be excluded. If continued therapy with ACE inhibitors is not considered necessary, women planning pregnancy should switch to alternative antihypertensive therapy with an established safety profile for use during pregnancy. Upon diagnosis of pregnancy, ACE inhibitor therapy should be discontinued immediately and, if necessary, alternative therapy initiated.

It is known that prolonged exposure to ACE inhibitors during the second and third trimesters of pregnancy induces fetotoxicity (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalaemia). In case of ACE inhibitor exposure during the second trimester of pregnancy, monitoring of renal function and skull ossification by ultrasound is recommended.

Infants whose mothers received lisinopril should be carefully monitored for arterial hypotension.

Breastfeeding

Since information on the possible use of lisinopril during breastfeeding is lacking, lisinopril is not recommended. During this period, alternative therapy with a better-established safety profile is preferable, especially if nursing a newborn or preterm infant.

Ability to influence reaction speed when driving or operating machinery.

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

Dosage and Administration.

Auroliza is recommended to be taken orally once daily at approximately the same time each day. The absorption of lisinopril is not affected by food intake. The dosage should be individually adjusted according to the patient's profile and blood pressure levels.

Essential Hypertension

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

Initial Dose

The recommended initial dose is usually 10 mg. In patients with highly active RAAS (particularly those with renovascular hypertension, increased salt (sodium chloride) excretion, reduced extracellular fluid volume, heart failure, or severe arterial hypertension), an excessive reduction in blood pressure may occur after the first dose. Therefore, such patients should be under medical supervision at the beginning of treatment, and the recommended initial dose is 2.5*-5 mg. Patients with renal impairment also require a reduced initial dose (see table).

Maintenance Dose

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

Patients Taking Diuretics

Symptomatic arterial hypotension may occur at the start of lisinopril therapy. This is more likely in patients who are concurrently receiving diuretics. Therefore, such patients should be treated with caution due to the potential for increased salt (sodium chloride) excretion and/or reduced extracellular fluid volume. Whenever possible, diuretic therapy should be discontinued 2–3 days before initiating lisinopril. For hypertensive patients who cannot discontinue diuretics, lisinopril therapy should be initiated at a starting dose of 5 mg, and medical supervision after the first dose is recommended due to the risk of symptomatic hypotension (peak effect occurs approximately 6 hours after administration). 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 reintroduced.

Dosing Adjustment in Patients with Renal Impairment

Dosing in patients with renal impairment should be based on creatinine clearance (see table).

Dosage adjustment in renal impairment

* Dosage and/or frequency of administration should be adjusted according to the response of arterial pressure.

The dose of the drug may be increased until control of arterial pressure is achieved or up to a maximum of 40 mg per day.

Use in children aged 6–16 years with arterial hypertension

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

In children with impaired renal function, a lower initial dose or extended dosing interval should be considered.

Heart failure. Patients with heart failure should take lisinopril as an adjunctive therapy to diuretics, digitalis preparations, or beta-blockers. Therapy with lisinopril may be initiated at a dose of 2.5 mg once daily; administration must be under medical supervision to monitor the initial effect of the drug on arterial pressure.

The dose of lisinopril should be increased:

• by increments not exceeding 10 mg;
• at intervals of no less than 2 weeks;
• to the highest dose tolerated by the patient, but not more than 35 mg once daily.

Dosage adjustment must take into account the clinical response of the individual patient.

In patients at high risk of symptomatic arterial hypotension, e.g., those with excessive salt depletion with or without hyponatremia, hypovolemia, or those receiving intensive diuretic therapy, these conditions should be corrected, if possible, prior to initiating lisinopril therapy. Renal function and serum potassium levels must be monitored.

Acute myocardial infarction. When indicated, patients should receive standard therapy – antithrombotic agents, acetylsalicylic acid, and beta-blockers. Intravenous or transdermal nitroglycerin may be used concomitantly with Auroriza.

Initial dose (first 3 days after infarction)

Lisinopril therapy should be initiated within 24 hours of the onset of symptoms; however, treatment should not be started if systolic arterial pressure is less than 100 mm Hg. The first dose of lisinopril is 5 mg (orally), the next (after 24 hours) – 5 mg, after 48 hours – 10 mg, and then 10 mg once daily. Patients with low systolic pressure (120 mm Hg or lower) at the beginning of treatment or during the first 3 days after infarction should be given a low dose of lisinopril – 2.5 mg orally (see section "Special precautions").

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

Maintenance dose

The maintenance dose is 10 mg once daily. If arterial hypotension develops (systolic arterial pressure less than or equal to 100 mm Hg), the daily maintenance dose should be 5 mg, temporarily reduced to 2.5 mg if necessary. Lisinopril therapy should be discontinued if sustained arterial hypotension occurs (systolic arterial pressure below 90 mm Hg for more than one hour).

Treatment should last for 6 weeks, after which it should be reviewed. Patients with symptoms of heart failure should continue lisinopril therapy.

Renal complications in diabetes mellitus. For patients with arterial hypertension and type 2 diabetes mellitus at an early stage of nephropathy, the dose of lisinopril is 10 mg once daily; if necessary, the dose may be increased to 20 mg once daily to achieve an optimal diastolic pressure below 90 mm Hg.

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

Elderly patients

Clinical studies have not established differences in efficacy or safety profile of the drug related to patient age. For prescribing the initial dose of lisinopril in elderly patients with impaired renal function, data from the table should be used. Then the dose may be adjusted according to arterial pressure values.

Use in patients after kidney transplantation

There is no experience with the use of lisinopril in patients with recent kidney transplantation. Therefore, treatment with Auroriza is not recommended in such patients.

Children

There is limited experience regarding the efficacy and safety of lisinopril in children aged 6 years and older with arterial hypertension, but there is no experience for other indications. Auroriza is not recommended for use in children for indications other than arterial hypertension.

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

Overdose.

Data on human overdose of the drug are limited.

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

Treatment: intravenous administration of physiological saline solution. In cases of arterial hypotension, the patient should be placed in a supine position with legs elevated. If available, administration of angiotensin II and/or intravenous catecholamines may be used. If the drug was recently administered, measures should be taken to remove lisinopril from the body (e.g., induce vomiting, gastric lavage, use of adsorbents and sodium sulfate). Lisinopril may be removed from systemic circulation by hemodialysis. A cardiac pacemaker is indicated in cases of therapy-resistant bradycardia. Vital organ parameters, electrolyte concentrations, and serum creatinine levels should be monitored frequently.

Side effects.

During treatment with lisinopril and other ACE inhibitors, the following adverse reactions have been reported, classified according to frequency of occurrence: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), frequency not known (cannot be estimated from available data).

Blood and lymphatic system disorders:

Rare: decreased hemoglobin and hematocrit levels;

Very rare: bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section "Special precautions"), hemolytic anemia, lymphadenopathy, autoimmune disorders.

Immune system disorders:

Frequency not known: anaphylactic/anaphylactoid reactions.

Metabolism and nutrition disorders:

Very rare: hypoglycemia.

Nervous system and psychiatric disorders:

Common: dizziness, headache;

Uncommon: sudden mood changes, paresthesia, vertigo, taste disturbances, sleep disorders, hallucinations;

Rare: confusion, olfactory disturbances;

Frequency not known: depressive symptoms, loss of consciousness.

Cardiovascular disorders:

Common: orthostatic effects (including arterial hypotension);

Uncommon: myocardial infarction and stroke, likely as complications of arterial hypotension in high-risk patients (see section "Special precautions"), palpitations, tachycardia, Raynaud's syndrome.

When lisinopril is used in patients with acute myocardial infarction, second- or third-degree atrioventricular block, severe arterial hypotension and/or renal dysfunction may occur, particularly within the first 24 hours; in isolated cases – cardiogenic shock.

Respiratory system disorders:

Common: cough;

Uncommon: rhinitis;

Very rare: bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders:

Common: diarrhea, vomiting;

Uncommon: nausea, abdominal pain and digestive disturbances;

Rare: dry mouth;

Very rare: pancreatitis, intestinal angioneurotic edema, hepatocellular or cholestatic hepatitis, jaundice or hepatic failure (see section "Special precautions").

Skin and subcutaneous tissue disorders:

Uncommon: rash, pruritus;

Rare: urticaria, alopecia, psoriasis, hypersensitivity/angioedema, including angioedema of the face, limbs, lips, tongue, glottis and/or larynx (see section "Special precautions");

Very rare: excessive sweating, bullous dermatosis, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, pseudolymphoma of the skin.

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

Renal and urinary disorders:

Common: renal dysfunction;

Rare: uremia, acute renal failure;

Very rare: oliguria/anuria.

Endocrine disorders:

Rare: impaired antidiuretic hormone secretion.

Reproductive system and breast disorders:

Uncommon: impotence;

Rare: gynecomastia.

General disorders:

Uncommon: increased fatigue, asthenia.

Laboratory findings:

Uncommon: increased blood urea nitrogen (BUN), increased serum creatinine, elevated liver enzymes, hyperkalemia;

Rare: increased serum bilirubin, hyponatremia, proteinuria.

Safety data 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.

Shelf life.

4 years.

Storage conditions.

Keep out of reach of children. Store at temperatures not exceeding 25 °C.

Packaging.

5 mg tablets: 10 tablets in a blister, 3 blisters in a cardboard box.

10 mg tablets: 10 tablets in a blister, 3 blisters in a cardboard box.

20 mg tablets: 10 tablets in a blister, 3 blisters in a cardboard box.

Prescription status. Prescription only.

Manufacturer.

Aurobindo Pharma Limited – Unit III / Aurobindo Pharma Limited – Unit III.

Manufacturer's address and place of business.

Survey No. 313, 314 – Blocks I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India / Survey no.: 313, 314 – Block I, II, III, IV, Bachupally, Bachupally Mandal, Medchal-Malkajgiri District, Telangana State, 500090, India.

Marketing Authorization Holder.

Aurobindo Pharma Ltd, India / Aurobindo Pharma Ltd, India.

Address of Marketing Authorization Holder.

Plot No. 2, Maitrivihar, Ameerpet, Hyderabad – 500038, Telangana, India / Plot № 2, Maitrivihar, Ameerpet, Hyderabad – 500038, Telangana, India.