Lisinopril-h

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

Composition:

Active substances: lisinopril dihydrate, hydrochlorothiazide;

One tablet contains lisinopril dihydrate equivalent to 100% substance 10 mg or 20 mg and hydrochlorothiazide 12.5 mg;

Excipients: mannitol (E 421), magnesium stearate, calcium hydrogen phosphate, corn starch, pregelatinized corn starch.

Pharmaceutical form. Tablets.

Main physicochemical characteristics: white or almost white tablets, flat-cylindrical in shape, with bevelled edges and a score line on one side.

Pharmacotherapeutic group.

Angiotensin-converting enzyme inhibitors (ACE inhibitors) and diuretics.

ATC code C09B A03.

Pharmacological properties.

Pharmacodynamics.

Lisinopril-N is a fixed-dose combination preparation of lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide, a thiazide diuretic. Both components exhibit mutually complementary and additive antihypertensive effects.

Lisinopril is an inhibitor of the enzyme peptidyl dipeptidase. It inhibits ACE, which catalyzes the conversion of angiotensin I into the vasoconstrictor peptide angiotensin II. Angiotensin II also stimulates aldosterone secretion by the adrenal cortex. Inhibition of ACE leads to a reduction in angiotensin II concentration, resulting in decreased vasoconstrictor activity and reduced aldosterone secretion. This further reduction may lead to an increase in serum potassium levels.

Lisinopril is believed to reduce blood pressure primarily through inhibition of the renin-angiotensin-aldosterone system (RAAS). However, lisinopril exerts antihypertensive effects even in hypertension with low renin activity. ACE is identical to kininase II, an enzyme involved in the degradation of bradykinin. It is not established whether increased bradykinin levels (a potent vasodilator peptide) contribute to the therapeutic effect of lisinopril.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects electrolyte reabsorption in the distal renal tubules and increases the excretion of sodium and chloride ions to a similar extent. Natriuresis may be accompanied by some loss of potassium and bicarbonates. The mechanism of antihypertensive action of thiazide diuretics is unknown. 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 hydrochlorothiazide and the occurrence 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 with 1,430,833 and 172,462 control subjects, respectively. The use of high cumulative doses of hydrochlorothiazide (≥ 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 indicated a possible association between lip cancer and hydrochlorothiazide use: 633 cases of lip cancer were compared with 63,067 control subjects using a random sampling strategy. 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").

Pharmacokinetics.

Concomitant administration of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of either component. There were no clinically significant pharmacokinetic interactions between the two components when administered together.

Lisinopril

Absorption. After oral administration, peak plasma concentrations of lisinopril are reached within approximately 7 hours. Based on urinary excretion data, the average absorption of lisinopril across the studied dose range (5–80 mg) is approximately 25%, with inter-individual variability ranging from 6% to 60%. Absolute bioavailability is reduced by approximately 16% in patients with heart failure. Absorption of lisinopril is not affected by food intake.

Distribution. Lisinopril does not bind to other plasma proteins except circulating ACE. Lisinopril is known to poorly penetrate the blood-brain barrier.

Elimination. Lisinopril is not metabolized and is excreted entirely unchanged by the kidneys. With multiple dosing, lisinopril has an effective accumulation half-life of 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 mL/min. The decline in serum concentration indicates a prolonged terminal phase, which is not due to drug accumulation. This terminal phase may reflect saturation of binding to ACE and is not dose-proportional.

Heart failure. Patients with heart failure show greater exposure to lisinopril compared to healthy volunteers (an increase in the area under the concentration-time curve (AUC) by an average of 125%). Based on urinary excretion data, absorption is reduced by approximately 16% compared to healthy volunteers.

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

Renal impairment. Impaired renal function reduces the elimination of lisinopril, which is excreted by the kidneys, but this reduction becomes clinically significant only when the glomerular filtration rate is below 30 mL/min. In mild to moderate renal impairment (creatinine clearance 30–80 mL/min), the mean AUC is increased by only 13%, whereas in severe renal impairment (creatinine clearance 5–30 mL/min), it is increased 4–5 fold.

Lisinopril can be removed from the body by dialysis. During 4 hours of hemodialysis, plasma concentrations of lisinopril decreased on average by 60%, with dialysis clearance ranging from 40 to 55 mL/min.

Hepatic impairment. Impaired liver function in patients with cirrhosis resulted in reduced absorption of lisinopril (approximately 30% as determined by urinary excretion), but enhanced its effect (by approximately 50%) compared to healthy volunteers due to reduced clearance.

Hydrochlorothiazide

Hydrochlorothiazide is rapidly absorbed from the gastrointestinal tract. In humans, approximately 70% of an orally administered therapeutic dose is absorbed, primarily in the duodenum and upper parts of the small intestine. Food intake does not affect absorption, and peak concentrations are reached within 2–4 hours after administration. The volume of distribution has been reported to range from 0.8 to 3 L/kg. Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. At least 61% of the dose is excreted unchanged within 24 hours. The elimination half-life ranges from 8 to 12 hours, and 95% of absorbed hydrochlorothiazide is eliminated by the kidneys. After oral administration, the diuretic effect begins within 2 hours, peaks at approximately 4 hours, and lasts 6–12 hours. Hydrochlorothiazide crosses the placental barrier but does not cross the blood-brain barrier.

Clinical characteristics.

Indications.

Mild to moderate arterial hypertension with stable course under therapy with lisinopril and hydrochlorothiazide at the same doses.

Contraindications.

• Hypersensitivity to the active substances or to any of the excipients listed in the section "Composition", to other ACE inhibitors or to any sulfonamide derivatives.
• History of angioedema associated with previous use of ACE inhibitors.
• Hereditary or idiopathic angioedema.
• Mitral or aortic stenosis, hypertrophic cardiomyopathy with significant hemodynamic disturbances.
• Severe renal impairment (creatinine clearance <30 mL/min) or end-stage disease.
• Severe hepatic dysfunction.
• Acute gout.
• Anuria.
• Hyperuricemia.
• Hyperaldosteronism.
• Renal artery stenosis (bilateral or unilateral).
• Cardiogenic shock.
• Unstable hemodynamic status following acute myocardial infarction.
• Hemodialysis using high-flux membranes (e.g., AN 69).
• Serum creatinine level > 220 µmol/L.
• Concomitant use of Lisinopril-N with medicinal products containing aliskiren is contraindicated in patients with diabetes mellitus or renal dysfunction (glomerular filtration rate <60 mL/min/1.73 m²) (see sections "Pharmacodynamics", "Interaction with other medicinal products and other forms of interaction", and "Special warnings and precautions for use").
• Concomitant use with sacubitril/valsartan; Lisinopril-N should not be initiated earlier than 36 hours after the last dose of sacubitril/valsartan (see also sections "Interaction with other medicinal products and other forms of interaction" and "Special warnings and precautions for use").
• Planned pregnancy.
• Pregnancy or breastfeeding.
• Pediatric age (under 18 years).

Interaction with other medicinal products and other forms of interaction.

Antihypertensive agents

Concomitant use with other antihypertensive drugs may enhance the antihypertensive effect. Combination with nitroglycerin, other nitrates, or vasodilators increases the antihypertensive effect.

Lisinopril should be avoided in combination with aliskiren-containing products (see sections "Contraindications" and "Special warnings and precautions for use").

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 reactions such as hypotension, hyperkalemia, and impaired renal function (including acute renal failure), compared to monotherapy affecting the RAAS (see sections "Contraindications" and "Special warnings and 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 warnings and precautions for use").

Concomitant use of ACE inhibitors with mammalian target of rapamycin (mTOR) inhibitors (e.g., temsirolimus, sirolimus, everolimus), neutral endopeptidase inhibitors (e.g., racecadotril), tissue plasminogen activator, or vildagliptin may increase the risk of angioedema.

Diuretics

The antihypertensive effect is usually enhanced when diuretics are co-administered with lisinopril. At the initiation of combination therapy with lisinopril and diuretics, patients may experience excessive reduction in blood pressure. The risk of symptomatic hypotension with lisinopril may be reduced by discontinuing diuretic therapy before starting lisinopril, increasing fluid or salt volume, and initiating therapy with low doses of ACE inhibitors.

Potassium-sparing diuretics, potassium-containing dietary supplements or salt substitutes, and other medicinal products that may increase plasma potassium levels

Although serum potassium levels usually remain within normal limits, hyperkalemia may occur in some patients during treatment with lisinopril. Potassium-sparing diuretics (e.g., spironolactone, triamterene, or amiloride), potassium-containing dietary supplements, or salt substitutes may lead to significant increases in serum potassium, particularly in patients with impaired renal function or type 2 diabetes mellitus. Caution should be exercised when lisinopril is used concomitantly with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), since trimethoprim has effects similar to potassium-sparing diuretics like amiloride. Therefore, concomitant use of lisinopril with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, the drugs should be used with caution and with periodic monitoring of serum potassium levels (see section "Special warnings and precautions for use").

Heparin

Concomitant use of ACE inhibitors and heparin may lead to hyperkalemia. Monitoring of serum potassium levels is recommended.

Tricyclic antidepressants/antipsychotics/anesthetics

Concomitant use of certain anesthetics, tricyclic antidepressants, or antipsychotics with ACE inhibitors may result in additional blood pressure reduction.

Narcotics/antipsychotics

Orthostatic hypotension may develop during ACE inhibitor therapy.

Barbiturates or narcotics

Orthostatic hypotension may be intensified.

Nonsteroidal anti-inflammatory drugs (NSAIDs)/antirheumatic agents

Prolonged use of NSAIDs (selective COX-2 inhibitors, acetylsalicylic acid >3 g/day, and nonselective NSAIDs) may reduce the antihypertensive effect of both ACE inhibitors and thiazides. Concomitant use of NSAIDs and ACE inhibitors may impair renal function. This effect is usually transient. In rare cases, acute renal failure may develop, particularly in elderly patients or those with pre-existing renal impairment and dehydration.

In some patients, NSAIDs may reduce the diuretic, natriuretic, and antihypertensive effects of diuretics.

Elevated serum potassium levels have been reported with concomitant use of NSAIDs and ACE inhibitors, potentially leading to impaired renal function.

Sympathomimetics

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

Other antihypertensive agents

The antihypertensive effect of Lisinopril-N may be enhanced when used concomitantly with other agents, potentially causing orthostatic hypotension. Concomitant use of glyceryl trinitrate, other nitrates, or other vasodilators may further reduce blood pressure.

Acetylsalicylic acid, thrombolytics, β-blockers, nitrates

Lisinopril-N may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytics, β-blockers, and/or nitrates under medical supervision.

Antidiabetic agents

Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemics) may enhance glucose-lowering effects, increasing the risk of hypoglycemia. This phenomenon is more likely during the first 2 weeks of combined therapy and in patients with impaired renal function.

Glucose tolerance may decrease, necessitating adjustment of antidiabetic agent dosage.

Antigout agents (probenecid, sulfinpyrazone, and allopurinol)

Concomitant use of ACE inhibitors and allopurinol increases the risk of renal damage and may increase the risk of leukopenia.

Dosage adjustment of uricosuric agents may be required, as hydrochlorothiazide may increase serum uric acid levels. Increased doses of probenecid or sulfinpyrazone may be necessary. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

Cyclosporine

Concomitant use of ACE inhibitors and cyclosporine increases the risk of renal impairment and hyperkalemia.

Lovastatin

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

Cytostatics, immunosuppressants, procainamide

Concomitant use with ACE inhibitors may increase the risk of leukopenia.

Gold preparations

Nitritoid reactions (vasodilatory symptoms including flushing, nausea, dizziness, and hypotension, potentially severe) following gold injections (e.g., sodium aurothiomalate) occur more frequently in patients concurrently taking lisinopril.

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

The hypokalemic effect of hydrochlorothiazide may be enhanced by agents affecting potassium levels and promoting hypokalemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin, carbenoxolone, salicylate derivatives).

Hypokalemia may develop with concomitant use of steroids or ACTH.

Calcium salts

Thiazide diuretics may increase serum calcium due to reduced excretion. If calcium or vitamin D supplements are required, careful monitoring of calcium levels is advised, with dose adjustment as needed.

Cardiac glycosides

Increased risk of cardiac glycoside toxicity due to thiazide-induced hypokalemia.

Cholestyramine and colestipol

Concomitant use with cholestyramine and colestipol reduces hydrochlorothiazide absorption. Therefore, sulfonamide diuretics should be taken at least 1 hour before or 4–6 hours after these agents.

Non-depolarizing muscle relaxants (e.g., tubocurarine)

Hydrochlorothiazide may potentiate the effect of these agents.

Medicinal products causing torsade de pointes ventricular tachycardia

Concomitant use of hydrochlorothiazide with agents that may cause torsade de pointes ventricular tachycardia (including certain antiarrhythmics, antipsychotics, and other drugs) should be done with caution due to hyperkalemia risk.

Periodic monitoring of serum potassium levels and ECG is recommended when hydrochlorothiazide is used concomitantly with drugs causing polymorphic ventricular tachycardia (torsade de pointes), as hypokalemia is a contributing factor:

• Class Ia antiarrhythmics (e.g., quinidine, hydroquinidine, disopyramide);
• Class III antiarrhythmics (e.g., amiodarone, sotalol, dofetilide, ibutilide);
• Certain neuroleptics (e.g., thioridazine, chlorpromazine, levomepromazine, trifluoperazine, zuclopenthixol, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol);
• Other medicinal products (e.g., bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vinpocetine).

Sotalol

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

Allopurinol

Concomitant use of ACE inhibitors and allopurinol increases the risk of renal damage and leukopenia.

Lithium preparations

Cases of reversible increases in serum lithium levels and signs of toxicity have been reported with concomitant use of lithium and ACE inhibitors. Diuretics and ACE inhibitors reduce renal lithium clearance, increasing the risk of toxicity. Therefore, concomitant use of lisinopril and hydrochlorothiazide with lithium preparations is not recommended. If such combination is necessary, serum lithium levels should be closely monitored (see section "Special warnings and precautions for use").

Trimethoprim

Concomitant use of ACE inhibitors and thiazides with trimethoprim increases the risk of hyperkalemia.

Corticosteroids, ACTH

Increased electrolyte loss, particularly hypokalemia.

Pressor amines (e.g., epinephrine (adrenaline))

Reduced response to pressor amines may occur, but not sufficient to preclude their use.

Alcohol

Alcohol may enhance the hypotensive effect of any antihypertensive agent.

Antacids

Reduce bioavailability of ACE inhibitors.

Metformin

Use with caution due to the risk of lactic acidosis from possible hydrochlorothiazide-induced functional renal impairment.

Anticholinergic agents (atropine, biperiden)

Reduced gastrointestinal motility and delayed gastric emptying may increase bioavailability of thiazide diuretics.

Cytotoxic agents (e.g., cyclophosphamide, methotrexate)

Thiazides may reduce renal excretion of cytotoxic drugs and potentiate their myelosuppressive effects.

Methyldopa

Isolated cases of hemolytic anemia have been reported with concomitant use of hydrochlorothiazide and methyldopa.

Effect on laboratory test results

Thiazides may affect parathyroid function assessment due to their influence on calcium metabolism.

Carbamazepine

Clinical and biological monitoring is required due to the risk of symptomatic hyponatremia.

Iodinated contrast agents

Diuretic-induced dehydration increases the risk of acute renal failure, particularly with high-dose iodinated contrast agents. Patients require rehydration before administration of iodinated agents.

β-blockers and diazoxide

Concomitant use of thiazide diuretics, including hydrochlorothiazide, with β-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may enhance the hyperglycemic effect of diazoxide.

Amantadine

Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects caused by amantadine.

Special precautions for use.

Non-melanoma skin cancer.

An increased risk of non-melanoma skin cancer (NMSC) with increasing cumulative dose of hydrochlorothiazide has been observed in two pharmacoepidemiological studies. The photosensitizing effect of hydrochlorothiazide may be a mechanism underlying this pathology.

Patients taking hydrochlorothiazide alone or in combination with other medicinal products should be informed about the risk of developing NMSC, particularly with long-term use, the need for regular skin examinations, and the necessity to promptly report any new skin lesions or suspicious skin neoplasms, as well as changes in existing skin lesions or moles.

To reduce the risk of skin cancer, patients should be advised about possible preventive measures, such as limiting exposure to sunlight and UV radiation, and, when exposure is unavoidable, ensuring adequate protection of the skin. Suspicious skin lesions should be promptly evaluated, including histological examination of biopsy specimens.

Patients who have previously experienced NMSC may also require reassessment of hydrochlorothiazide use.

Double blockade of the renin-angiotensin-aldosterone system

Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure).

If therapy involving dual blockade is absolutely necessary, it should be administered only under specialist supervision with continuous careful 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.

Arterial hypotension and electrolyte imbalance

As with any other antihypertensive therapy, arterial hypotension may occur in some patients.

In patients with arterial hypertension, hypotensive episodes are more likely in the presence of fluid depletion, such as during diuretic therapy, salt-restricted diet, dialysis, diarrhea, or vomiting, or in cases of severe renin-dependent hypertension (see sections "Interaction with other medicinal products and other forms of interaction" and "Adverse reactions"). Symptomatic hypotension may also occur in patients with heart failure with or without renal impairment.

This condition is more likely in patients with severe degrees of heart failure due to high-dose loop diuretic therapy, hyponatremia, or functional renal impairment.

Patients at risk of symptomatic hypotension during initial therapy or dose adjustment should be closely monitored.

Serum electrolyte levels should be periodically assessed in such patients.

Particular caution is required when treating patients with ischemic heart disease or cerebrovascular disease, as 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 and, if necessary, intravenous infusion of physiological saline should be initiated. Transient hypotensive response is not a contraindication to continuing therapy. After restoration of effective blood volume and blood pressure, therapy may be resumed at a reduced dose or with one of the components of the drug administered separately.

Patients should be under appropriate medical supervision to allow timely detection of clinical signs of fluid and electrolyte imbalance (e.g., hypovolemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia), which may develop during concomitant diarrhea or vomiting. In warm seasons, hyponatremia may occur in patients with edema due to hemodilution. Hypovolemia and/or reduced extracellular fluid volume should be corrected, if possible, before initiating lisinopril therapy, and the effect of the initial dose on blood pressure should be carefully monitored. Lisinopril is contraindicated in acute myocardial infarction if vasodilator therapy may worsen the patient's hemodynamic status (e.g., systolic blood pressure ≤100 mm Hg) or in cases of cardiogenic shock.

Aortic and mitral valve stenosis/hypertrophic cardiomyopathy

As with other ACE inhibitors, lisinopril should be used with caution in patients with left ventricular outflow tract obstruction. If the obstruction is hemodynamically significant, the use of Lisinopril-N is contraindicated (see section "Contraindications").

Renal impairment

Thiazides are not suitable for use in patients with renal impairment and are ineffective when creatinine clearance is ≤30 mL/min (severe renal impairment).

Lisinopril-N should not be prescribed to patients with mild to moderate renal impairment (creatinine clearance 30–80 mL/min) until the required doses of individual components have been established through titration.

In patients with impaired renal function (creatinine clearance <80 mL/min), the initial dose of lisinopril should be adjusted based on creatinine clearance values and clinical response to treatment. These patients require regular monitoring of serum potassium and creatinine levels. In patients with heart failure, arterial hypotension occurring after initiation of ACE inhibitor therapy may lead to impaired renal function. Cases of acute renal failure, usually reversible, have been reported.

In some patients with unilateral or bilateral renal artery stenosis or stenosis of the artery of a solitary kidney receiving ACE inhibitor therapy, increases in blood urea nitrogen and serum creatinine have been observed, usually reversible upon discontinuation of therapy. The likelihood of this condition is higher in patients with pre-existing renal impairment. If renovascular hypertension is also present, there is an increased risk of severe arterial hypotension and renal failure. Treatment of such patients should be initiated with low doses under close monitoring, and cautious dose titration is required. Since diuretic therapy may promote the development of the above-mentioned conditions, renal function should be monitored during the first few weeks of Lisinopril-N therapy.

In some patients with arterial hypertension and no prior history of kidney disease, concomitant use of lisinopril and diuretics has led to mild, transient increases in blood urea nitrogen and serum creatinine. If this occurs during Lisinopril-N therapy, the combined drug should be discontinued. Therapy may be resumed after dose reduction or with one of the components administered separately.

Post-kidney transplant state

As there are no data on the use of lisinopril in patients after kidney transplantation, administration of the drug to this patient group is not recommended.

Patients undergoing hemodialysis

The use of Lisinopril-N is not indicated in patients undergoing hemodialysis due to renal failure.

Anaphylactic reactions in patients undergoing hemodialysis

A high risk of anaphylactic reactions has been reported in patients undergoing hemodialysis with high-flux membranes (e.g., AN 69) while receiving concomitant ACE inhibitor therapy. For such patients, consideration should be given to using a different type of dialysis membrane or prescribing another class of antihypertensive agents.

Liver disease, hepatic impairment

Very rarely, ACE inhibitors have been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant hepatic necrosis, sometimes fatal. The mechanism of this syndrome is unclear. Patients who develop jaundice or show marked elevation of liver enzymes during treatment should discontinue Lisinopril-N and remain under appropriate medical supervision.

Thiazides, including hydrochlorothiazide, should be used with caution in patients with impaired liver function or progressive liver disease, as they may cause intrahepatic cholestasis, and even minor fluid and electrolyte imbalances may precipitate hepatic encephalopathy.

Surgery/anesthesia

In patients undergoing major surgery or anesthesia with agents causing arterial hypotension, lisinopril may additionally block angiotensin II formation due to compensatory renin release. If arterial hypotension is considered a consequence of this mechanism, it can be corrected by administration of large volumes of fluids.

Metabolic and endocrine effects

It is known that concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may increase blood glucose concentration and reduce the risk of hypoglycemia. This phenomenon is more likely during the first weeks of combination therapy and in patients with renal impairment.

Thiazide therapy may reduce glucose tolerance. Dose adjustment of antidiabetic agents, including insulin, may be required. Thiazides may reduce urinary calcium excretion and may cause a slight, transient increase in serum calcium levels. Marked hypercalcemia may be a sign of occult hyperparathyroidism. Thiazide diuretics should be discontinued before testing parathyroid function. Increases in cholesterol and triglyceride levels may be associated with thiazide diuretic therapy.

Thiazide therapy may accelerate the onset of hyperuricemia and/or gout in some patients. However, lisinopril may increase urinary uric acid excretion and thereby attenuate the hyperuricemic effect of hydrochlorothiazide.

Hypersensitivity/angioedema

Isolated cases of angioedema involving the face, extremities, lips, tongue, vocal cords, and/or larynx have 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, and appropriate monitoring should be instituted to ensure complete resolution of symptoms before patient discharge. Even isolated tongue swelling without respiratory compromise may require prolonged observation, as antihistamines and corticosteroids may be insufficient.

Very rarely, fatal cases of laryngeal or lingual angioedema have been reported. If swelling of the tongue, glottis, or larynx develops, which may potentially cause airway obstruction, immediate appropriate emergency treatment should be initiated. This may include administration of epinephrine and/or measures to maintain airway patency. The patient should remain under close medical supervision until symptoms have completely and stably resolved. Angioedema may also affect the intestines and present as acute abdominal pain, nausea, vomiting, and diarrhea.

Patients with a history of angioedema unrelated to ACE inhibitor use may 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 lisinopril. Lisinopril 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").

In patients receiving thiazide therapy, hypersensitivity reactions may develop regardless of prior history of allergy or bronchial asthma. Exacerbation or activation of systemic lupus erythematosus has been reported during thiazide use.

Race

The incidence of angioedema associated with ACE inhibitor use is higher in black patients compared to patients of other races. As with other ACE inhibitors, lisinopril may be less effective in reducing blood pressure in black patients compared to patients of other races, possibly due to the higher prevalence of low-renin hypertension in this population.

Anaphylactic reactions associated with low-density lipoprotein (LDL) apheresis

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

Desensitization

Continuous anaphylactic reactions have been observed in patients receiving ACE inhibitors during desensitization therapy (e.g., for hymenoptera venom). Such reactions were avoided in these patients by temporarily discontinuing ACE inhibitor therapy but recurred upon accidental re-administration of the drug.

Hyperkalemia

Elevated serum potassium levels have been observed in some patients receiving ACE inhibitor therapy, including lisinopril. Patients at risk of hyperkalemia include those with renal impairment, diabetes mellitus, and those receiving concomitant potassium-sparing diuretics, potassium supplements, potassium-containing salt substitutes, or other medicinal products that may increase serum potassium levels (e.g., heparin). If concomitant use of these agents is considered necessary, regular monitoring of serum potassium is recommended.

Neutropenia/agranulocytosis/thrombocytopenia/anemia

Neutropenia, agranulocytosis, thrombocytopenia, and anemia have been reported in patients receiving ACE inhibitor therapy. Neutropenia is rare in patients with normal renal function and no other complicating factors. Neutropenia and agranulocytosis resolve upon discontinuation of ACE inhibitors.

Lisinopril should be used with extreme caution in patients with collagen vascular disease receiving immunosuppressants, allopurinol, or procainamide, or with a combination of these risk factors, especially in the presence of pre-existing renal impairment. Serious infections, sometimes unresponsive to intensive antibacterial therapy, have occurred in some of these patients. In such patients, regular monitoring of white blood cell counts is recommended, and patients should be advised to report signs of infection.

Cough

Cough has been reported in patients taking ACE inhibitors. The cough is non-productive, persistent, and resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough.

Lithium-containing medications

Concomitant use of ACE inhibitors and lithium-containing medications should be avoided.

Anti-doping test

The medicinal product contains hydrochlorothiazide, which may lead to positive results in anti-doping tests.

Photosensitization reactions

Cases of photosensitization reactions have been reported during therapy with thiazide diuretics. If photosensitization reactions occur during treatment, discontinuation of the drug is recommended. If the physician considers re-administration necessary, protection of skin areas exposed to sunlight or artificial UV radiation is recommended.

Laboratory parameters

The drug may affect the results of certain laboratory tests: hydrochlorothiazide may decrease plasma protein-bound iodine levels (hydrochlorothiazide therapy should be discontinued before laboratory testing to assess parathyroid function) and increase serum free bilirubin concentration.

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

Drugs 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 sudden decrease in 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 interventions may be necessary. A history of sulfonamide or penicillin allergy is a risk factor for acute angle-closure glaucoma.

Acute respiratory toxicity

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

Use during pregnancy or breastfeeding.

Pregnancy.

The drug is contraindicated in pregnant women or women planning to become pregnant.

If pregnancy is confirmed during treatment with this drug, therapy should be discontinued immediately, and if necessary, replaced with another medicinal product approved for use during pregnancy.

Breastfeeding.

The drug is contraindicated during breastfeeding.

It is unknown whether lisinopril and hydrochlorothiazide pass into breast milk in quantities sufficient to affect the infant, even at therapeutic doses.

Due to the potential for serious adverse reactions in breastfed newborns, a decision should be made whether to discontinue breastfeeding or discontinue Lisinopril-N, taking into account the necessity of treatment for the mother.

Effect on ability to drive and operate machinery.

Due to the potential for adverse reactions, particularly at the beginning of therapy, the drug may mildly or moderately affect reaction speed; therefore, driving or operating machinery should be avoided. The risk is increased if Lisinopril-N is taken concomitantly with alcohol.

Method of Administration and Dosage.

Arterial Hypertension.

Adults.

Fixed-dose combination therapy is not suitable for initiating treatment. The fixed-dose combination may replace the combination of 10 mg or 20 mg lisinopril and 12.5 mg hydrochlorothiazide in patients whose condition has been stabilized on therapy with the individual active substances at the same doses administered as separate agents. The usual dose is 1 tablet once daily. As with any other medication taken once daily, Lisinopril-N should be taken at approximately the same time each day.

If the desired therapeutic effect is not achieved within 2–4 weeks of treatment, the dose may be increased to 2 tablets once daily.

Previous Diuretic Therapy.

After the first dose of Lisinopril-N, symptomatic hypotension may develop; this condition is more likely in patients with dehydration and/or salt depletion due to prior diuretic therapy. Diuretic therapy should be discontinued 2–3 days before starting treatment with Lisinopril-N. If this is not possible, treatment should be initiated with low doses of the individual components (lisinopril 5 mg).

Patients with Renal Impairment.

Lisinopril-N must not be used as initial therapy in patients with renal impairment.

In patients with mild to moderate renal impairment (creatinine clearance ≤ 80 mL/min), Lisinopril-N may be used only after dose titration of the individual components.

In such cases, the recommended dose of lisinopril when administered as a single agent is 5–10 mg.

Elderly Patients.

It is known that the efficacy and tolerability of lisinopril and hydrochlorothiazide when administered together are similar in elderly patients and younger patients with arterial hypertension.

Within the dose range of 20 mg to 80 mg, the efficacy of lisinopril was comparable in elderly patients (aged 65 years and older) and younger patients with arterial hypertension. In elderly patients with arterial hypertension, monotherapy with lisinopril was as effective in reducing diastolic blood pressure as monotherapy with hydrochlorothiazide or atenolol. If an elderly patient has impaired renal function, the initial dose of lisinopril should be adjusted accordingly.

Children.

The drug must not be administered to children, as the safety and efficacy of the drug in children (under 18 years of age) have not been established.

Overdose.

There is no specific information available regarding overdose with lisinopril/hydrochlorothiazide.

Lisinopril.

Symptoms: arterial hypotension, electrolyte imbalance, renal failure, circulatory shock, hyperventilation, tachycardia, increased heart rate, bradycardia, dizziness, restlessness, and cough.

Hydrochlorothiazide.

The most commonly observed symptoms are those caused by electrolyte depletion (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive diuretic use: seizures; paresis; renal failure; impaired consciousness, including coma.

Symptoms: tachycardia, shock, weakness, confusion, dizziness, muscle spasms, paresthesia, exhaustion, disturbances of consciousness, nausea, vomiting, thirst, polyuria, oliguria, anuria, hypokalemia, hyponatremia, hypochloremia, alkalosis, elevated blood urea nitrogen (mainly due to renal failure). When cardiac glycosides are administered concomitantly, hypokalemia may exacerbate cardiac arrhythmias.

Treatment: symptomatic and supportive therapy. Treatment with Lisinopril-N should be discontinued, and careful monitoring of the patient should be initiated. Therapeutic measures depend on the nature and severity of symptoms. Measures should be taken to prevent absorption and to accelerate elimination.

In case of severe arterial hypotension, the patient should be placed in a supine position (with legs elevated) and promptly given intravenous infusion of physiological saline solution. Angiotensin II therapy may be considered (if available). As with all ACE inhibitors, lisinopril may be removed from systemic circulation by hemodialysis. The use of high-flux polyacrylonitrile dialysis membranes should be avoided. Bradycardia or significant vagal reaction may be alleviated by intravenous administration of atropine. Cardiac pacing is indicated for bradycardia unresponsive to therapy.

If the desired response is not achieved with these measures, intravenous administration of catecholamines is necessary.

Vital signs, serum electrolyte concentrations, and creatinine levels should be continuously monitored.

Adverse Reactions.

Adverse effects associated with lisinopril and other ACE inhibitors:

Blood system disorders: lymphadenopathy, anemia, agranulocytosis, bone marrow suppression, hemolytic anemia, leukopenia, thrombocytopenia, neutropenia, autoimmune diseases, decreased hemoglobin levels, reduced hematocrit;

Immune system disorders: anaphylactic/anaphylactoid reaction;

Cardiovascular disorders: palpitations, tachycardia, arterial hypotension (including orthostatic hypotension), palpitation, flushing, cerebrovascular disorders, Raynaud's phenomenon; myocardial infarction or stroke, possibly due to pronounced arterial hypotension in high-risk patients;

Psychiatric disorders: mood changes, sleep disturbances, confusion, disorientation, symptoms of depression, hallucinations;

Nervous system disorders: dizziness, loss of balance, paresthesia, headache, taste disturbances, olfactory disturbances, syncope, vertigo;

Ear disorders: vertigo;

Respiratory system disorders: cough*, bronchospasm, dyspnea, rhinitis, sinusitis, allergic alveolitis and/or eosinophilic pneumonia, upper respiratory tract infections;

Gastrointestinal disorders: diarrhea, vomiting, nausea, dry mouth, glossitis, pancreatitis, intestinal angioedema, abdominal pain, indigestion, loss of appetite, constipation, dyspepsia;

Hepatobiliary disorders: hepatitis (hepatocellular or cholestatic), jaundice, hepatic failure**;

Skin disorders: rash, hypersensitivity, angioedema***, syndrome****, alopecia, urticaria, pruritus, psoriasis, increased sweating, sensation of warmth, skin hyperemia, severe skin reactions (pemphigus, toxic epidermal necrolysis, Stevens–Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma)****;

Metabolic disorders: hypoglycemia;

Musculoskeletal system disorders: muscle cramps, muscle weakness;

Endocrine disorders: syndrome of inappropriate antidiuretic hormone secretion (SIADH);

Renal and urinary disorders: oliguria/anuria, renal dysfunction, acute renal failure, proteinuria, uremia;

General disorders: increased fatigue, asthenia, chest discomfort;

Reproductive system disorders: impotence, gynecomastia;

Laboratory findings *****: increased liver enzyme activity, increased serum creatinine concentration, elevated blood urea levels, decreased hemoglobin content, reduced hematocrit, increased serum bilirubin, hyperkalemia.

*Cough associated with ACE inhibitor therapy is characterized as persistent and non-productive, and resolves upon discontinuation of the drug. This should be considered when performing differential diagnosis of cough.

**Very rare cases have been reported in which adverse development of hepatitis led to hepatic failure. Patients who develop jaundice or a significant increase in liver enzyme activity during treatment should discontinue the drug and undergo appropriate medical evaluation.

***Isolated cases of angioedema involving the face, extremities, lips, tongue, glottis and/or larynx have been reported.

****Cases of a syndrome have been reported, which may include one or more of the following symptoms: fever, vasculitis, myalgia, arthralgia/arthritis, positive antinuclear antibodies (ANA), elevated erythrocyte sedimentation rate (ESR), eosinophilia and leukocytosis, rash, photosensitivity, or other dermatological manifestations.

*****Slight increases in serum creatinine and blood urea concentrations have been observed. These effects are usually reversible upon discontinuation of the drug. Slight decreases in hemoglobin and hematocrit levels have been reported, as well as bone marrow suppression manifesting as anemia and/or thrombocytopenia. Hyper- or hypokalemia and hyponatremia have also been observed. Isolated cases of increased liver enzyme activity and/or serum bilirubin levels have been reported, but a causal relationship with the drug containing lisinopril and hydrochlorothiazide has not been established.

Cases of syncope and chest pain have been reported, but a causal relationship with the drug containing lisinopril and hydrochlorothiazide has not been established.

There have been reports of neuropathy developing during treatment with ACE inhibitors.

Adverse effects associated with hydrochlorothiazide:

Infections and infestations: sialadenitis;

Immune system disorders: hypersensitivity reactions, including anaphylactic reaction, shock;

Blood system disorders: leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow function suppression;

Metabolic disorders: anorexia; hyperglycemia; glucosuria; hyperuricemia, which may provoke gout attacks in patients with asymptomatic disease; electrolyte imbalance, including hyponatremia and hypokalemia, hypochloremic alkalosis, hypomagnesemia; hypercalcemia; increased blood lipid levels; gout; decreased glucose tolerance, potentially leading to manifestation of latent diabetes mellitus; hypochloremic alkalosis, which may induce hepatic encephalopathy or hepatic coma; increased cholesterol and triglyceride concentrations, gout;

Psychiatric disorders: restlessness, depression, mood changes, sleep disturbances, confusion, disorientation, somnolence, nervousness, agitation;

Nervous system disorders: dizziness, headache, convulsions, paresthesia, decreased appetite, pre-comatose state;

Eye disorders: blurred vision, xanthopsia, conjunctivitis, acute myopia and secondary acute angle-closure glaucoma, choroidal effusion, transient decrease in visual acuity;

Ear disorders: vertigo;

Cardiovascular disorders: arrhythmia, orthostatic hypotension, necrotizing angiitis (vasculitis, cutaneous vasculitis);

Respiratory disorders: respiratory distress syndrome (very rare), including pneumonitis and pulmonary edema;

Gastrointestinal disorders: gastric mucosa irritation, constipation, dry mouth, thirst sensation, nausea, vomiting, diarrhea;

Hepatobiliary disorders: jaundice (jaundice due to intrahepatic cholestasis), pancreatitis, cholecystitis;

Skin disorders: vasculitis, necrotizing angiitis, toxic epidermal necrolysis, Stevens–Johnson syndrome, photosensitivity reactions, rash, eczema, lupus-like skin reactions, reactivation of skin manifestations of systemic lupus erythematosus, urticaria, purpura, anaphylactic reactions;

Musculoskeletal disorders: muscle cramps and pain, muscle weakness;

Renal and genital disorders: renal failure, renal dysfunction and interstitial nephritis, sexual disorders;

General disorders: exhaustion, weakness, fever.

Neoplasms: non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) (see sections "Pharmacodynamics" and "Special precautions").

Description of selected adverse reactions

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

Reporting of possible adverse reactions.

Reporting suspected adverse reactions after drug registration is of great importance. It ensures continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions via the national reporting system.

Shelf life. 3 years.

Storage conditions.

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

Keep out of reach of children.

Packaging.

10 tablets in a blister; 1, 2 or 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer.

LLC "ASTRAFARM".

Manufacturer's address and location of business activity.

6, Kyivska Street, Vyshneve, Kyiv-Sviatoshyn District, Kyiv Oblast, 08132, Ukraine.