Lopril bosnalek® h 20

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT LOPRIL BOSNALEK® H 10 (LOPRIL Bosnalijek® H 10) LOPRIL Bosnalijek® H 20 (LOPRIL Bosnalijek® H 20)

Composition:

1 tablet of Lopril Bosnalijek® H 10 contains lisinopril 10 mg in the form of dihydrate, hydrochlorothiazide 12.5 mg;

1 tablet of Lopril Bosnalijek® H 20 contains lisinopril 20 mg in the form of dihydrate, hydrochlorothiazide 12.5 mg;

Excipients: calcium hydrogen phosphate dihydrate, mannitol (E 421), maize starch, pregelatinized starch, magnesium stearate, talc, colloidal anhydrous silicon dioxide, yellow iron oxide E 172; for Lopril Bosnalijek® H 20 – red iron oxide E 172.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Lopril Bosnalijek® H 10: hexagonal tablets of light yellow to yellow color, with a dividing line;

Lopril Bosnalijek® H 20: hexagonal tablets of light pink to pink color, with a dividing line.

Pharmacotherapeutic group. Angiotensin-converting enzyme (ACE) inhibitors, combinations. ACE inhibitors and diuretics.

ATC code C09BA03.

Pharmacological properties.

Pharmacodynamics.

Lopril Bosnalek® H is a combination of the angiotensin-converting enzyme (ACE) inhibitor lisinopril and the diuretic hydrochlorothiazide.

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

Although the primary mechanism by which lisinopril lowers blood pressure is believed to be inhibition of the renin-angiotensin-aldosterone system, lisinopril reduces blood pressure also in patients with low-renin hypertension. ACE is identical to kininase II, an enzyme that degrades bradykinin. It is not yet established whether increased levels of the potent vasodilator peptide bradykinin contribute to the therapeutic effect of lisinopril.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It reduces electrolyte reabsorption in the distal renal tubules, thereby increasing diuresis, which reduces blood volume and lowers elevated arterial pressure. A significant reduction in systolic and diastolic blood pressure occurs within 3–4 days after initiation of hydrochlorothiazide treatment, while the optimal antihypertensive effect is achieved after 3–4 weeks of therapy.

The combination of lisinopril and hydrochlorothiazide provides a more pronounced antihypertensive effect than either component alone.

Non-melanoma skin cancer (NMSC). Epidemiological data indicate a cumulative dose-dependent association between hydrochlorothiazide use and the development of NMSC. One study included 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC), compared with 1,430,833 and 172,426 control subjects, respectively. High cumulative doses of hydrochlorothiazide (≥ 50,000 mg) were associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval (CI): 1.23–1.35) for basal cell carcinoma and 3.98 (95% CI: 3.68–4.31) for squamous cell carcinoma. A clear dose-response relationship was observed in patients with 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 matched controls using risk-set sampling. A cumulative dose-response relationship was demonstrated with an adjusted OR of 2.1 (95% CI: 1.7–2.6), increasing to OR 3.9 (3.0–4.9) with high-dose exposure (~25,000 mg) and OR 7.7 (5.7–10.5) with the highest dose (~100,000 mg).

Pharmacokinetics.

The maximum plasma concentration of lisinopril is reached 7 hours after oral administration, although in patients with acute myocardial infarction a slight delay in the time to peak plasma concentration has been observed. The mean absorption value is approximately 25%, varying between 6% and 60% in individual patients within the studied dose range (5–80 mg). Bioavailability is reduced by approximately 16% in patients with heart failure.

Lisinopril is only slightly bound to plasma proteins, except for circulating ACE. It is not metabolized and is excreted unchanged in the urine. With repeated dosing, the effective cumulative half-life of lisinopril is 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 mL/min. The decline in serum concentration shows a prolonged terminal phase, which does not lead to drug accumulation. This phase likely reflects saturation of binding to ACE and is not dose-proportional. In patients with cirrhosis, impaired liver function leads to reduced absorption of lisinopril (by about 30%) and, due to decreased clearance, increased exposure (by about 50%) compared to healthy volunteers.

In renal impairment, lisinopril elimination is reduced, but this is clinically significant only when glomerular filtration rate is below 30 mL/min. In moderate renal impairment (creatinine clearance 30–80 mL/min), the mean AUC increases by only 13%, whereas in severe renal impairment (creatinine clearance 5–30 mL/min), AUC increases 4–5 fold. Lisinopril can be removed by dialysis. During 4 hours of hemodialysis, plasma lisinopril concentration decreased on average by 60% (creatinine clearance 40–55 mL/min).

Patients with heart failure have higher lisinopril exposure (mean AUC increase of 125%) but reduced absorption (mean reduction of 16%) compared to healthy volunteers.

Elderly patients have higher plasma levels of lisinopril and an approximately 60% higher AUC compared to younger patients.

Clinical characteristics.

Indications.

For the treatment of mild to moderate arterial hypertension in patients whose condition has been stabilized by using lisinopril and hydrochlorothiazide separately at the same doses.

Contraindications.

• Hypersensitivity to the active substances or to any excipient of the medicinal product, to other angiotensin-converting enzyme (ACE) inhibitors, or to any sulfonamide derivatives;
• Angioedema associated with previous use of ACE inhibitors, hereditary or idiopathic angioedema;
• Pregnancy and planned pregnancy (see "Use during pregnancy or breastfeeding");
• Anuria, severe renal impairment (creatinine clearance < 30 mL/min);
• Severe hepatic impairment;
• Concomitant use with aliskiren-containing products in patients with diabetes mellitus or renal impairment (eGFR < 60 mL/min/1.73 m²) (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use");
• Concomitant use with sacubitril/valsartan; initiation of Lopril Bosnalék H® should not begin earlier than 36 hours after the last dose of sacubitril/valsartan (see sections "Interaction with other medicinal products and other forms of interaction" and "Special precautions for use").

Interaction with other medicinal products and other forms of interaction.

Antihypertensive agents: combination with other antihypertensive agents may further reduce arterial pressure. When taken with nitroglycerin or other nitrates or other vasodilators, additional lowering of arterial pressure may occur.

Combination with aliskiren-containing products should be avoided. Clinical studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased risk of arterial hypotension, hyperkalemia, and renal function impairment (including acute renal failure) compared to monotherapy.

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

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

Lithium: concomitant use with ACE inhibitors may lead to reversible increases in serum lithium concentrations with possible toxic effects. Thiazide diuretics increase the risk of lithium toxicity. Therefore, lithium-containing medications should not be used concomitantly with lisinopril and hydrochlorothiazide. If combination therapy is necessary, serum lithium levels should be monitored.

Dietary supplements containing potassium, potassium-sparing diuretics, or potassium-containing salt substitutes. Potassium loss caused by thiazide diuretics 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 during treatment with lisinopril. Use of potassium-containing dietary supplements, potassium-sparing diuretics (spironolactone, triamterene, amiloride), or potassium-containing salt substitutes may lead to hyperkalemia, particularly in patients with impaired renal function or type 2 diabetes mellitus. Concomitant use of ACE inhibitors with other agents that increase serum potassium levels, such as trimethoprim and co-trimoxazole (trimethoprim/sulfamethoxazole), increases the risk of hyperkalemia. Therefore, concomitant use of this medicinal product with the above-mentioned agents is not recommended. If concomitant use is necessary, caution is required and periodic monitoring of serum potassium levels is advised (see section "Special precautions for use").

Heparin: hyperkalemia may occur when used concomitantly with ACE inhibitors. Monitoring of serum potassium levels is recommended.

Medicinal products capable of inducing torsades de pointes ventricular tachycardia. Caution is required when hydrochlorothiazide is used concomitantly with medicinal products capable of inducing torsades de pointes ventricular tachycardia (some antiarrhythmics, antipsychotics, and other agents) due to the risk of hypokalemia.

Tricyclic antidepressants, neuroleptics, anesthetics, alcohol, barbiturates, narcotics: further reduction in arterial pressure may occur when used concomitantly with ACE inhibitors. Alcohol, barbiturates, and anesthetics may potentiate orthostatic hypotension.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid. Prolonged use of NSAIDs (selective cyclooxygenase-2 inhibitors, acetylsalicylic acid at doses > 3 g/day, nonselective NSAIDs) may reduce the antihypertensive and diuretic effects of ACE inhibitors and thiazides. Concomitant use of NSAIDs and ACE inhibitors may lead to increased serum potassium levels and worsening of renal function. These effects are usually reversible. In rare cases, renal failure may develop, particularly in patients with pre-existing renal impairment, elderly patients, or dehydrated patients.

Gold: nitritoid reactions (vasodilation symptoms including flushing, nausea, dizziness, and hypotension, which may be severe) following gold injection (sodium aurothiomalate) have been more frequently reported in patients receiving ACE inhibitors.

Sympathomimetics: may reduce the antihypertensive effect of ACE inhibitors. Thiazides may reduce vascular responsiveness to norepinephrine, but not sufficiently to preclude the pressor effect.

Antidiabetic agents (oral hypoglycemic agents and insulin): thiazide use may impair glucose tolerance. This effect is more commonly observed during the first weeks of combination therapy and in patients with impaired renal function. Dose adjustment of hypoglycemic agents may be required.

Thiazide diuretics may potentiate the hyperglycemic effect of diazoxide.

Amphotericin B (parenteral), carbenoxolone, corticosteroids, corticotropin (ACTH), or stimulant laxatives. The hypokalemic effect of hydrochlorothiazide may be enhanced by medicinal products affecting potassium levels and promoting hypokalemia (e.g., other potassium-wasting diuretics, laxatives, amphotericin, carbenoxolone, salicylate derivatives).

Hypokalemia may develop during concomitant use of steroids or ACTH.

Calcium salts: increased serum calcium levels may occur due to reduced calcium excretion. If concomitant use of calcium supplements or vitamin D is necessary, careful monitoring of calcium levels is recommended, with dose adjustment as needed.

Cardiac glycosides. Hypokalemia may increase cardiac sensitivity or response to toxic effects of digitalis preparations (including increased ventricular excitability).

Cholestyramine and colestipol: reduced absorption of hydrochlorothiazide. Therefore, Lopril Bosnalék® H should be taken at least 1 hour before or 4–6 hours after administration of these agents.

Non-depolarizing muscle relaxants (e.g., tubocurarine): thiazides may enhance the effect of these medicinal products.

Sotalol: thiazide-induced hypokalemia increases the risk of arrhythmia.

Allopurinol: concomitant use with ACE inhibitors increases the risk of renal impairment and leukopenia.

Cyclosporine: concomitant use with ACE inhibitors increases the risk of renal damage and hyperkalemia. Monitoring of serum potassium levels is recommended. When used concomitantly with cyclosporine, hyperuricemia may be enhanced and the risk of complications such as gout may increase.

Lovastatin: concomitant use with ACE inhibitors increases the risk of hyperkalemia.

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

Amantadine: thiazides increase the risk of adverse effects of amantadine.

Special precautions for use.

Symptomatic hypotension. In patients with uncomplicated hypertension, symptomatic hypotension is rarely observed. Hypotension is more likely to occur in the presence of dehydration due to diuretic therapy, low-salt diets, dialysis, diarrhea, or vomiting, or in cases of severe renin-dependent hypertension. Such patients require regular monitoring of serum electrolytes. Patients at high risk of developing symptomatic hypotension should initiate therapy and dose titration under close medical supervision. Particular attention is required in patients with ischemic heart disease or cerebrovascular disorders, in whom excessive blood pressure reduction may lead to myocardial infarction or stroke.

If hypotension occurs, the patient should be placed in a supine position and, if necessary, administered physiological saline via intravenous infusion. A transient hypotensive response is not a contraindication for continued use of the medicinal product. Once blood pressure has increased following restoration of fluid volume, the drug may be administered, either as the combination or each component separately.

In some patients with heart failure who have normal or low blood pressure, administration of lisinopril may result in additional blood pressure reduction. This effect is expected and usually does not require discontinuation of treatment. In case of clinically significant hypotension, the dose should be reduced or the drug discontinued.

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

Dual blockade of the renin-angiotensin-aldosterone system (RAAS). Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is associated with an increased risk of arterial hypotension, hyperkalemia, and renal dysfunction (including acute renal failure). Therefore, dual blockade of the RAAS by concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren is not recommended (see section "Interaction with other medicinal products and other forms of interaction").

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

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

Renal impairment. Thiazides cannot be used as diuretics in patients with impaired renal function. Thiazides are ineffective when creatinine clearance is ≤30 mL/min or lower (moderate or severe renal impairment).

Lopril Bosnalék® H should not be prescribed to patients with renal impairment (creatinine clearance ≤80 mL/min) until doses of the individual components corresponding to those in the combination product have been established.

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

In some patients with bilateral renal artery stenosis or stenosis of the renal artery of a single kidney, especially in the presence of renal impairment, treatment with ACE inhibitors has been associated with increased serum urea and creatinine levels, which were usually reversible upon discontinuation of therapy. In patients with renovascular hypertension, the risk of severe hypotension and renal failure is increased. Such patients should start therapy under close medical supervision with low doses and careful dose titration. Renal function should be monitored during the first weeks of treatment with the combination of lisinopril and hydrochlorothiazide.

In some patients with arterial hypertension without obvious signs of kidney disease, concomitant use of lisinopril and a diuretic may lead to a usually mild and transient increase in serum urea and creatinine levels. This phenomenon is most likely in patients with impaired renal function. In such cases, dose reduction or discontinuation of the diuretic and/or lisinopril may be required.

Previous diuretic therapy should be discontinued 2–3 days before initiating therapy with Lopril Bosnalék® H. If this is not possible, therapy should be initiated with 5 mg of lisinopril alone.

Use in patients with transplanted kidney: not recommended due to lack of sufficient experience.

Anaphylactic reactions in patients undergoing hemodialysis. The combination of lisinopril/hydrochlorothiazide is not indicated for the treatment of patients with renal impairment requiring hemodialysis. Anaphylactic reactions have been reported in patients undergoing hemodialysis (including with high-flux AN 69 membranes) while receiving ACE inhibitors. In such cases, either the type of membrane or the class of antihypertensive agents should be changed.

Anaphylactic reactions during low-density lipoprotein (LDL) apheresis. In patients receiving ACE inhibitors, life-threatening anaphylactic reactions have occasionally occurred during LDL apheresis using dextran sulfate. To avoid this, ACE inhibitors should be temporarily discontinued before each apheresis procedure.

Hepatic impairment. Thiazides should be used with caution in patients with impaired liver function or progressive liver disease due to the risk of hepatic coma resulting from fluid and electrolyte imbalance. In isolated cases, administration of ACE inhibitors has been associated with a syndrome beginning with cholestatic jaundice and progressing to necrosis, and sometimes to fatal outcome. The mechanism of this syndrome is unknown. Patients taking lisinopril/hydrochlorothiazide who develop jaundice or increased liver enzymes should discontinue the drug and seek appropriate medical care.

Surgery/anesthesia. During surgical procedures or anesthesia with agents causing arterial hypotension, lisinopril may block angiotensin II formation in response to compensatory renin release. In cases of arterial hypotension attributable to this mechanism, volume expansion is indicated.

Metabolic and endocrine effects. Glucose tolerance may decrease during therapy with ACE inhibitors and thiazides. Adjustment of antidiabetic medication doses, including insulin, may be required. In patients receiving oral antidiabetic agents or insulin, blood glucose levels should be closely monitored during the first month of ACE inhibitor therapy. Thiazide therapy may unmask latent diabetes mellitus.

Elevated cholesterol and triglyceride levels may be associated with thiazide therapy.

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

Fluid and electrolyte imbalance. Patients on diuretic therapy require regular monitoring of serum electrolytes. Thiazides may cause disturbances in fluid and electrolyte balance (hypovolemia, hypokalemia, hyponatremia, hypochloremic alkalosis). Warning signs include dry mouth, thirst, weakness, lethargy, drowsiness, muscle pain and cramps, muscle fatigue, arterial hypotension, oliguria, tachycardia, and gastrointestinal disturbances (nausea, vomiting). In patients with edema during hot weather, hyponatremia of dilution may develop. Chloride deficiency is usually mild and does not require treatment. Thiazides increase urinary magnesium excretion, which may lead to hypomagnesemia.

Thiazides may reduce urinary calcium excretion and cause a slight transient increase in serum calcium. Marked hypercalcemia may indicate occult hyperparathyroidism. Thiazide diuretics should be discontinued before parathyroid function testing.

Hyperkalemia. ACE inhibitors may increase serum potassium levels due to suppression of aldosterone secretion. This effect is usually mild in patients with normal renal function. Risk factors for hyperkalemia include renal impairment, diabetes mellitus, concomitant use of potassium-sparing diuretics, potassium-containing dietary supplements (including salt substitutes), or drugs that may increase potassium levels (heparin, trimethoprim, co-trimoxazole [trimethoprim/sulfamethoxazole]), and especially aldosterone antagonists or angiotensin receptor blockers. If concomitant use of such agents is necessary, serum potassium and renal function should be monitored.

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

Hypersensitivity/angioedema. Angioedema (at any time during treatment) may occur rarely during ACE inhibitor therapy. Patients prescribed Lopril Bosnalék® H should be informed about the signs of angioedema so they can seek medical attention promptly (facial swelling, limb swelling, lip swelling, tongue swelling, pharyngeal and/or laryngeal swelling). If such a reaction occurs, the drug should be discontinued immediately; the patient should receive appropriate therapy and remain under medical supervision until symptoms completely resolve. Even in cases of isolated tongue swelling (without respiratory compromise), prolonged observation is required, as antihistamines and corticosteroids may be ineffective.

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

Patients with a history of angioedema unrelated to ACE inhibitor use are more susceptible to angioedema during ACE inhibitor therapy.

Concomitant use of ACE inhibitors with sacubitril/valsartan is contraindicated due to increased risk of angioedema. Treatment with sacubitril/valsartan may be initiated only 36 hours after the last dose of Lopril Bosnalék® H. Treatment with Lopril Bosnalék® H 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 racemizedotril, mTOR inhibitors (e.g., sirolimus, everolimus, temsirolimus), or vildagliptin increases the risk of angioedema (e.g., airway or tongue swelling, with or without respiratory distress). Caution should be exercised when initiating therapy with racemizedotril, mTOR inhibitors, or vildagliptin in patients already receiving ACE inhibitors.

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

Desensitization. In patients receiving ACE inhibitors, anaphylactic reactions may occur during desensitization procedures (e.g., insect venom immunotherapy). This can be avoided by temporarily discontinuing the ACE inhibitor.

Non-melanoma skin cancer (NMSC). Two epidemiological studies have shown an increased risk of non-melanoma skin cancer (basal cell carcinoma and squamous cell carcinoma) associated with cumulative exposure to hydrochlorothiazide. The photosensitizing effect of hydrochlorothiazide may be a potential mechanism for NMSC development. Patients taking hydrochlorothiazide should be informed about the risk of NMSC, advised to regularly check their skin for new lesions, and promptly report any suspicious skin changes. Such patients should be advised to take preventive measures to reduce exposure to sunlight and ultraviolet radiation. The use of hydrochlorothiazide should also be reconsidered in patients with a prior history of NMSC (see section "Side effects").

Neutropenia/agranulocytosis. Neutropenia/agranulocytosis, thrombocytopenia, and anemia, which are reversible upon discontinuation of the ACE inhibitor, may occur during ACE inhibitor therapy. In patients with normal renal function and no other risk factors, neutropenia is rare. Extreme caution is required when administering lisinopril to patients with autoimmune or collagen diseases, immunosuppressive therapy, or treatment with allopurinol or procainamide, especially in the presence of renal impairment. Serious infections resistant to intensive antibiotic therapy may develop in such patients; therefore, periodic blood cell counts should be performed, and patients should be informed to report any signs of infection.

Race. ACE inhibitors are more likely to cause angioedema in patients of African descent and may be less effective, possibly due to a more prevalent low-renin status in this population.

Cough. A persistent, non-productive cough has been reported with ACE inhibitor use, which resolves after discontinuation of therapy. A possible association between cough and ACE inhibitor use should be considered in the differential diagnosis of cough.

Antidoping test. Use of hydrochlorothiazide may lead to positive results in antidoping tests.

Choroidal effusion, acute myopia, and secondary angle-closure glaucoma. Medicinal products containing sulfonamide or sulfonamide derivatives may cause an idiosyncratic reaction leading to choroidal effusion with visual field defects, transient myopia, and acute angle-closure glaucoma. Symptoms include acute onset of decreased visual acuity or eye pain and usually occur within hours or weeks of starting the drug. Untreated acute angle-closure glaucoma may lead to permanent vision loss. The primary treatment is prompt discontinuation of the drug. If intraocular pressure remains uncontrolled, medical or surgical intervention may be 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 taking hydrochlorothiazide. Initial symptoms include dyspnea, fever, worsening lung condition, and hypotension. If ARDS is suspected, hydrochlorothiazide should be discontinued and appropriate treatment initiated. Hydrochlorothiazide should not be prescribed to patients who previously experienced ARDS after taking hydrochlorothiazide.

Use during pregnancy or breastfeeding.

The medicinal product is contraindicated in pregnant women or women planning pregnancy. Epidemiological data on teratogenic effects of ACE inhibitors during pregnancy indicate fetal toxicity (renal dysfunction, oligohydramnios, cranial hypoplasia) and neonatal complications (renal failure, arterial hypotension, hyperkalemia). Alternative antihypertensive therapy with an established safety profile during pregnancy should be selected when planning pregnancy. If pregnancy is confirmed during treatment with this drug, its use must be immediately discontinued and replaced with another medicinal product approved for use during pregnancy. In such cases, ultrasound monitoring of fetal renal and cranial function is recommended. Newborns whose mothers received ACE inhibitors should be examined for arterial hypotension.

Experience with hydrochlorothiazide use during pregnancy is limited. Hydrochlorothiazide crosses the placenta. Use of hydrochlorothiazide in the second and third trimesters may impair fetoplacental perfusion and lead to fetal and neonatal jaundice, electrolyte imbalances, and thrombocytopenia.

Hydrochlorothiazide should not be used to treat gestational edema, arterial or gestational hypertension, or preeclampsia in pregnant women, as instead of beneficial effects on disease course, it increases the risk of plasma volume reduction and decreased placental perfusion.

The use of the drug is contraindicated during breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

Like other antihypertensive agents, the combination of lisinopril/hydrochlorothiazide may slightly or moderately affect reaction speed due to adverse reactions, depending on individual patient sensitivity, especially at the beginning of therapy or during dose changes, and particularly if alcohol is consumed concurrently. Therefore, during the initial period of drug use (duration individually determined by the physician), patients should refrain from driving or operating machinery. Subsequent restrictions should be individually determined by the physician.

Dosage and Administration

Arterial Hypertension. The recommended dose is 1 tablet daily, taken at the same time each day. Generally, if the desired therapeutic effect is not achieved within 2–4 weeks, the dose may be increased to 2 tablets once daily.

Prior Diuretic Therapy. Symptomatic hypotension may occur at the initiation of Lopril BosnaLek® H. The occurrence of this condition is more likely in patients with dehydration and/or depletion of salt stores due to prior diuretic therapy. Therefore, it is recommended to discontinue diuretic treatment 2–3 days before starting Lopril BosnaLek® H. If this is not possible, therapy should be initiated with 5 mg of lisinopril.

Renal Impairment. Thiazide diuretics should not be administered in cases of severe renal impairment—they are ineffective when creatinine clearance is below 30 mL/min. Lopril BosnaLek® H is not used as initial therapy in patients with renal impairment.

Lopril BosnaLek® H may be used when creatinine clearance is > 30 and < 80 mL/min, but only after individual component dosing has been established. The recommended dose of lisinopril in mild renal impairment is 5–10 mg.

Elderly Patients. Dose adjustment is not required.

In clinical studies, the efficacy and tolerability of lisinopril and hydrochlorothiazide in combination therapy were similar in elderly and younger patients with arterial hypertension. Lisinopril, at daily doses of 20 to 80 mg, was equally effective in elderly individuals (aged 65 years and older) and younger patients. Monotherapy with lisinopril effectively reduced diastolic blood pressure, as did monotherapy with hydrochlorothiazide or atenolol; age did not affect the tolerability of lisinopril.

Children.

Safety and efficacy in pediatric patients have not been established; therefore, this medicinal product should not be used in pediatric practice.

Overdose.

Data on human overdose are limited.

Symptoms associated with angiotensin-converting enzyme (ACE) inhibitor overdose may include arterial hypotension, vascular collapse, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, and cough.

The most common signs of hydrochlorothiazide overdose are symptoms caused by decreased serum electrolyte levels (hypokalemia, hypochloremia, hyponatremia) as well as dehydration resulting from excessive diuresis. These may include tachycardia, arrhythmia, arterial hypotension, shock, weakness, confusion, disturbances of consciousness, depressed consciousness (including coma), dizziness, muscle spasms, seizures, paresthesia, exhaustion, nausea, vomiting, thirst, polyuria, oliguria, anuria, alkalosis, elevated blood urea nitrogen (mainly in renal impairment), and renal failure.

In patients receiving cardiac glycosides, hypokalemia may increase the risk of cardiac arrhythmias.

Treatment involves intravenous infusion of physiological saline. In cases of arterial hypotension, the patient should be placed in a supine position with low head elevation. If necessary, infuse angiotensin II and/or intravenous catecholamines. If the drug was recently ingested, measures should be taken to remove it from the body (gastric lavage, induction of emesis, administration of adsorbents or sodium sulfate). Lisinopril may be removed from the blood by hemodialysis. Bradycardia or significant vagal response may be alleviated with atropine. In cases of treatment-resistant bradycardia, a pacemaker may be indicated. Vital functions, electrolyte levels, and creatinine should be monitored.

Adverse Reactions

Lisinopril

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

Immune system disorders: anaphylactic/anaphylactoid reaction.

Endocrine system disorders: Parhon's syndrome (syndrome of inappropriate antidiuretic hormone secretion).

Metabolic disorders: hypoglycemia.

Psychiatric and nervous system disorders: dizziness, headache, syncope, paresthesia, loss of consciousness, taste disturbances, sleep disorders, mood changes, symptoms of depression, confusion, olfactory disorders, hallucinations.

Cardiovascular system disorders: orthostatic reactions including orthostatic hypotension, myocardial infarction or cerebrovascular accidents, possibly due to excessive reduction in arterial pressure in high-risk patients, palpitations, tachycardia, Raynaud's syndrome, flushing.

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

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

Hepatobiliary disorders: increased liver enzyme activity and bilirubin levels, hepatitis (hepatocellular or cholestatic), jaundice, liver failure.*

Skin and subcutaneous tissue disorders: rash, pruritus, hypersensitivity/angioneurotic edema of the face, limbs, lips, tongue, glottis and/or larynx; urticaria, alopecia, psoriasis, increased sweating, bullous eruption, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, cutaneous pseudolymphoma**.

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

Reproductive system disorders: impotence, gynecomastia.

General disorders: asthenia, fatigue.

Laboratory findings: increased blood urea and serum creatinine levels, hyperkalemia, hyponatremia.

* Hepatitis progressing to liver failure has been very rarely reported. If jaundice develops or liver enzymes increase during treatment with the combination of lisinopril/hydrochlorothiazide, the drug should be discontinued and the patient should remain under medical supervision.

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

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.

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

Psychiatric disorders: anxiety, depression, sleep disturbances.

Nervous system disorders: loss of appetite, paresthesia, pre-syncope.

Eye disorders: xanthopsia, transient visual disturbances, acute myopia, acute angle-closure glaucoma, choroidal effusion (cases of choroidal effusion with visual field defects have been reported after use of thiazide and thiazide-like diuretics; frequency is unknown).

Ear and labyrinth disorders: dizziness.

Cardiac disorders: orthostatic hypotension.

Vascular disorders: necrotizing vasculitis (vasculitis, cutaneous vasculitis).

Respiratory, thoracic and mediastinal disorders: respiratory insufficiency (including pneumonia and pulmonary edema). Very rarely – acute respiratory distress syndrome (ARDS) (see section "Special precautions").

Gastrointestinal disorders: gastric 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, exacerbation of systemic lupus erythematosus, urticaria, anaphylactic reactions, toxic epidermal necrolysis.

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

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

General disorders: fever, weakness.

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

Reporting suspected adverse reactions associated with the use of this medicinal product is important for determining the safety profile and supporting ongoing benefit-risk monitoring. Healthcare professionals, pharmacists, and patients are encouraged to report any suspected adverse reactions or lack of therapeutic effect to the email address of Bosnalijek d.d.: [email protected].

Shelf life. 3 years.

Storage conditions. Store out of reach of children at a temperature not exceeding 30 °C.

Packaging. 10 tablets per blister, 2 blisters per cardboard box.

Prescription status. Prescription only.

Manufacturer/Marketing Authorization Holder. Bosnalijek d.d.

Manufacturer's address and location of operations.
71000 Sarajevo, Yukicheva 53, Bosnia and Herzegovina.