Statorim®-h

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT STATORAM®-H (STATORAM®-H)

Composition:

Active substances: lisinopril, hydrochlorothiazide;

One tablet contains 20 mg of lisinopril dihydrate calculated as lisinopril and 12.5 mg of hydrochlorothiazide;

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

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white, round, flat tablets with an imprint "K" on one side and smooth on the other side.

Pharmacotherapeutic group. Angiotensin-converting enzyme inhibitors and diuretics. ATC code C09B A03.

Pharmacological Properties.

Pharmacodynamics.

Statoram®-H is a fixed-dose combination drug containing lisinopril – an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide (HCTZ) – a thiazide diuretic. Both components have distinct mechanisms of action and produce an additive antihypertensive effect that is mutually complementary.

Lisinopril

Lisinopril is a peptidyl-dipeptidase inhibitor. It inhibits ACE, the enzyme responsible for converting angiotensin I into angiotensin II – a vasoconstrictive peptide. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE leads to reduced angiotensin II levels, thereby decreasing vasoconstriction and aldosterone secretion. Reduced aldosterone secretion may result in increased serum potassium concentration.

Lisinopril primarily lowers blood pressure by inhibiting the renin-angiotensin-aldosterone system (RAAS). Nevertheless, lisinopril exerts antihypertensive effects even in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that promotes bradykinin degradation. It remains uncertain whether the increased bradykinin levels – a potent vasodilatory peptide – contribute to the therapeutic effect of lisinopril.

Hydrochlorothiazide

HCTZ is a diuretic and antihypertensive agent. It affects electrolyte reabsorption in the distal renal tubules and increases the excretion of sodium and chloride in approximately equimolar amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate. The mechanism of the antihypertensive effect of thiazides is not fully understood. Thiazides generally do not affect normal blood pressure.

Non-melanoma skin cancer (NMSC)

Results from two pharmacoepidemiological studies based on data from the Danish National Cancer Registry demonstrated a cumulative dose-dependent association between HCTZ and the development of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). One study included a population of 71,533 patients with BCC and 8,629 patients with SCC, compared to 1,430,833 and 172,462 control subjects, respectively. Use of high cumulative doses of HCTZ (≥ 50,000 mg) was associated with an adjusted risk ratio (RR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for BCC and 3.98 (95% CI: 3.68–4.31) for SCC. A clear cumulative dose-dependent relationship was observed for both BCC and SCC. Another study showed a possible association between lip cancer (SCC) and HCTZ use: 633 cases of lip cancer (SCC) were compared with 63,067 control subjects using a nested case-control design. A cumulative dose-dependent relationship was demonstrated with an adjusted RR of 2.1 (95% CI: 1.7–2.6), increasing to RR 3.9 (3.0–4.9) for high doses (~25,000 mg) and RR 7.7 (5.7–10.5) for the highest cumulative dose (~100,000 mg) (see section "Special precautions for use").

Pharmacokinetics.

There is no clinically significant pharmacokinetic interaction between lisinopril and HCTZ. The combined tablet is bioequivalent to the co-administration of the individual components.

Lisinopril

Absorption

Following oral administration of lisinopril, peak serum concentration (Cmax) is reached within approximately 7 hours, although in patients with acute myocardial infarction, there is a tendency toward a slight delay in the time required to reach Cmax. The mean absorption of lisinopril is approximately 25%, with individual variability (6–60%) across all tested doses (5–80 mg). Absolute bioavailability decreases by approximately 16% in patients with heart failure.

Food intake does not affect lisinopril absorption.

Distribution

Lisinopril does not bind to other serum proteins except circulating ACE.

Preclinical studies have shown that lisinopril poorly penetrates the blood-brain barrier.

Elimination

Lisinopril is not biotransformed and is excreted entirely unchanged in urine. After multiple dosing, the elimination 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 does not lead to drug accumulation. This terminal phase may reflect saturation of binding to ACE and is not proportionally dose-dependent.

Hepatic impairment

Liver dysfunction in patients with cirrhosis leads to decreased (by approximately 30%) lisinopril absorption and increased (by approximately 50%) exposure 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 becomes clinically significant only when glomerular filtration rate (GFR) is below 30 mL/min.

With creatinine clearance of 30–80 mL/min, the mean area under the concentration-time curve (AUC) increases by only 13%, whereas with creatinine clearance of 5–30 mL/min, AUC increases 4–5 fold.

Lisinopril is removed during hemodialysis. During 4 hours of hemodialysis, plasma lisinopril concentration decreases on average by 60%, and dialysis clearance ranges between 40–55 mL/min.

Heart failure

Patients with heart failure exhibit greater exposure to lisinopril compared to healthy volunteers (AUC increases on average by 125%). However, based on urinary excretion data, absorption of the drug in patients with heart failure is approximately 16% lower compared to healthy volunteers.

Elderly patients

Elderly patients have higher (approximately by 60%) plasma lisinopril concentrations and AUC values compared to younger patients.

Hydrochlorothiazide

Absorption

When plasma hydrochlorothiazide levels were maintained for at least 24 hours, the elimination half-life ranged from 5.6 to 14.8 hours.

Distribution

Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.

Elimination

At least 61% of the HCTZ dose is excreted unchanged within 24 hours. After oral administration, urinary excretion of HCTZ begins within 2 hours, peaks at approximately 4 hours, and continues for 6–12 hours.

Clinical characteristics.

Indications.

The medicinal product Statorim®-N is indicated for the treatment of mild to moderate arterial hypertension in patients whose condition has been stabilized by treatment with the individual components in the same proportions.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients of the medicinal product.

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

Hypersensitivity to any sulfonamide-containing medicinal product.

Concomitant use with sacubitril/valsartan.

Treatment with Statorim®-N must 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").

History of angioedema associated with previous treatment with ACE inhibitors.

Hereditary or idiopathic angioedema.

Second and third trimesters of pregnancy (see sections "Special precautions for use" and "Use during pregnancy or breast-feeding").

Severe renal impairment (creatinine clearance < 30 mL/min).

Anuria.

Severe hepatic impairment.

Concomitant use of the medicinal product Statorim®-N with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal 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

In combination with other antihypertensive medicinal products, Statorim®-N may lead to a reduction in arterial blood pressure. Concomitant use of nitroglycerin and other nitrates or other vasodilating agents may further reduce arterial blood pressure.

Combination of lisinopril with aliskiren-containing medicinal products should be avoided (see sections "Contraindications" and "Special precautions for use").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS) by combined use of ACE inhibitors, angiotensin II receptor blockers, and aliskiren is associated with a higher incidence of adverse reactions such as arterial hypotension, hyperkalaemia, and reduced renal function (including acute renal failure), compared to use of a single RAAS-acting medicinal product (see sections "Pharmacodynamics", "Contraindications", and "Special precautions for use").

Medicinal products that may 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").

Concomitant treatment with tissue plasminogen activators may increase the risk of angioedema.

Lithium

Cases of reversible increases in serum lithium concentrations and, consequently, lithium toxicity have been reported with concomitant use of ACE inhibitors. Diuretics and ACE inhibitors reduce renal clearance of lithium and increase the risk of lithium toxicity. Combination of lisinopril and hydrochlorothiazide with lithium is not recommended; if concomitant use is necessary, careful monitoring of serum lithium levels should also be performed (see section "Special precautions for use").

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

The potassium-wasting effect of thiazide diuretics is usually counterbalanced by the potassium-sparing effect of lisinopril.

Although serum potassium levels usually remain within normal limits, hyperkalaemia may occur in some patients receiving this medicinal product.

Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or potassium-containing salt substitutes may lead to significant increases in serum potassium levels. Caution should also be exercised when Statorim®-N is used concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim is known to act as a potassium-sparing diuretic similar to amiloride. Therefore, combination of Statorim®-N with the aforementioned medicinal products is not recommended. If concomitant use is necessary, they should be used with caution and frequent monitoring of serum potassium levels (see section "Special precautions for use").

Medicinal products capable of inducing ventricular arrhythmia (torsades de pointes)

Due to the increased risk of hypokalaemia with concomitant use of hydrochlorothiazide (HCTZ) and medicinal products that may induce ventricular arrhythmia (e.g., antiarrhythmics, certain antidepressants, and other medicinal products capable of inducing ventricular arrhythmia), they should be used with caution.

Tricyclic antidepressants/antipsychotics/anaesthetics

Concomitant use of certain anaesthetics, tricyclic antidepressants, and antipsychotic medicinal products with ACE inhibitors may subsequently lead to a reduction in arterial blood pressure (see section "Special precautions for use").

Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid

Prolonged use of NSAIDs (selective cyclooxygenase-2 inhibitors, acetylsalicylic acid (> 3 g/day), and non-selective NSAIDs) may reduce the antihypertensive and diuretic effects of ACE inhibitors and thiazide diuretics. In addition, NSAIDs and ACE inhibitors may have an additive effect on increasing serum potassium levels and may lead to impaired renal function. These effects are usually reversible. Rarely, acute renal failure may occur, particularly in patients with impaired renal function (elderly patients or those with dehydration).

Gold preparations

Nitritoid reactions (symptoms of vasodilation, including flushing, nausea, dizziness, hypotension, which may be severe) after injection of gold preparations (e.g., sodium aurothiomalate) have been reported more frequently in patients receiving ACE inhibitors.

Sympathomimetics

Sympathomimetics may reduce the antihypertensive effect of ACE inhibitors. Thiazides may reduce arterial sensitivity to noradrenaline, but not sufficiently to preclude the pressor effect of vasoactive agents.

Antidiabetic medicinal products

Treatment with thiazide diuretics may impair glucose tolerance. The likelihood of this phenomenon is higher during the first 2 weeks of combination therapy and in patients with impaired renal function. Dose adjustment of insulin or oral hypoglycaemic agents may be required in patients with diabetes mellitus. Thiazide diuretics may enhance the hyperglycaemic effect of diazoxide.

Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin, or laxatives

The hypokalaemic effect of HCTZ may be enhanced by medicinal products affecting potassium levels and hypokalaemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin, carbenoxolone, salicylate derivatives).

Hypokalaemia may develop during treatment with steroids or adrenocorticotropic hormone (ACTH).

Calcium salts

Thiazide diuretics may increase serum calcium levels due to reduced calcium excretion. If calcium or vitamin D supplements are required, serum calcium levels should be monitored and dosage adjusted accordingly.

Cardiac glycosides

Hypokalaemia may increase cardiac sensitivity or response to toxic effects induced by digitalis preparations (including increased ventricular excitability).

Cholestyramine and colestipol

Absorption of HCTZ is reduced by colestipol or cholestyramine. Therefore, sulfonamide diuretics should be taken 1 hour before or 4–6 hours after administration of these medicinal products.

Non-depolarizing muscle relaxants

Thiazides may increase sensitivity to non-depolarizing muscle relaxants (e.g., tubocurarine).

Trimethoprim

Concomitant use of ACE inhibitors, thiazides, and trimethoprim increases the risk of hyperkalaemia.

Sotalol

Thiazide-induced hypokalaemia may increase the risk of sotalol-induced arrhythmia.

Allopurinol

Concomitant use of ACE inhibitors with allopurinol increases the risk of renal impairment, which may lead to an increased risk of leucopenia.

Cyclosporine
Concomitant use of ACE inhibitors and cyclosporine increases the risk of renal impairment and hyperkalaemia. Monitoring of serum potassium levels is recommended. Concomitant treatment with cyclosporine may increase the risk of hyperuricaemia and gout-like complications.

Heparin

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

Lovastatin

Concomitant use of ACE inhibitors and lovastatin increases the risk of hyperkalaemia.

Cytostatic agents, immunosuppressants, procainamide

Thiazides may reduce renal excretion of cytotoxic agents (e.g., cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects (see section "Special precautions for use").

Amantadine

Thiazides, including HCTZ, may increase the risk of adverse reactions caused by amantadine.

Co-trimoxazole (trimethoprim/sulfamethoxazole)

Patients receiving co-trimoxazole (trimethoprim/sulfamethoxazole) concomitantly may have an increased risk of hyperkalaemia (see section "Special precautions for use").

Alcohol, barbiturates, or anaesthetics

Postural hypotension may be intensified by concomitant use of alcohol, barbiturates, or anaesthetics.

Special precautions for use.

Non-melanoma skin cancer (NMSC)

Two epidemiological studies conducted using the Danish National Cancer Registry have shown an increased risk of developing NMSC (BCC and SCC) with increasing cumulative dose of hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for the development of NMSC.

Patients taking HCTZ should be informed about the risk of developing NMSC, the need for regular skin examinations to detect new lesions, and the importance of promptly reporting any suspicious skin changes. To minimize the risk of skin cancer, patients should be advised to follow preventive measures, including limiting exposure to sunlight and UV radiation, and using appropriate protective measures when exposure is unavoidable. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy material. Additionally, the continued use of HCTZ should be reconsidered in patients with a history of NMSC (see section "Adverse reactions").

Symptomatic hypotension

Symptomatic arterial hypotension is rarely observed in patients with uncomplicated arterial hypertension, but the risk of reduced blood pressure is higher in patients with reduced circulating blood volume, such as those on diuretic therapy, on a salt-restricted diet, undergoing hemodialysis, or experiencing diarrhea or vomiting, as well as in patients with severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions").

In such patients, serum electrolyte levels should be monitored regularly. Dose titration and treatment of patients at increased risk of clinically significant hypotension should begin under close medical supervision.

Patients with ischemic heart disease or cerebrovascular disease should be treated with caution, as excessive reduction in blood pressure may lead to myocardial infarction or acute cerebrovascular events.

If hypotension develops, the patient should be placed in a supine position and, if necessary, receive intravenous infusion of physiological saline. Transient hypotension is not a contraindication for taking the next dose.

After restoration of circulating blood volume and normalization of blood pressure, therapy may be resumed at lower doses or one of the components may be initiated as monotherapy.

In some patients with heart failure but with normal or low blood pressure on lisinopril therapy, a reduction in systemic arterial pressure may occur. This effect is expected and usually does not require discontinuation of the drug. However, if clinically significant hypotension develops, dose reduction or discontinuation of lisinopril and hydrochlorothiazide therapy may be necessary.

Aortic and mitral valve stenosis / hypertrophic cardiomyopathy

Like other ACE inhibitors, lisinopril should be used with caution in patients with mitral valve stenosis or left ventricular outflow tract obstruction (e.g., due to aortic stenosis or hypertrophic cardiomyopathy).

Dual blockade of the RAAS

It is known that concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren increases the risk of hypotension, hyperkalemia, 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 section "Interaction with other medicinal products and other forms of interaction").

If dual blockade is absolutely necessary, it should be performed under specialist supervision with regular monitoring of renal function, electrolyte levels, and blood pressure.

ACE inhibitors and angiotensin II receptor blockers should not be used concomitantly in patients with diabetic nephropathy.

Renal impairment

Thiazides are not recommended for use in patients with renal impairment; thiazides are ineffective when creatinine clearance is ≤30 mL/min (corresponding to moderate or severe renal insufficiency).

The combination of lisinopril and HCTZ should not be prescribed to patients with renal insufficiency (creatinine clearance ≤80 mL/min) until appropriate doses of the individual components, corresponding to those in the fixed-dose combination, have been established.

Arterial hypotension occurring after initiation of ACE inhibitor therapy in patients with heart failure may lead to further deterioration of renal function. In some cases, acute renal failure (usually reversible) has been reported.

In patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney, treatment with ACE inhibitors may lead to increased serum urea and creatinine concentrations, usually reversible upon discontinuation of therapy.

The likelihood of this condition is higher in patients with pre-existing renal impairment. In patients with renovascular hypertension, there is an increased risk of severe hypotension and renal failure. Treatment of such patients should begin under close medical supervision using low doses of the drug, with careful dose titration. During the first weeks of treatment with the combination of lisinopril and HCTZ, renal function should be closely monitored, as diuretics may contribute to the development of the aforementioned changes.

In some patients with arterial hypertension (without significant underlying kidney disease), concomitant use of lisinopril and diuretics may lead to increased serum urea and creatinine concentrations. The likelihood of such disturbances is higher in patients with a history of renal impairment. In such cases, dose reduction and/or discontinuation of lisinopril and/or diuretic therapy may be required.

Prior diuretic therapy

Diuretic therapy should be discontinued 2–3 days before initiating treatment with the lisinopril and HCTZ combination. If this is not possible, treatment should begin with monotherapy using lisinopril at a dose of 5 mg.

Patients after kidney transplantation

Since there is no experience with the use of the lisinopril and HCTZ combination in patients after kidney transplantation, the use of the medicinal product Statoram®-N is not recommended in this patient group.

Anaphylactoid reactions in patients undergoing hemodialysis

The combination of lisinopril and HCTZ is not indicated for the treatment of patients with renal failure requiring hemodialysis.

There have been reports of anaphylactoid reactions in patients receiving ACE inhibitors during certain types of hemodialysis (e.g., using high-flux AN69 membranes) or during low-density lipoprotein (LDL) apheresis with dextran sulfate. In such cases, dialysis membranes of another type should be used or antihypertensive agents from other classes should be administered.

Anaphylactoid reactions in patients undergoing LDL apheresis

In isolated cases, life-threatening anaphylactic reactions have occurred in patients receiving ACE inhibitors during LDL apheresis with dextran sulfate. To prevent such reactions, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure.

Hepatic impairment

Thiazide diuretics should be used with caution in patients with hepatic impairment or progressive liver disease, as even minor disturbances in fluid and electrolyte balance may precipitate hepatic coma (see section "Contraindications"). Rarely, cholestatic jaundice or hepatitis progressing to fulminant hepatic necrosis, sometimes fatal, has been observed during ACE inhibitor therapy. The mechanism of this syndrome is unclear. If jaundice or a marked increase in liver enzymes occurs during treatment with the combination of lisinopril and HCTZ, administration of Statoram®-N should be discontinued; the patient should remain under close medical supervision.

Surgery and anesthesia

During surgical procedures or anesthesia with agents that may cause hypotension, lisinopril may block the formation of angiotensin II in response to compensatory renin release. If hypotension occurs due to this mechanism, volume expansion is indicated.

Effects on metabolism and endocrine system

Impaired glucose tolerance may occur during treatment with ACE inhibitors and thiazides. Adjustment of antidiabetic medication doses, including insulin, may be necessary. In patients with diabetes receiving oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy.

Thiazide diuretics may precipitate latent diabetes into overt diabetes.

Therapy with thiazides may increase cholesterol and triglyceride levels.

In some patients, thiazide therapy may provoke hyperuricemia and/or gout. However, lisinopril may enhance renal excretion of uric acid, thereby counteracting the hyperuricemic effect of HCTZ.

Electrolyte imbalance

Regular monitoring of serum electrolytes is recommended during diuretic therapy. Thiazides, including HCTZ, may cause disturbances in fluid or electrolyte balance (hypokalemia, hyponatremia, hypochloremic alkalosis). Signs of fluid or electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting). In patients with edema during hot weather, hyperdynamic hyponatremia may develop. Chloride deficiency is usually mild and does not require treatment. Thiazides are known to increase urinary magnesium excretion, which may lead to hypomagnesemia.

Thiazides may reduce urinary calcium excretion and cause mild, transient increases in serum calcium levels. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide diuretics should be discontinued before assessing parathyroid function.

Hyperkalemia

ACE inhibitors may cause hyperkalemia due to suppression of aldosterone secretion. This effect is usually clinically insignificant in patients with normal renal function. However, hyperkalemia may develop in patients with renal impairment, type 2 diabetes, and/or in those taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics, or other drugs that may increase serum potassium levels (such as heparin, trimethoprim, or the combination drug co-trimoxazole, known as trimethoprim/sulfamethoxazole, and particularly aldosterone antagonists or angiotensin receptor blockers). When concomitant use of these agents is necessary, regular monitoring of serum potassium and renal function is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Patients with diabetes

In patients with diabetes receiving oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy (see section "Interaction with other medicinal products and other forms of interaction").

Hypersensitivity, angioedema

Angioedema of the face, extremities, lips, tongue, pharynx, and/or larynx may occur rarely during treatment with ACE inhibitors, including lisinopril, at any time during therapy. Angioedema may occur at any time during treatment.

If such a reaction occurs, lisinopril should be discontinued immediately, and the patient should receive appropriate treatment and remain under medical supervision until symptoms completely resolve.

Even if only tongue swelling occurs (without respiratory compromise), prolonged observation is required, as antihistamines and corticosteroids may be ineffective.

In rare cases, angioedema of the larynx or tongue may be fatal. Swelling of the tongue, vocal cords, or larynx may cause airway obstruction, especially in patients who have undergone surgery on the respiratory tract. In such cases, emergency treatment is required. Administration of epinephrine solution and/or securing airway patency may be necessary. The patient should remain under close medical supervision until symptoms have completely and stably resolved.

Angioedema occurs more frequently in patients of African descent receiving ACE inhibitors than in individuals of other races.

Patients with a history of angioedema unrelated to ACE inhibitor use may be more susceptible to developing angioedema during ACE inhibitor therapy (see section "Contraindications").

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

Concomitant use of ACE inhibitors with racécadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), and vildagliptin may increase the risk of 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").

When initiating treatment with racécadotril, mTOR inhibitors, or vildagliptin in patients already receiving ACE inhibitors, caution is advised.

Thiazides

Hypersensitivity reactions may occur in patients taking thiazides, regardless of a history of allergy or bronchial asthma. Cases of induction or exacerbation of systemic lupus erythematosus have been reported during treatment with thiazide diuretics.

Desensitization

Anaphylactoid reactions may occur in patients receiving ACE inhibitors during desensitization procedures (e.g., insect venom immunotherapy). These reactions may be avoided by temporarily discontinuing the ACE inhibitor, although adverse reactions may recur upon accidental re-exposure to the drug.

Neutropenia/agranulocytosis

Cases of neutropenia (agranulocytosis), thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitors. Neutropenia is rare in patients with normal renal function and no other complicating factors. Neutropenia and agranulocytosis are reversible and resolve after discontinuation of the ACE inhibitor. Lisinopril should be used with extreme caution in patients with systemic connective tissue diseases, those receiving immunosuppressants, or those treated with allopurinol or procainamide, or in combination with these complicating factors, particularly in patients with renal impairment. Occasionally, severe infections, including those unresponsive to intensive antibiotic therapy, have been observed in this patient group. Periodic monitoring of white blood cell counts is recommended when prescribing lisinopril to such patients. Patients should be informed of the need to promptly report any signs of infection.

Ethnic origin

Angioedema occurs more frequently in patients of African descent receiving ACE inhibitors than in individuals of other races.

Like other ACE inhibitors, lisinopril is less effective in lowering blood pressure in patients of African descent compared to patients of other races. This is likely related to the predominantly low renin levels in African-descent patients with arterial hypertension.

Cough

Cough may develop during treatment with ACE inhibitors. The cough is typically non-productive and persistent, and resolves after discontinuation of therapy. Cough due to ACE inhibitor use should be considered in differential diagnosis.

Lithium preparations

Concomitant use of ACE inhibitors and lithium preparations is generally not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Anti-doping test

The medicinal product Statoram®-N contains HCTZ, the use of which may lead to positive anti-doping test results.

Pregnancy

ACE inhibitor therapy should not be initiated during pregnancy. Patients planning pregnancy who are currently receiving ACE inhibitors should be switched to alternative antihypertensive therapy with agents having an established safety profile during pregnancy. If pregnancy occurs, ACE inhibitor therapy should be discontinued immediately, and alternative therapy should be initiated if possible (see sections "Contraindications" and "Use during pregnancy or breastfeeding").

Acute respiratory toxicity

Very rare, severe cases of acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after HCTZ administration. Pulmonary edema usually develops within minutes or hours after HCTZ intake. Initial symptoms include dyspnea, fever, worsening of lung condition, and hypotension. If ARDS is suspected, Statoram®-N should be discontinued and appropriate treatment initiated. Statoram®-N should not be prescribed to patients who have previously experienced ARDS after HCTZ administration.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma

Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical intervention may be necessary. A history of allergy to sulfonamides or penicillin is a risk factor for developing acute angle-closure glaucoma.

Use during pregnancy or breastfeeding.

Pregnancy

ACE inhibitors

The available data on the risk of teratogenic effects associated with exposure to ACE inhibitors during the first trimester of pregnancy are inconclusive; however, a small increased risk cannot be excluded.

When continued therapy with ACE inhibitors is considered necessary, women planning pregnancy should be switched to alternative antihypertensive treatment, including medications with an established safety profile during pregnancy. If pregnancy occurs, treatment with ACE inhibitors must be discontinued immediately, and, if necessary, alternative therapy should be initiated.

It is known that the use of ACE inhibitors during the second and third trimesters of pregnancy causes fetal toxicity in humans (impaired renal function, oligohydramnios, delayed skull ossification) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If ACE inhibitors have been used during the third trimester of pregnancy, ultrasound monitoring of fetal renal function and skull ossification is recommended. Newborns whose mothers have taken ACE inhibitors should be closely monitored for possible development of arterial hypotension (see sections "Contraindications" and "Special precautions").

Hydrochlorothiazide

Clinical experience with HCTZ during pregnancy, particularly in the first trimester, is limited. Animal studies provide insufficient data.

HCTZ crosses the placenta. Its pharmacological mechanism of action suggests that its use during the second and third trimesters of pregnancy may impair fetoplacental perfusion and lead to fetal and neonatal adverse effects such as jaundice, electrolyte imbalances, and thrombocytopenia.

HCTZ must not be used to treat edema, arterial hypertension, or preeclampsia in pregnant women, as instead of providing beneficial effects on the course of the disease, it increases the risk of plasma volume reduction and worsens uteroplacental blood flow.

HCTZ should not be used to treat essential hypertension in pregnant women except when alternative medications cannot be used.

Breastfeeding period

ACE inhibitors

Since there are no data on the use of lisinopril/hydrochlorothiazide during breastfeeding, lisinopril/hydrochlorothiazide is not recommended; alternative agents with a well-established safety profile should be preferred, especially when breastfeeding a newborn or preterm infant.

Hydrochlorothiazide

HCTZ is excreted in small amounts into breast milk. High doses of thiazides may enhance diuresis, potentially leading to reduced breast milk production.

The use of lisinopril/HCTZ during breastfeeding is contraindicated. If alternative treatment is not possible during breastfeeding, the lowest possible dose of lisinopril/HCTZ should be prescribed.

Effect on the ability to drive and use machines

Like other antihypertensive agents, lisinopril/HCTZ may mildly or moderately affect the ability to drive or operate machinery. The risk is higher at the beginning of treatment or when the dose is changed, and when the combined medication is taken concomitantly with alcohol. However, this effect depends on individual patient sensitivity.

Dizziness and fatigue should be considered when driving or operating machinery.

Dosage and Administration

Essential hypertension

The usual dose is 1 tablet once daily. Statorém®-N should be taken at approximately the same time each day. If the expected therapeutic effect is not achieved within 2–4 weeks, the dose may be increased to 2 tablets once daily.

Renal impairment

Thiazides should not be used in patients with impaired renal function and are ineffective in moderate to severe renal insufficiency (creatinine clearance ≤ 30 mL/min).

The medicinal product Statorém®-N is not recommended for initial treatment of patients with renal insufficiency.

In patients with creatinine clearance > 30 and < 80 mL/min, the medicinal product Statorém®-N may be used after individual dose titration of its components. The recommended initial dose of lisinopril monotherapy in such patients is 5–10 mg.

Previous diuretic therapy

Symptomatic arterial hypotension may occur after administration of the first dose of Statorém®-N. This primarily affects dehydrated patients (e.g., as a result of diuretic therapy). Diuretic treatment should be discontinued 2–3 days prior to initiating Statorém®-N. If this is not possible, treatment should be initiated with lisinopril alone at a dose of 5 mg.

Elderly patients

No dose adjustment is required.

When using lisinopril/HCTZ, no differences in efficacy or tolerability related to age have been observed.

Lisinopril at daily doses of 20–80 mg was equally effective in elderly patients (aged 65 years and older) and younger adult patients. Monotherapy with lisinopril demonstrated the same efficacy in reducing diastolic blood pressure as monotherapy with HCTZ or atenolol. Age did not affect lisinopril tolerability.

Children

The safety and efficacy of the lisinopril/HCTZ combination in children have not been established.

Overdose

Symptoms

Data on human overdose are limited.

The most likely symptoms of ACE inhibitors overdose include: arterial hypotension, circulatory shock, electrolyte disturbances, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

Additional symptoms of HCTZ overdose may include: increased diuresis, impaired consciousness (including coma), seizures, paresis, arrhythmia, and renal failure.

Concomitant use of digitalis preparations may lead to hypokalemia, increasing the risk of arrhythmias.

Treatment

For the management of overdose, intravenous administration of physiological saline is recommended. In case of severe arterial hypotension, the patient should be placed in a supine position. Administration of angiotensin II (if available) or intravenous catecholamines may be considered. If drug intake was recent, measures aimed at removing lisinopril from the body should be taken (induced emesis, gastric lavage, administration of adsorbents and sodium sulfate). Lisinopril can be removed from systemic circulation by hemodialysis (see section "Pharmacological properties"). For treatment of refractory bradycardia, cardiac pacing is indicated. Frequent monitoring of vital signs, serum electrolytes, and creatinine is required.

Bradycardia or excessive vagal reactions may also be alleviated by administration of atropine.

Adverse Reactions

Below are the adverse reactions reported during treatment with lisinopril and/or HCTZ, classified by organ systems and frequency: 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 cases), frequency not known (frequency cannot be estimated based on available data).

The most commonly observed adverse reactions during treatment with lisinopril and/or HCTZ were: cough, dizziness, arterial hypotension, and headache.

Lisinopril

Blood and lymphatic system disorders: rare – decreased hemoglobin levels, decreased hematocrit; very rare – bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis (see section "Special precautions for use"), hemolytic anemia, lymphadenopathy, autoimmune disorders.

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

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

Metabolism and nutrition disorders: very rare – hypoglycemia.

Nervous system disorders: common – dizziness, headache, syncope; uncommon – paresthesia, vertigo, taste disturbances, sleep disturbances; rare – smell disturbances.

Psychiatric disorders: uncommon – mood changes, depression; rare – confusion; frequency not known – hallucinations.

Cardiac and vascular disorders: common – arterial hypotension (including orthostatic); uncommon – myocardial infarction or stroke due to significant arterial hypotension in high-risk patients (see section "Special precautions for use"), palpitations, tachycardia, Raynaud's syndrome; frequency not known – flushing.

Respiratory, thoracic and mediastinal disorders: common – cough (see section "Special precautions for use"); 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.

Hepatobiliary disorders: uncommon – increased liver enzyme activity and serum bilirubin; very rare – hepatitis (hepatocellular or cholestatic), jaundice, hepatic failure (see section "Special precautions for use")*.

Skin and subcutaneous tissue disorders: uncommon – rash, pruritus; rare – hypersensitivity/angioedema (face, extremities, lips, tongue, glottis and/or larynx) (see section "Special precautions for use"), urticaria, alopecia, psoriasis; very rare – increased sweating, bullous dermatosis, severe skin reactions (pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma**).

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

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

General disorders: uncommon – increased fatigue, asthenia.

Investigations: uncommon – increased blood urea nitrogen, increased serum creatinine concentration, hyperkalemia; rare – hyponatremia.

*Very rare cases of hepatitis leading to hepatic failure have been reported. Patients who develop jaundice or marked increases in liver enzyme activity during therapy should discontinue the drug and undergo appropriate medical evaluation.

**A syndrome has been reported which may include one or more of the following: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear factor (ANF), elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitization, or other dermatological manifestations.

Hydrochlorothiazide

Infections and infestations: frequency not known – sialadenitis.

Benign, malignant and unspecified neoplasms, including cysts and polyps: frequency not known – non-melanoma skin cancer (NMSC) (basal cell carcinoma and squamous cell carcinoma of the skin).

Blood and lymphatic system disorders: frequency not known – leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow suppression.

Metabolism and nutrition disorders: frequency not known – anorexia, hyperglycemia, glucosuria, hyperuricemia, electrolyte imbalance (including hyponatremia, hypokalemia, hypochloremic alkalosis, hypomagnesemia), increased cholesterol and triglyceride levels, gout.

Psychiatric disorders: frequency not known – restlessness, depression, sleep disturbances.

Nervous system disorders: frequency not known – loss of appetite, paresthesia, dizziness.

Eye disorders: frequency not known – xanthopsia, transient visual disturbances, acute myopia, acute angle-closure glaucoma, choroidal effusion.

Ear and labyrinth disorders: frequency not known – vertigo.

Cardiac and vascular disorders: frequency not known – orthostatic hypotension, necrotizing vasculitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders: very rare – acute respiratory distress syndrome (ARDS) (see section "Special precautions for use"); frequency not known – respiratory distress syndrome, including pneumonitis and pulmonary edema.

Gastrointestinal disorders: frequency not known – gastric mucosal irritation, diarrhea, constipation, pancreatitis.

Hepatobiliary disorders: frequency not known – jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders: frequency not known – photosensitivity reactions, rash, systemic lupus erythematosus, lupus-like skin reactions, reactivation of skin manifestations of systemic lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: frequency not known – muscle cramps, muscle weakness.

Renal and urinary disorders: frequency not known – renal function impairment, interstitial nephritis.

General disorders: fever, weakness.

Description of selected adverse reactions

Non-melanoma skin cancer (NMSC): based on available data from epidemiological studies, an association has been described between cumulative dose of HCTZ and NMSC (see sections "Pharmacological properties" and "Special precautions for use").

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is highly important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and patients, as well as their legal representatives, should report any suspected adverse reactions and lack of efficacy via the Automated Information System for Pharmacovigilance at the following link: https://aisf.dec.gov.ua.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach and sight of children.

Packaging.

10 tablets in a blister. 3 or 6 blisters in a cardboard package.

14 tablets in a blister. 2 or 6 blisters in a cardboard package.

Prescription status. Prescription only.

Manufacturer.

LLC "KUSUM PHARM".

Manufacturer's location and address of its place of business.

54 Skryabina Street, Sumy, Sumy region, 40020, Ukraine.

or

Manufacturer.

LLC "GLEDPHARM LTD".

Manufacturer's location and address of its place of business.

54 Davydovskoho Hryhorii Street, Sumy, Sumy region, 40020, Ukraine.