Lisinopril h-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT Lisinopril H-Teva (Lisinopril H-Teva)

Composition:

Active substances: lisinopril; hydrochlorothiazide;

One tablet contains 10 mg or 20 mg of lisinopril as lisinopril dihydrate and 12.5 mg of hydrochlorothiazide;

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

Pharmaceutical form. Tablets.

Main physical and chemical properties: oval, slightly biconvex white tablets, engraved with "LZ 10" (tablets 10 mg/12.5 mg) or "LZ 20" (tablets 20 mg/12.5 mg) on one side and a score line on the other.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors and diuretics. ATC code C09BA03.

Pharmacological properties.

Pharmacodynamics.

Lisinopril and hydrochlorothiazide — an ACE inhibitor and a diuretic — have complementary actions and produce an additive antihypertensive effect. ACE catalyzes the conversion of angiotensin I to angiotensin II, which has a potent vasoconstrictive effect and stimulates aldosterone secretion. The antihypertensive effect of lisinopril is primarily related to inhibition of the renin-angiotensin-aldosterone system, resulting in decreased plasma concentrations of angiotensin II and aldosterone. Lisinopril exerts antihypertensive activity even in patients with low-renin hypertension. ACE is similar to kininase II, an enzyme responsible for bradykinin degradation. It remains unclear whether increased bradykinin levels (a potent vasodilator) play a role in the therapeutic effect of lisinopril.

Hydrochlorothiazide is a thiazide diuretic and antihypertensive agent that increases plasma renin levels. Hydrochlorothiazide reduces renal reabsorption of electrolytes in the distal segment of the loop of Henle and increases excretion of sodium, chloride, potassium, magnesium, bicarbonate, and water. Calcium excretion may be reduced. Concomitant administration of lisinopril and hydrochlorothiazide provides a more pronounced antihypertensive effect than either agent used alone in monotherapy. Lisinopril generally reduces potassium loss induced by hydrochlorothiazide.

Pharmacokinetics.

Absorption. Lisinopril: approximately 25%, with interindividual variability ranging from 6% to 60% at studied doses (5–80 mg). The presence of food in the gastrointestinal tract does not affect lisinopril absorption. Peak serum concentration is reached within 6–8 hours. Onset of antihypertensive effect occurs within 1–2 hours. Maximum effect is achieved within 6 hours and lasts for at least 24 hours.

Hydrochlorothiazide: diuretic effect begins within 2 hours. Maximum effect is reached within 4 hours. Clinically significant action lasts 6–12 hours.

Distribution. Protein binding: apart from ACE, lisinopril does not bind to other plasma proteins. Elderly patients have higher plasma concentrations of lisinopril due to reduced volume of distribution compared to younger patients.

Elimination half-life. Lisinopril – 12 hours (after multiple doses). Hydrochlorothiazide – 5.5–15 hours.

Metabolism/elimination. Both active components are excreted unchanged by the kidneys. After oral administration, approximately 60% of hydrochlorothiazide is excreted within 24 hours.

Clinical characteristics.

Indications.

The lisinopril/hydrochlorothiazide combination is used for the treatment of mild to moderate arterial hypertension in patients whose condition has been stabilized using the individual components at the same doses.

Contraindications.

Hypersensitivity to lisinopril and other ACE inhibitors, to hydrochlorothiazide and sulfonamide derivatives, or to any other components of the medicinal product.

History of angioedema (including angioedema after use of ACE inhibitors, idiopathic or hereditary angioedema (Quincke's edema)).

Anuria, severe renal impairment (creatinine clearance < 30 mL/min).

Severe hepatic impairment.

Acute gout.

Concomitant use of aliskiren-containing medicinal products in patients with diabetes mellitus or renal impairment (GFR < 60 mL/min/1.73 m²).

Concomitant use with sacubitril/valsartan. Treatment with Lisinopril N-Teva may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Special warnings and precautions for use" and "Interaction with other medicinal products and other forms of interaction").

Mitral or aortic valve stenosis, hypertrophic obstructive cardiomyopathy.

Primary hyperaldosteronism.

Renal artery stenosis (bilateral or unilateral).

Cardiogenic shock.

Porphyria.

Unstable hemodynamic status following acute myocardial infarction.

Use in patients undergoing hemodialysis with high-flux membranes (e.g., AN 69).

Serum creatinine level > 220 µmol/L.

Refractory hypokalemia or hypercalcemia.

Refractory hyponatremia.

Pregnancy or women planning to become pregnant (see "Use during pregnancy or breastfeeding").

Interaction with other medicinal products and other forms of interaction.

Lisinopril

Medicinal products increasing the risk of angioedema. Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema (see sections "Contraindications" and "Special warnings and 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 warnings and precautions for use").

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor antagonists, or aliskiren has been shown to be associated with a higher incidence of adverse reactions such as hypotension, hyperkalemia, and renal dysfunction (including acute renal failure), compared to monotherapy.

Concomitant use of aliskiren-containing medicinal products with lisinopril should be avoided.

Diuretics. Adding a diuretic to lisinopril therapy usually potentiates the antihypertensive effect.

At the initiation of combination therapy with lisinopril and diuretics, patients may occasionally experience excessive reduction in blood pressure. The risk of symptomatic hypotension with lisinopril may be reduced by discontinuing diuretic therapy prior to starting lisinopril.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid. 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 thiazide diuretics. Concomitant use of NSAIDs and ACE inhibitors may impair renal function. This effect is usually reversible. In rare cases, acute renal failure may occur, particularly in elderly patients, those with impaired renal function, and those who are dehydrated.

In some patients, administration of nonsteroidal anti-inflammatory drugs 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, which may impair renal function.

Other antihypertensive agents. The antihypertensive effect of lisinopril and hydrochlorothiazide may be enhanced when used concomitantly with other agents, potentially leading to orthostatic hypotension. Concomitant use with nitroglycerin and other nitrates or other vasodilators may further reduce blood pressure.

Tricyclic antidepressants/neuroleptics/anesthetics. Concomitant use of certain anesthetic agents, tricyclic antidepressants, and neuroleptics with ACE inhibitors may subsequently lead to a reduction in blood pressure.

Sympathomimetic agents. Sympathomimetic agents may reduce the antihypertensive effect of ACE inhibitors.

Antidiabetic agents. Concomitant use of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may enhance the blood glucose-lowering effect, increasing the risk of hypoglycemia (usually during the first weeks of combination therapy and in patients with renal impairment).

Acetylsalicylic acid, thrombolytic agents, beta-blockers, nitrates. Lisinopril N-Teva may be used concomitantly with acetylsalicylic acid (at cardiologic doses), thrombolytic agents, beta-blockers, and/or nitrates.

Allopurinol. Concomitant use of ACE inhibitors with allopurinol increases the risk of renal failure and may increase the risk of leukopenia.

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

Cyclosporine. Concomitant use of ACE inhibitors with cyclosporine may lead to hyperkalemia. Monitoring of serum potassium levels is recommended. Additionally, concomitant use of ACE inhibitors and cyclosporine increases the risk of renal impairment.

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

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

Procainamide, cytostatic agents, or immunosuppressive medicinal products. Concomitant use of these agents with ACE inhibitors may increase the risk of leukopenia.

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

Use during hemodialysis. Lisinopril/hydrochlorothiazide should not be administered to patients requiring dialysis due to a high frequency of reports of anaphylactoid reactions in patients undergoing dialysis with high-flux membranes while receiving an ACE inhibitor. Such a combination should be avoided.

Hydrochlorothiazide

Amphotericin B (for parenteral use), carbenoxolone, corticosteroids, corticotropin (ACTH), or stimulant laxatives. Concomitant use with hydrochlorothiazide may cause electrolyte imbalance, particularly hypokalemia.

Calcium salts. Serum calcium levels may increase due to reduced excretion when used concomitantly with thiazide diuretics.

Cardiac glycosides. There is an increased risk of digitalis toxicity in the setting of hypokalemia induced by thiazide diuretics.

Cholestyramine and colestipol. Concomitant use with hydrochlorothiazide may reduce or delay absorption of hydrochlorothiazide. 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 chloride). The effect of these agents may be potentiated by hydrochlorothiazide.

Agents causing torsades de pointes-type ventricular tachycardia. Due to the risk of hypokalemia, particular caution should be exercised when using hydrochlorothiazide concomitantly with agents associated with paroxysmal torsades de pointes-type ventricular tachycardia.

Periodic monitoring of serum potassium levels and ECG monitoring are recommended when hydrochlorothiazide is used concomitantly with agents whose effects are influenced by changes in serum potassium levels and the following agents known to cause polymorphic torsades de pointes (ventricular tachycardia), including certain antiarrhythmics:

• 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 vinca alkaloids).

Sotalol. Hypokalemia induced by thiazide diuretics may increase the risk of sotalol-induced arrhythmias.

Lisinopril/Hydrochlorothiazide

Ethanol/barbiturates/narcotic analgesics. Orthostatic hypotension may occur.

Antidiabetic medicinal products (oral agents and insulin). Dosage adjustment of antidiabetic agents may be required.

Immunosuppressants, cytostatics. Concomitant use may increase the risk of leukopenia.

Corticosteroids, ACTH. Increased electrolyte loss, particularly hypokalemia, may occur.

Pressor amines (e.g., epinephrine (adrenaline)). Reduced response to pressor amines may occur, but not to the extent that their use should be discontinued.

Alcohol. Alcohol may potentiate the hypotensive effect of any antihypertensive agent.

Antacids. Reduce the bioavailability of ACE inhibitors.

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

Cytoxic agents (e.g., cyclophosphamide, methotrexate). Thiazides may reduce renal excretion of cytotoxic drugs and potentiate their myelosuppressive effect.

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

Anticholinergic agents (atropine, biperiden). Due to decreased gastrointestinal motility and delayed gastric emptying, bioavailability of thiazide diuretics may increase.

Potassium-containing dietary supplements, potassium-sparing diuretics, or potassium-containing salt substitutes. Potassium excretion during thiazide diuretic therapy is generally counterbalanced by the potassium-sparing effect of lisinopril. Although serum potassium levels usually remain within normal limits, hyperkalemia 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 a significant increase in serum potassium levels. Caution should also be exercised when using Lisinopril N-Teva concomitantly with other medicinal products that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), as trimethoprim is known to act as a potassium-sparing diuretic, similar to amiloride. Therefore, combination of Lisinopril N-Teva with the above-mentioned medicinal products is not recommended. If concomitant use is necessary, it should be done with caution and frequent monitoring of serum potassium levels (see section "Special warnings and precautions for use").

Lithium. Lithium preparations should generally not be used concomitantly with diuretics or ACE inhibitors. Reversible increases in serum lithium concentration and lithium toxicity have been reported with concomitant use of lithium and ACE inhibitors. Diuretics and ACE inhibitors reduce renal clearance of lithium and increase the risk of lithium toxicity. If concomitant use is unavoidable, serum lithium levels should be closely monitored (see section "Special warnings and precautions for use").

Effect on laboratory test results. Thiazides may affect parathyroid function assessment due to their influence on calcium metabolism (see section "Special warnings and precautions for use").

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

Iodinated contrast agents. In cases of diuretic-induced dehydration, the risk of acute renal failure is increased, particularly with high doses of iodinated contrast agents. Patients require rehydration prior to administration of iodinated contrast agents.

Beta-blockers and diazoxide. Concomitant use of thiazide diuretics, including hydrochlorothiazide, with beta-blockers may increase the risk of hyperglycemia. Thiazide diuretics, including hydrochlorothiazide, may potentiate the hyperglycemic effect of diazoxide.

Amantadine. Thiazides, including hydrochlorothiazide, may increase the risk of adverse effects associated with amantadine.

Other concomitant therapies. Concomitant use of tissue plasminogen activators may increase the risk of angioedema.

Special precautions for use.

Lisinopril

Symptomatic arterial hypotension. Symptomatic arterial hypotension was rarely observed in patients with uncomplicated arterial hypertension. The likelihood of developing arterial hypotension increases in dehydrated patients (e.g., due to diuretic therapy, salt restriction in diet, dialysis, diarrhea, or vomiting), as well as in patients with severe forms of renin-dependent arterial hypertension.

Symptomatic arterial hypotension has been observed in patients with heart failure, regardless of whether it is associated with renal failure. This most commonly occurs in patients with severe heart failure who are required to take high doses of loop diuretics and who have diagnosed hyponatremia or functional renal failure. Patients at increased risk of arterial hypotension require careful monitoring during the initial period of treatment and dose titration. In such patients, serum electrolyte levels should be regularly checked.

In patients at increased risk of symptomatic arterial hypotension, initiation of therapy and dose adjustment should be performed under close medical supervision. Particular attention should be paid to therapy in patients with ischemic heart disease or cerebrovascular disorders, as excessive reduction in blood pressure may lead to myocardial infarction or stroke.

If arterial hypotension develops, the patient should be placed in a supine position and, if necessary, intravenous infusion of physiological saline should be initiated. A transient hypotensive response is not a contraindication to continuing therapy. After restoration of effective blood volume and arterial pressure, therapy may be resumed at a reduced dose or with one of the components administered separately.

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

Patients should be under appropriate medical supervision to promptly detect clinical signs of disturbances in water-electrolyte balance (e.g., hypovolemia, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia), which may develop in cases of concomitant diarrhea or vomiting. During warm seasons, hyponatremia may occur in edematous patients due to hemodilution. Hypovolemia and/or reduced extracellular fluid volume should, if possible, be corrected 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., if systolic blood pressure is 100 mm Hg or lower) or in cases of cardiogenic shock.

Stenosis of aortic and mitral valves/hypertrophic cardiomyopathy. As with other ACE inhibitors, lisinopril should be administered with caution to patients with mitral stenosis or impaired outflow from the left ventricle (e.g., aortic stenosis or hypertrophic cardiomyopathy). If stenosis is hemodynamically significant, drug administration is contraindicated (see section "Contraindications").

Renal function impairment. In patients with kidney disease, thiazides may cause azotemia. Cumulative effects of drugs may occur in patients with impaired renal function. In progressive kidney disease characterized by increased non-protein nitrogen levels, the appropriateness of continuing therapy should be carefully evaluated, and discontinuation of diuretic therapy should be considered.

Thiazides are not suitable for use in patients with renal failure; they are ineffective when creatinine clearance is 30 mL/min or lower (i.e., moderate or severe renal failure).

Lisinopril H-Teva should not be prescribed to patients with renal failure (creatinine clearance ≤ 80 mL/min) until individual component titration has established that the patient requires the exact doses contained in the combined tablet.

In patients with impaired renal function (creatinine clearance < 80 mL/min), the initial dose of lisinopril should be selected based on creatinine clearance values (see section "Dosage and administration") and clinical response to treatment. Continuous monitoring of blood potassium and creatinine concentrations is recommended for such patients.

In patients with heart failure, arterial hypotension occurring after initiation of ACE inhibitor therapy may lead to impaired renal function. Acute renal failure has been reported in such cases, which is usually reversible.

In some patients with bilateral renal artery stenosis or stenosis of the artery of a solitary kidney receiving ACE inhibitor therapy, increased blood urea and serum creatinine concentrations have been observed, usually reversible upon discontinuation of therapy. The likelihood of developing this condition is higher in patients with renal failure. If renovascular hypertension is also present, there is an increased risk of severe arterial hypotension and renal failure. For such patients, treatment should be initiated at low doses under strict medical supervision, and careful 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 therapy.

In some patients with arterial hypertension who have no history of kidney disease, concomitant use of lisinopril and diuretics has led to a usually mild, transient increase in blood urea and serum creatinine concentrations. This primarily affects patients with a history of kidney disease. Dose reduction and/or discontinuation of the diuretic and/or lisinopril may be necessary.

If this occurs during treatment with Lisinopril H-Teva, the combined drug should be discontinued. Therapy may be resumed at a lower dose or one of the components may be used separately.

Patients after kidney transplantation. Since there is no experience with the use of lisinopril in patients who have undergone kidney transplantation surgery, lisinopril is not recommended for such patients.

Hypersensitivity/angioedema. In isolated cases, angioedema of the face, extremities, lips, tongue, glottis, and larynx has been reported in patients taking ACE inhibitors, including lisinopril. Angioedema may develop at any time during treatment. In such cases, lisinopril should be immediately discontinued, appropriate treatment initiated, and the patient placed under observation. Even in cases where swelling is limited only to the tongue and respiratory symptoms are absent, the patient's condition should be monitored, as treatment with antihistamines and corticosteroids may be insufficient.

Fatal cases due to laryngeal or tongue angioedema have been reported. If swelling extends to the tongue, glottis, or larynx, respiratory distress may develop, particularly in patients who have previously undergone surgery on the respiratory tract. In such cases, immediate emergency measures should be taken, including administration of adrenaline and/or securing airway patency. The patient should remain under close medical supervision until symptoms have completely and stably resolved. ACE inhibitors cause angioedema more frequently in patients of African descent.

Angioedema may also affect the intestine 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 in response to drugs of this class.

In patients receiving thiazide therapy, hypersensitivity reactions may develop regardless of the presence or absence of a history of allergy or bronchial asthma. Exacerbation or reactivation of systemic lupus erythematosus has been reported during thiazide therapy.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to an increased risk of angioedema. Sacubitril/valsartan therapy may be initiated only 36 hours after the last dose of Lisinopril H-Teva. Lisinopril H-Teva therapy may be initiated only 36 hours after the last dose of sacubitril/valsartan (see sections "Contraindications" and "Interaction with other medicinal products and other forms of interaction").

Concomitant use of ACE inhibitors with rac-cadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin may increase the risk of angioedema (e.g., angioedema of the airways or tongue with or without respiratory distress) (see section "Interaction with other medicinal products and other forms of interaction").

Caution is required when initiating rac-cadotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin in patients already taking an ACE inhibitor.

Anaphylactoid reactions during hemodialysis. Lisinopril/hydrochlorothiazide is not indicated for patients requiring dialysis due to renal failure. Anaphylactoid reactions have been reported in patients undergoing hemodialysis using high-flux membranes (e.g., AN 69) or low-density lipoprotein apheresis while concurrently receiving ACE inhibitor therapy. These patients should be advised to switch to dialysis membranes of another type or to use an antihypertensive drug of another class.

Anaphylactoid reactions during low-density lipoprotein (LDL) apheresis. Rarely, life-threatening anaphylactic reactions may occur during LDL apheresis with dextran sulfate in patients receiving ACE inhibitors. These reactions can be avoided by temporarily discontinuing ACE inhibitor therapy before each apheresis session.

Desensitization. In patients taking ACE inhibitors during desensitization therapy (e.g., for hymenoptera venom), persistent anaphylactoid reactions may occur. These reactions were avoided in the same patients by temporarily discontinuing ACE inhibitors, but recurred after inadvertent re-administration of the medicinal product.

Hepatic function impairment. Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as the drug may cause intrahepatic cholestasis, and even minimal changes in water-electrolyte balance may provoke hepatic encephalopathy (see section "Contraindications").

Very rarely, ACE inhibitor use has been associated with a syndrome beginning with cholestatic jaundice and progressing to fulminant necrosis and (sometimes) fatal outcome. The mechanism of this syndrome is unclear. Patients who develop jaundice or marked elevation of liver enzymes during lisinopril therapy should discontinue the drug and remain under appropriate medical supervision.

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 upon discontinuation of the ACE inhibitor. Lisinopril should be prescribed with extreme caution to patients with collagenosis, those undergoing immunosuppressive therapy, those taking allopurinol or procainamide, and in combination with these factors, especially in the presence of impaired renal function. Severe infections, which are not always responsive to intensive antibiotic therapy, may develop in some of these patients. Periodic monitoring of blood leukocyte count and patient education about reporting any signs of infection are recommended when using the drug in such patients.

Racial origin. ACE inhibitors may cause more pronounced angioedema in patients with dark skin compared to Caucasian patients. Also, in this patient group, the antihypertensive effect of lisinopril is less pronounced due to predominant low renin fractions.

Cough. A persistent, non-productive cough may occur during ACE inhibitor use, which resolves after discontinuation of therapy. ACE inhibitor-induced cough should be considered in the differential diagnosis of cough as one of the possible causes.

Surgery/anesthesia. In patients undergoing surgery or anesthesia with agents that lower blood pressure, lisinopril may block the increase in angiotensin II formation due to compensatory renin release. If arterial hypotension occurs due to this mechanism, circulating blood volume (CBV) should be corrected.

Lithium. Generally, the combination of lithium and lisinopril is not recommended.

Serum potassium levels. Increased serum potassium levels have been observed in some patients taking ACE inhibitors, including lisinopril. Patients at risk of hyperkalemia include those with renal failure or diabetes mellitus, and those with hypoaldosteronism.

ACE inhibitors may cause hyperkalemia as they inhibit aldosterone release. This effect is usually insignificant in patients with normal renal function. However, hyperkalemia may occur in patients with impaired renal function and/or in patients taking potassium-containing dietary supplements (including salt substitutes), potassium-sparing diuretics, or patients taking other drugs that increase serum potassium levels (e.g., heparin, trimethoprim, or co-trimoxazole, also known as trimethoprim/sulfamethoxazole), and especially aldosterone antagonists or angiotensin receptor blockers. Caution is required when using potassium-sparing diuretics and angiotensin receptor blockers in patients taking ACE inhibitors. Serum potassium levels and renal function should be monitored in such patients.

If concomitant use of the above-mentioned drugs during ACE inhibitor therapy is necessary, regular monitoring of serum potassium levels is recommended (see section "Interaction with other medicinal products and other forms of interaction").

Diabetic patients. In patients with diabetes mellitus receiving oral antidiabetic agents or insulin, blood glucose levels should be carefully monitored during the first month of ACE inhibitor therapy.

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been reported to increase the risk of arterial hypotension, hyperkalemia, and renal function impairment (including acute renal failure). Therefore, dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended.

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

Hydrochlorothiazide

Renal function impairment. In patients with kidney disease, thiazides may provoke azotemia. Cumulative effects may occur with impaired renal function. In progressive renal failure characterized by increased non-protein nitrogen, the appropriateness of continuing therapy should be carefully evaluated, and discontinuation of diuretics should be considered.

Hepatic function impairment. Thiazides should be used with caution in patients with impaired liver function or progressive liver disease, as minor changes in water-electrolyte balance may provoke hepatic encephalopathy.

Metabolic and endocrine effects. It is known that concomitant administration of ACE inhibitors and antidiabetic agents (insulin, oral hypoglycemic agents) may increase blood glucose concentration, thereby reducing the risk of hypoglycemia. This phenomenon is more likely to develop during the first weeks of combination therapy and in patients with renal failure (see section "Interaction with other medicinal products and other forms of interaction").

Therapy with ACE inhibitors and thiazides may impair glucose tolerance. Dose adjustment of antidiabetic agents, including insulin, may be required. Blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy in diabetic patients receiving oral antidiabetic agents or insulin.

Latent diabetes mellitus may manifest during thiazide therapy.

Thiazides may reduce calcium excretion in urine and may cause a transient and slight increase in serum calcium. Marked hypercalcemia may indicate latent hyperparathyroidism. Thiazide diuretic use should be discontinued before performing tests to assess parathyroid gland function.

Increased cholesterol and triglyceride concentrations 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 levels and thereby attenuate the hyperuricemic effect of hydrochlorothiazide.

Electrolyte imbalance. As with therapy using any diuretics, patients should have periodic determination of serum electrolyte levels. Thiazides, including hydrochlorothiazide, may lead to water-electrolyte imbalance (hypokalemia, hyponatremia, and hypochloremic alkalosis). Symptoms of water-electrolyte imbalance include dry mouth, thirst, weakness, lethargy, somnolence, muscle pain or cramps, muscle weakness, arterial hypotension, oliguria, tachycardia, and gastrointestinal disorders such as nausea and vomiting. In hot weather, hyponatremia may occur in patients prone to edema. Thiazides may increase renal magnesium excretion, potentially leading to hypomagnesemia.

Chloride deficiency is usually mild and does not require treatment.

Thiazides may reduce urinary calcium excretion and cause a slight, transient increase in serum calcium levels. Significant hypercalcemia may indicate latent hyperparathyroidism; therefore, discontinuation of thiazide diuretics is recommended before evaluating parathyroid function.

Although hypokalemia may develop during thiazide diuretic use, concomitant use with lisinopril may reduce diuretic-induced hypokalemia. High-risk groups for hypokalemia include patients with liver cirrhosis, those with high diuresis, those with inadequate oral electrolyte replacement, and patients receiving concomitant corticosteroid or adrenocorticotropic hormone (ACTH) therapy.

Doping test. Hydrochlorothiazide may cause a positive doping test.

Non-melanoma skin cancer (NMSC). An increased risk of non-melanoma skin cancer (NMSC) [basal cell carcinoma (BCC) and squamous cell carcinoma (SCC)] with increasing cumulative exposure to hydrochlorothiazide was noted in two epidemiological studies based on data from the Danish National Cancer Registry. The photosensitizing effect of hydrochlorothiazide may be a possible mechanism for NMSC development.

Patients taking hydrochlorothiazide should be informed about the risk of NMSC and advised to regularly check their skin for new lesions and promptly report any suspicious skin changes. To reduce the risk of skin cancer, patients should be advised to take preventive measures such as limiting exposure to sunlight and ultraviolet radiation or using appropriate protective measures when exposed to solar or ultraviolet rays. Suspicious skin lesions should be promptly examined with histological analysis of biopsy material. Re-evaluation of hydrochlorothiazide use may be necessary in patients with a history of NMSC (see also section "Adverse reactions").

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 defect, 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 medicinal product.

Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is immediate discontinuation of the medicinal product. If intraocular pressure remains uncontrolled, immediate medical or surgical intervention may be required. Risk factors for acute angle-closure glaucoma may include a history of allergy to sulfonamides or penicillin.

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 hydrochlorothiazide intake. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, this drug should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after hydrochlorothiazide intake.

Other. In patients receiving thiazides, hypersensitivity reactions may occur regardless of a history of allergy or bronchial asthma. Exacerbation or reactivation of systemic lupus erythematosus has been reported during thiazide therapy.

Lisinopril/hydrochlorothiazide

Arterial hypotension and water-electrolyte imbalance. Symptomatic arterial hypotension may occasionally occur after the first dose of lisinopril/hydrochlorothiazide. In patients with arterial hypertension, the risk of hypotension is higher in the presence of disturbances in fluid or electrolyte balance, such as dehydration, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia, which may result from diuretic therapy, low-salt diet, dialysis, or intercurrent illness: diarrhea or vomiting. In such patients, serum electrolyte levels should be regularly monitored. Initiation of therapy and dose titration in patients at increased risk of symptomatic hypotension should be performed under strict medical supervision. Therapy in patients with ischemic heart disease or cerebrovascular disorders requires special caution, as excessive blood pressure reduction in such patients may promote the development of myocardial infarction or cerebral hemorrhage.

In severe arterial hypotension, the patient should be placed in anti-shock position and intravenous infusion of physiological saline should be rapidly administered. A temporary hypotensive reaction is not a contraindication for continuing therapy. After normalization of circulating blood volume and arterial pressure, therapy may be resumed with a lower dose or continued with one of the drug components.

As with other vasodilating agents, lisinopril/hydrochlorothiazide should be prescribed with caution to patients with aortic stenosis or hypertrophic cardiomyopathy.

Renal function impairment. Thiazides are ineffective in patients with creatinine clearance below 30 mL/min (particularly in moderate to severe renal failure). Lisinopril/hydrochlorothiazide should not be prescribed to patients with creatinine clearance of 30–80 mL/min until individual component titration has established that the patient requires the exact doses contained in the combined preparation.

In some patients without confirmed history of renovascular disorders, concomitant use of lisinopril and diuretics has led to slight, transient increases in blood urea and serum creatinine concentrations. If this phenomenon occurs during lisinopril/hydrochlorothiazide therapy, treatment should be discontinued. If necessary, therapy may be resumed with a lower dose or with only one of the drug components.

Prior diuretic use. Diuretic therapy should be discontinued 2–3 days before initiating lisinopril/hydrochlorothiazide therapy. If this is not possible, therapy should be initiated with monotherapy using lisinopril at a dose of 5 mg.

Hypokalemia risk. The combination of an ACE inhibitor with a thiazide diuretic does not exclude the possibility of hypokalemia development. Regular monitoring of potassium levels is required.

Neutropenia/agranulocytosis. If neutropenia (neutrophil count < 1000/mm³) is detected or suspected, fixed combination therapy with lisinopril and hydrochlorothiazide should be discontinued.

Use during pregnancy or breastfeeding.

Pregnancy

ACE inhibitors

The drug should not be used in pregnant women or women planning to become pregnant. If pregnancy is confirmed during treatment with this medicinal product, its use should be immediately discontinued and, if necessary, replaced with another medicinal product approved for use during pregnancy.

Breastfeeding

ACE inhibitors

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

Hydrochlorothiazide

Hydrochlorothiazide is excreted in breast milk in small amounts. Thiazides in large doses causing intense diuresis may suppress milk production.

Therefore, the drug is contraindicated during breastfeeding.

Ability to affect reaction speed when driving vehicles or operating machinery.

Like other antihypertensive agents, Lisinopril H-Teva may weakly or moderately affect the ability to drive vehicles or operate machinery. The risk increases at the beginning of treatment or when changing dose, and when Lisinopril H-Teva is taken with alcohol, although this effect depends on individual patient sensitivity.

The possibility of developing dizziness and fatigue should be considered when driving vehicles or operating machinery.

Method of Administration and Dosage

The determination of the effective dose of the drug depends on the clinical assessment of the patient's condition.

The usual dose is 1 tablet of 10 mg/12.5 mg or 20 mg/12.5 mg once daily. Lisinopril H-Teva should be taken daily at approximately the same time.

Fixed-dose combination of lisinopril and hydrochlorothiazide is generally recommended after individual component doses have been optimized. In certain clinical situations, direct transition from monotherapy to the fixed combination may be considered.

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

The maximum daily dose of Lisinopril H-Teva is 40 mg/25 mg.

Previous Diuretic Therapy

Symptomatic arterial hypotension may occur after the first dose of lisinopril/hydrochlorothiazide, particularly in dehydrated patients (e.g., due to diuretic treatment). Diuretic therapy should be discontinued 2–3 days before initiating lisinopril/hydrochlorothiazide. If this is not feasible, treatment should be initiated with lisinopril alone at a dose of 5 mg.

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 combination of lisinopril/hydrochlorothiazide should not be used for initial treatment of patients with renal insufficiency.

In patients with creatinine clearance > 30 and < 80 mL/min, the combination of lisinopril/hydrochlorothiazide may be used after individual component doses have been optimized. The recommended initial dose of lisinopril monotherapy in such patients is 5–10 mg.

Elderly Patients

Dose adjustment is not required.

No age-related differences in efficacy or tolerability of the lisinopril/hydrochlorothiazide combination have been reported.

Lisinopril at daily doses of 20–80 mg was equally effective in elderly patients (aged 65 years and older) and younger adults. Monotherapy with lisinopril was as effective in reducing diastolic blood pressure as monotherapy with hydrochlorothiazide or atenolol. Age has not been reported to affect lisinopril tolerability.

Children

The safety and efficacy of the lisinopril/hydrochlorothiazide combination in children have not been established; therefore, Lisinopril H-Teva should not be prescribed to this age group.

Overdose

Human data on overdose are limited.

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

Treatment of overdose includes intravenous administration of normal saline. In case of severe arterial hypotension, the patient should be placed in a supine position. Infusion of angiotensin II (if available) or intravenous administration of catecholamines may be considered. If drug intake was recent, measures to remove lisinopril from the body should be initiated (induced emesis, gastric lavage, use of adsorbents and sodium sulfate). Lisinopril may be removed from systemic circulation by hemodialysis (see section "Pharmacological Properties"). For refractory bradycardia, cardiac pacing may be indicated. Frequent monitoring of vital signs, serum electrolytes, and serum creatinine is required.

Additional symptoms of hydrochlorothiazide overdose may include: increased diuresis, depression of consciousness (including coma), seizures, paresis, arrhythmias, and renal failure.

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

Concomitant use of cardiac glycosides may lead to hypokalemia, increasing the risk of arrhythmias.

Specific information on the management of lisinopril/hydrochlorothiazide overdose is lacking. Symptomatic and supportive therapy should be provided. The drug should be discontinued immediately, and careful monitoring of the patient should be ensured. Therapeutic measures depend on the nature and severity of symptoms. Steps should be taken to prevent absorption and enhance elimination of the drug. Dehydration, electrolyte imbalances, and arterial hypotension should be managed in the conventional manner. If overdose occurred recently, gastric lavage may be considered; however, this should not delay timely administration of activated charcoal to prevent absorption. Elimination may be accelerated by appropriate laxatives such as sodium sulfate.

Adverse Reactions

The following adverse reactions were most commonly observed during administration of lisinopril and/or hydrochlorothiazide: cough, dizziness, arterial hypotension, headache.

Adverse effects associated with the lisinopril/hydrochlorothiazide combination

Metabolism and nutrition disorders: gout.

Nervous system disorders: dizziness, headache, fatigue.

Psychiatric disorders: paresthesia, asthenia.

Respiratory system disorders: dry persistent cough, which resolves after discontinuation of treatment.

Cardiovascular system disorders: arterial hypotension, including orthostatic hypotension, tachycardia, chest pain, muscle cramps, and muscle weakness.

Gastrointestinal disorders: diarrhea, nausea, vomiting, dyspepsia, pancreatitis, dry mouth.

Skin and subcutaneous tissue disorders: rash, angioedema of the face, extremities, lips, tongue, glottis and/or larynx.

Reproductive system disorders: impotence.

Other disorders: a syndrome that may include one or more of the following manifestations: fever, vasculitis, myalgia, arthralgia or arthritis, positive antinuclear antibody (ANA) test results; elevated erythrocyte sedimentation rate (ESR), eosinophilia, leukocytosis, rash, photosensitivity, or other dermatological manifestations.

Laboratory findings: hyperglycemia, hyperuricemia, hyperkalemia or hypokalemia. A slight transient increase in blood urea nitrogen (BUN) and serum creatinine is usually observed in patients without pre-existing renal impairment. Even if such elevation persists, it typically resolves after discontinuation of treatment.

Cases of bone marrow suppression manifested as anemia and/or thrombocytopenia and/or leukopenia have been reported. There have been rare reports of agranulocytosis; however, a causal relationship to the drug has not been established.

A minor decrease in hemoglobin levels and hematocrit values has been reported in patients with arterial hypertension treated with the lisinopril/hydrochlorothiazide combination; however, this decrease rarely becomes clinically significant except when another cause of anemia is present simultaneously.

Isolated cases of increased liver enzymes and/or serum bilirubin have been observed; however, a causal relationship to the lisinopril/hydrochlorothiazide combination has not been established. Rare cases of hemolytic anemia have also been reported.

Adverse effects associated with lisinopril and other ACE inhibitors

Blood and lymphatic system disorders: decreased hemoglobin, decreased hematocrit, bone marrow suppression, anemia, thrombocytopenia, leukopenia, neutropenia, agranulocytosis, hemolytic anemia, lymphadenopathy, autoimmune disorders.

Metabolism and nutrition disorders: hypoglycemia.

Nervous system disorders: dizziness, headache, syncope, paresthesias, vertigo, taste disturbances, olfactory disturbances, stroke due to significant hypotension in patients at high risk, confusion, hallucinations.

Psychiatric disorders: mood changes, depression, confusion, sleep disturbances.

Cardiovascular disorders: arterial hypotension (including orthostatic), myocardial infarction due to significant hypotension in patients at high risk, palpitations, tachycardia, Raynaud's phenomenon, flushing.

Respiratory system disorders: cough, rhinitis, bronchospasm, sinusitis, allergic alveolitis/eosinophilic pneumonia.

Gastrointestinal disorders: diarrhea, vomiting, nausea, abdominal pain, dyspepsia, dry mouth, pancreatitis, intestinal angioedema.

Hepatobiliary disorders: increased liver enzyme activity and serum bilirubin, hepatitis, hepatocellular or cholestatic jaundice, liver failure.

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

Skin and subcutaneous tissue disorders: rash, pruritus, hypersensitivity/angioedema (of the face, extremities, lips, tongue, glottis and/or larynx), urticaria, alopecia, psoriasis, increased sweating, severe skin reactions (pemphigus, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma).

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

Renal and urinary disorders: impaired renal function, uremia, acute renal failure, oliguria/anuria.

Reproductive system and breast disorders: impotence, gynecomastia.

Musculoskeletal system disorders: muscle cramps, muscle weakness.

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

General disorders: increased fatigue, asthenia.

Laboratory findings: increased blood urea nitrogen (BUN), increased serum creatinine concentration, hyperkalemia, hyponatremia.

Adverse effects associated with hydrochlorothiazide

Infections and infestations: sialadenitis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma).

Blood and lymphatic system disorders: leukopenia, neutropenia/agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, bone marrow suppression.

Immune system disorders: hypersensitivity reactions, including anaphylactic reaction and shock.

Metabolism and nutrition disorders: anorexia, hyperglycemia, glucosuria, hyperuricemia, electrolyte imbalance (including hyponatremia, hypokalemia, hypochloremic alkalosis, hypomagnesemia), increased cholesterol and triglyceride levels, gout.

Psychiatric disorders: restlessness, depression, sleep disturbances.

Nervous system disorders: loss of appetite, paresthesias, dizziness.

Eye disorders: xanthopsia, transient visual disturbances, acute myopia, acute angle-closure glaucoma, choroidal effusion.

Ear and labyrinth disorders: vertigo.

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

Respiratory, thoracic and mediastinal disorders: acute respiratory distress syndrome, respiratory distress (including pneumonitis and pulmonary edema).

Gastrointestinal disorders: gastric mucosal irritation, diarrhea, constipation, pancreatitis.

Hepatobiliary disorders: jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders: photosensitivity reactions, rash, systemic lupus erythematosus, lupus-like skin reactions, reactivation of cutaneous manifestations of systemic lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis.

Musculoskeletal and connective tissue disorders: muscle cramps, muscle weakness.

Renal and urinary disorders: impaired renal function, interstitial nephritis.

General disorders: fever, weakness.

Description of selected adverse reactions

Non-melanoma skin cancer. Epidemiological data have shown an association between the occurrence of non-melanoma skin cancer and cumulative dose of hydrochlorothiazide (see section "Special precautions for use").

Shelf life. 2 years.

Storage conditions. Store at temperatures not exceeding 30°C, in a place inaccessible to children.

Packaging. 10 tablets in a blister; 3 blisters per carton.

Prescription status. Prescription only.

Manufacturer. Teva Pharmaceutical Works Private Limited Company.

Manufacturer's address and location of operations.
Site 1; Pallagi str. 13, H-4042 Debrecen, Hungary.