Co-Diroton^® (Tablets) Instructions for Use

Marketing Authorization Holder

Gedeon Richter, Plc. (Hungary)

Manufactured By

Gedeon Richter Poland, Co. Ltd. (Poland)

Contact Information

GEDEON RICHTER Plc. (Hungary)

ATC Code

C09BA03 (Lisinopril and diuretics)

Active Substances

Hydrochlorothiazide (Rec.INN registered by WHO)

Lisinopril (Rec.INN registered by WHO)

Dosage Forms

	Co-Diroton®	Tablets 12.5 mg+10 mg: 30 pcs.
		Tablets 12.5 mg+20 mg: 30 pcs.

Dosage Form, Packaging, and Composition

Tablets light blue in color with a few inclusions of a darker color, round, flat-cylindrical, with a bevel; one side is engraved with the symbol “C43”.

Excipients: mannitol, indigo carmine aluminum lake (E132), pregelatinized starch, corn starch, calcium hydrogen phosphate dihydrate, partially pregelatinized starch, magnesium stearate.

10 pcs. – blisters (3) – cardboard packs.

Tablets light green in color with a few inclusions of a darker color, round, flat-cylindrical, with a bevel; one side is engraved with the symbol “C44”.

Excipients: mannitol, indigo carmine aluminum lake (E132), yellow iron oxide (E172), pregelatinized starch, corn starch, calcium hydrogen phosphate dihydrate, partially pregelatinized starch, magnesium stearate.

10 pcs. – blisters (3) – cardboard packs.

Clinical-Pharmacological Group

Antihypertensive drug

Pharmacotherapeutic Group

Agents acting on the renin-angiotensin system; angiotensin-converting enzyme (ACE) inhibitors, combinations; ACE inhibitors and diuretics

Pharmacological Action

The drug Co-Diroton^® is a fixed combination of hydrochlorothiazide, a thiazide diuretic, and lisinopril, an ACE inhibitor. Both components have complementary mechanisms of antihypertensive action.

Hydrochlorothiazide

The mechanism of action of thiazide diuretics (thiazides) is not fully understood. Thiazides block the reabsorption of sodium and chloride ions in the early part of the renal tubules. Thus, they increase the excretion of sodium and chloride and, consequently, the removal of water from the body.

As a result of the diuretic action of hydrochlorothiazide (HCT), the volume of circulating fluid decreases, which leads to an increase in plasma renin activity and aldosterone levels. This results in increased urinary excretion of potassium ions and a decrease in blood potassium levels (hypokalemia). Hydrochlorothiazide also increases the excretion of magnesium ions and decreases the urinary excretion of calcium ions. Thiazide diuretics reduce the renal excretion of uric acid and increase its blood levels.

Thiazide diuretics also reduce carbonic anhydrase activity by enhancing the excretion of bicarbonate ions. However, this effect is usually mild and does not affect urine pH.

At maximum therapeutic doses, the diuretic/natriuretic effect of all thiazide diuretics is approximately the same. Natriuresis and diuresis occur within 2 hours and reach their maximum approximately 4 hours after administration.

The duration of the diuretic effect of hydrochlorothiazide is from 6 to 12 hours.

Hydrochlorothiazide has an antihypertensive effect. Thiazide diuretics do not affect normal blood pressure.

Non-melanoma skin cancer (NMSC) Based on available data from epidemiological studies, a relationship has been described between the cumulative dose of HCT and NMSC. One study included 71,533 cases of basal cell carcinoma (BCC) and 8,629 cases of squamous cell carcinoma (SCC); the control group consisted of 1,430,833 and 172,462 control subjects, respectively. The use of HCT in high doses (cumulative dose ≥50,000 mg) was associated with an adjusted odds ratio (OR) of 1.29 (95% confidence interval (CI): 1.23-1.35) for BCC and 3.98 (95% CI: 3.68-4.31) for SCC. A clear dose-response relationship was observed for both BCC and SCC risk. Another study described a possible relationship between lip cancer (SCC) and HCT intake: 633 cases of lip cancer were compared with 63,067 control subjects using a random sampling method. A dose-response relationship was demonstrated for the risk of lip cancer with an OR of 2.1 (95% CI: 1.7-2.6); at a higher cumulative HCT dose (about 25,000 mg) the OR increased to 3.9 (3.0-4.9), and at the highest cumulative dose (about 100,000 mg) the OR was 7.7 (5.7-10.5) (see also the “Special Instructions” section).

Lisinopril

Lisinopril is an ACE inhibitor that suppresses the conversion of angiotensin I to angiotensin II. The decrease in angiotensin II concentration leads to a direct reduction in aldosterone secretion. Lisinopril inhibits the degradation of bradykinin and increases the synthesis of prostaglandins. It reduces systemic vascular resistance, blood pressure, preload, and pulmonary capillary pressure. In patients with chronic heart failure (CHF), it increases cardiac output and improves myocardial tolerance to physical exertion. It dilates arteries to a greater extent than veins. Some effects are explained by its action on the tissue renin-angiotensin system. With long-term use, it reduces hypertrophy of the myocardium and walls of resistive arteries.

Lisinopril improves blood supply to the ischemic myocardium.

In patients with CHF, ACE inhibitors increase life expectancy; in patients who have had a myocardial infarction without clinical manifestations of heart failure, Lisinopril slows the progression of left ventricular dysfunction.

The onset of the antihypertensive effect is within 1 hour after oral administration. The maximum effect is achieved within 6-7 hours; the duration of the effect is 24 hours. In patients with arterial hypertension, the effect appears within the first days after starting treatment; stabilization of the effect occurs within 1-2 months of treatment. Cases of a marked increase in blood pressure after abrupt withdrawal of the drug have not been reported. Lisinopril provides both a reduction in blood pressure and a decrease in albuminuria. In patients with hyperglycemia, the drug helps restore the function of damaged glomerular endothelium. In patients with diabetes mellitus, Lisinopril does not affect plasma glucose concentration; taking the drug does not lead to an increased incidence of hypoglycemia.

Pharmacokinetics

Hydrochlorothiazide

Absorption and Distribution

Hydrochlorothiazide is incompletely but fairly rapidly absorbed from the gastrointestinal tract. After oral administration of a 100 mg dose, C_max of hydrochlorothiazide in plasma is reached in 1.5-2.5 hours. At the peak of diuretic activity (approximately 4 hours after administration), the concentration of hydrochlorothiazide in plasma is 2 µg/ml. Plasma protein binding is 40%.

Hydrochlorothiazide crosses the placental barrier and is excreted in breast milk; it does not cross the blood-brain barrier.

Metabolism

Hydrochlorothiazide is not metabolized in the human body.

Elimination

The primary route of elimination is renal (filtration and secretion) unchanged. Approximately 61% of the orally administered dose is excreted within 24 hours. In patients with normal renal function, T_1/2 ranges from 5.6 to 14.8 hours (average 6.4 hours).

Pharmacokinetics in Special Patient Groups

Renal impairment. In patients with moderate renal impairment, the T_1/2 of hydrochlorothiazide averages 11.5 hours, and in patients with CrCl less than 30 ml/min, it is 20.7 hours.

Lisinopril

Absorption

About 25% of lisinopril is absorbed from the gastrointestinal tract after oral administration. Food intake does not affect absorption. Absorption averages 30%, bioavailability is 29%.

Distribution

C_max is reached 6-8 hours after oral administration. The degree of binding to plasma proteins is low. Lisinopril poorly crosses the blood-brain barrier.

Metabolism

Lisinopril is not biotransformed in the human body.

Elimination

Lisinopril is excreted by the kidneys unchanged. T_1/2 is 12 hours.

Pharmacokinetics in Special Patient Groups

Patients with chronic heart failure. In patients with CHF, the absorption and clearance of lisinopril are reduced. In this category of patients, the absolute bioavailability of lisinopril decreases by approximately 16%; however, AUC increases by an average of 125% compared to healthy volunteers.

Patients with renal impairment. Impaired renal function leads to an increase in AUC and T_1/2 of lisinopril, but these changes become clinically significant only when GFR falls below 30 ml/min/1.73 m². In mild and moderate renal impairment (CrCl from 30 to 80 ml/min), the mean AUC increases by 13%, while in severe renal impairment (CrCl from 5 to 30 ml/min), an increase in mean AUC of 4.5 times is observed.

Patients with hepatic impairment. In patients with liver cirrhosis, the absorption of lisinopril is reduced (by approximately 30%), but the exposure (AUC) of the drug increases (by approximately 50%) compared to healthy volunteers due to reduced clearance.

Elderly patients (over 65 years). In elderly patients, the plasma concentration and AUC of lisinopril are 2 times higher than in young patients.

Indications

• Arterial hypertension (in patients for whom combination therapy is indicated).

ICD codes

Dosage Regimen

Orally.

Essential arterial hypertension

The fixed combination is not intended for initial therapy. The fixed-dose combination drug can replace the combination of 10 mg or 20 mg lisinopril and 12.5 mg HCT in patients whose condition has been stabilized on therapy with individual drugs (in doses similar to those in the combination drug).

The usual dose is 1 tablet per day. Co-Diroton^® should be taken every day at approximately the same time. If the desired therapeutic effect is not achieved after 2-4 weeks of use, the dose can be increased to 2 tablets per day.

The maximum daily dose of HCT is 100 mg, and of lisinopril is 80 mg.

If a change in the dose of one of the active substances in the Co-Diroton^® combination drug is required (for example, due to a newly diagnosed disease, change in the patient’s condition, or drug interaction), an individual selection of doses of the individual components is necessary.

Renal impairment

Thiazide diuretics are not recommended for use in patients with impaired renal function; thiazides are ineffective at CrCl values of 30 ml/min or below (i.e., in severe renal failure).

Co-Diroton^® should not be used as initial therapy in patients with renal impairment.

In patients with CrCl 30-80 ml/min, Co-Diroton^® can be used only after individual dose selection of each of the drug’s components. The recommended dose of lisinopril when used as monotherapy in mild renal impairment is 5-10 mg.

Prior diuretic therapy

After taking the first dose of Co-Diroton^®, clinically significant arterial hypotension may develop. This effect is most likely in patients with water and electrolyte balance disorders due to prior diuretic therapy. Diuretic intake should be discontinued 2-3 days before starting therapy with Co-Diroton^®. If this is not possible, treatment should be started with lisinopril monotherapy at a dose of 5 mg.

Elderly patients

Dose adjustment is not required.

Children

The safety and efficacy of this medicinal product in children have not been established.

Adverse Reactions

The adverse drug reactions (ADRs) listed below, reported during the use of lisinopril and/or hydrochlorothiazide, are distributed by frequency of occurrence: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10,000 to <1/1000), very rare (<1/10,000), frequency not known (cannot be estimated from the available data).

Among ADRs, cough, dizziness, arterial hypotension, and headache were most frequently observed (occurring in 1-10% of patients). According to clinical studies, adverse effects were moderate, transient, and in most cases did not require discontinuation of therapy.

Contraindications

• Hypersensitivity to hydrochlorothiazide, other sulfonamide derivatives, lisinopril, other ACE inhibitors and/or any of the excipients of the drug;
• History of angioedema, including that associated with the use of ACE inhibitors;
• Hereditary or idiopathic angioedema;
• Severe renal failure (creatinine clearance less than 30 ml/min);
• Anuria;
• Severe hepatic failure or hepatic encephalopathy (risk of hepatic coma);
• Refractory hypokalemia, hyponatremia, hypercalcemia;
• Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus or moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area);
• Concomitant use with angiotensin II receptor antagonists (ARA II) in patients with diabetic nephropathy;
• Concomitant use with neutral endopeptidase inhibitors (e.g., drugs containing sacubitril) due to the high risk of angioedema;
• Pregnancy;
• Breastfeeding period;
• Children under 18 years of age.

With caution

Arterial hypotension, bilateral renal artery stenosis or stenosis of the artery of a solitary kidney; renovascular hypertension; mild to moderate renal impairment; status after kidney transplantation; aortic stenosis, mitral stenosis, hypertrophic obstructive cardiomyopathy; chronic heart failure; coronary artery disease or cerebrovascular diseases; systemic connective tissue diseases (including systemic lupus erythematosus, scleroderma), bone marrow depression, immunosuppressive therapy, concomitant use of allopurinol or procainamide, or a combination of these complicating factors (risk of neutropenia and agranulocytosis); mild to moderate hepatic impairment, progressive liver diseases; diabetes mellitus; hyperkalemia; concomitant use with potassium-sparing diuretics, potassium preparations, potassium-containing salt substitutes; concomitant use with lithium preparations; burdened allergic history; concomitant desensitization with hymenoptera venom allergen; concomitant LDL apheresis procedure using dextran sulfate; hemodialysis using high-flux membranes (such as AN69^®); conditions accompanied by a decrease in circulating blood volume (including during diuretic therapy, salt-restricted diet, dialysis, diarrhea or vomiting); use during major surgical interventions or during general anesthesia; hypokalemia; hyponatremia; hypercalcemia; prolonged QT interval on ECG; concomitant use of drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type or prolong the QT interval on ECG; concomitant use of drugs that can cause hypokalemia, cardiac glycosides; history of allergic reactions to penicillin; hyperparathyroidism; hyperuricemia, gout; use in patients of the Black race; use in elderly patients (over 65 years of age).

Use in Pregnancy and Lactation

The use of the drug Co-Diroton^® during pregnancy and breastfeeding is contraindicated.

Hydrochlorothiazide

Pregnancy

There is limited experience with the use of hydrochlorothiazide during pregnancy (especially in the first trimester). Preclinical data on safety are insufficient.

Hydrochlorothiazide crosses the placental barrier and is detected in umbilical cord blood. Considering the mechanism of pharmacological action of hydrochlorothiazide, its use in the second and third trimesters of pregnancy may impair fetoplacental perfusion and lead to the development of complications in the fetus and newborn, such as jaundice, water-electrolyte imbalance disorders and thrombocytopenia. Cases of thrombocytopenia in newborns whose mothers received thiazide diuretics have been described.

The use of hydrochlorothiazide during pregnancy is contraindicated. Hydrochlorothiazide should not be used to treat pregnancy-induced hypertension in the second half of pregnancy (edema, arterial hypertension or pre-eclampsia), as it increases the risk of decreased circulating blood volume and placental hypoperfusion, but does not have a beneficial effect on the course of these pregnancy complications. Diuretics do not prevent the development of pregnancy-induced hypertension.

Breastfeeding period

Hydrochlorothiazide passes into breast milk, therefore its use during breastfeeding is contraindicated. If the use of hydrochlorothiazide during lactation is absolutely necessary, breastfeeding should be discontinued.

Lisinopril

Pregnancy

The use of lisinopril during pregnancy is contraindicated. If pregnancy is established, the drug should be discontinued as soon as possible. The use of ACE inhibitors in the second and third trimesters of pregnancy has an adverse effect on the fetus (possible marked decrease in blood pressure, renal failure, hyperkalemia, skull bone hypoplasia, intrauterine death). There are no data on negative effects of the drug on the fetus in case of use in the first trimester. Newborns and infants who have been exposed to ACE inhibitors in utero should be monitored for timely detection of marked hypotension, oliguria, hyperkalemia.

Breastfeeding period

Breastfeeding should be discontinued during treatment with Co-Diroton^®.

Use in Hepatic Impairment

With caution hepatic impairment.

Use in Renal Impairment

Contraindicated in severe renal failure (creatinine clearance less than 30 ml/min).

With caution: bilateral renal artery stenosis, stenosis of the artery of a solitary kidney with progressive azotemia, status after kidney transplantation, renal failure (creatinine clearance more than 30 ml/min).

Pediatric Use

Contraindicated in children and adolescents under 18 years of age.

Geriatric Use

Use with caution in elderly patients.

Special Precautions

The drug Co-Diroton^® should not be used to relieve a hypertensive crisis.

Alcohol

It is not recommended to consume alcoholic beverages during treatment with Co-Diroton^®, as alcohol enhances its antihypertensive effect.

Hydrochlorothiazide

Renal impairment

In patients with renal impairment, Hydrochlorothiazide may cause azotemia. In renal failure, accumulation of hydrochlorothiazide is possible.

In patients with reduced renal function, periodic monitoring of creatinine clearance is necessary. If renal function impairment progresses and/or oliguria (anuria) occurs, Hydrochlorothiazide should be discontinued.

Hepatic impairment

When using thiazide diuretics in patients with hepatic impairment, hepatic encephalopathy may develop. The use of thiazides is contraindicated in patients with severe hepatic failure or hepatic encephalopathy. In patients with mild to moderate hepatic impairment and/or progressive liver diseases, Hydrochlorothiazide should be used with caution, since even a slight change in water-electrolyte balance and accumulation of ammonium in the blood serum can cause hepatic coma. If symptoms of encephalopathy appear, diuretics should be discontinued immediately.

Water-electrolyte balance and metabolic disorders

Thiazide diuretics (including Hydrochlorothiazide) can cause a decrease in circulating blood volume (hypovolemia) and disturbances in water-electrolyte balance (including hypokalemia, hyponatremia, hypochloremic alkalosis). Clinical symptoms of water-electrolyte balance disorders are dry mouth, thirst, weakness, lethargy, fatigue, drowsiness, restlessness, muscle pain or cramps, muscle weakness, marked decrease in blood pressure, oliguria, tachycardia, arrhythmia and gastrointestinal disorders (such as nausea and vomiting). In patients receiving hydrochlorothiazide therapy (especially during long-term course treatment), clinical symptoms of water-electrolyte balance disorders should be regularly identified and blood electrolyte levels should be monitored.

Sodium

All diuretic drugs can cause hyponatremia, sometimes leading to serious complications. Hyponatremia and hypovolemia can lead to dehydration and orthostatic hypotension. Concomitant decrease in chloride ions can lead to secondary compensatory metabolic alkalosis, but the frequency and severity of this effect are insignificant. It is recommended to determine plasma sodium ion levels before starting treatment and regularly monitor this indicator while taking hydrochlorothiazide.

Potassium

When using thiazide and thiazide-like diuretics, there is a risk of a sharp decrease in plasma potassium levels and the development of hypokalemia (potassium concentration less than 3.4 mmol/l). Hypokalemia increases the risk of cardiac rhythm disorders (including severe arrhythmias) and enhances the toxic effect of cardiac glycosides. In addition, hypokalemia (as well as bradycardia) is a condition that contributes to the development of polymorphic ventricular tachycardia of the “torsades de pointes” type, which can be fatal.

Hypokalemia is most dangerous for the following groups of patients: elderly persons, patients simultaneously receiving therapy with antiarrhythmic and non-antiarrhythmic drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type or prolong the QT interval on ECG, patients with hepatic impairment, coronary artery disease, chronic heart failure. In addition, patients with a prolonged QT interval are at increased risk. It does not matter whether this prolongation is caused by congenital causes or by the action of drugs.

In all the cases described above, it is necessary to avoid the risk of hypokalemia and regularly monitor plasma potassium levels. The first measurement of blood potassium ion levels should be performed within the first week of starting treatment. If hypokalemia occurs, appropriate treatment should be prescribed. Hypokalemia can be corrected by using potassium-containing drugs or by eating foods rich in potassium (dried fruits, fruits, vegetables).

Calcium

Thiazide diuretics can reduce the renal excretion of calcium ions, leading to a slight and temporary increase in plasma calcium levels. In some patients with long-term use of thiazide diuretics, pathological changes in the parathyroid glands with hypercalcemia and hyperphosphatemia have been observed, but without typical complications of hyperparathyroidism (nephrolithiasis, decreased bone mineral density, peptic ulcer). Severe hypercalcemia may be a manifestation of previously undiagnosed hyperparathyroidism. The drug should be used with caution in patients with hyperparathyroidism

Due to their effect on calcium metabolism, thiazides can affect laboratory parameters of parathyroid gland function. Thiazide diuretics (including Hydrochlorothiazide) should be discontinued before testing parathyroid gland function.

Magnesium

Thiazides have been found to increase renal excretion of magnesium, which can lead to hypomagnesemia. The clinical significance of hypomagnesemia remains unclear.

Glucose

Treatment with thiazide diuretics may impair glucose tolerance. When using hydrochlorothiazide in patients with manifest or latent diabetes mellitus, blood glucose concentration should be regularly monitored. Dose adjustment of hypoglycemic drugs may be required.

Uric acid

In patients with gout, the frequency of attacks may increase or the course of gout may worsen. Careful monitoring of patients with gout and impaired uric acid metabolism (hyperuricemia) is necessary.

Lipids

When using hydrochlorothiazide, the concentration of cholesterol and triglycerides in plasma may increase.

Acute myopia/secondary angle-closure glaucoma

Hydrochlorothiazide can cause an idiosyncratic reaction leading to the development of acute myopia and an acute attack of secondary angle-closure glaucoma. Symptoms include: sudden decrease in visual acuity or eye pain, which usually appear within several hours or weeks of starting hydrochlorothiazide therapy. If left untreated, acute angle-closure glaucoma can lead to irreversible vision loss. If symptoms appear, hydrochlorothiazide should be discontinued as soon as possible. If intraocular pressure remains uncontrolled, emergency medical treatment or surgery may be required. Risk factors for the development of acute angle-closure glaucoma are: history of allergic reaction to sulfonamides or penicillin.

Immune system disorders

There are reports that thiazide diuretics (including Hydrochlorothiazide) can cause exacerbation or progression of systemic lupus erythematosus, as well as lupus-like reactions.

In patients receiving thiazide diuretics, hypersensitivity reactions may occur even in the absence of a history of allergic reactions or bronchial asthma.

Photosensitivity

There is information on cases of photosensitivity reactions when taking thiazide diuretics. If photosensitivity occurs while taking hydrochlorothiazide, treatment should be discontinued. If continuation of the diuretic is necessary, the skin should be protected from exposure to sunlight or artificial ultraviolet rays.

Non-melanoma skin cancer

In two epidemiological studies conducted using the Danish National Cancer Patient Registry, an increased risk of non-melanoma skin cancer (NMSC) [basal cell skin cancer (BCC) and squamous cell carcinoma (SCC)] was recorded with increasing cumulative dose of hydrochlorothiazide (HCT).

The photosensitizing effect of HCT may act as a possible mechanism for the development of NMSC.

Patients taking HCT should be informed about the risk of developing NMSC and recommended to regularly assess the condition of their skin to detect new lesions, as well as to promptly report any suspicious skin changes. To minimize the risk of skin cancer, patients should be recommended to take preventive measures, in particular, to limit exposure to sunlight and UV rays, and in case of exposure, to use appropriate protective equipment. Suspicious skin changes should be carefully examined; histological examination of biopsy specimens may be used. In addition, the possibility of using HCT in patients with a history of NMSC should be reconsidered (see also the section “Adverse Reactions”).

Acute respiratory toxicity

Very rare cases of severe acute respiratory toxicity, including acute respiratory distress syndrome (ARDS), have been reported after taking hydrochlorothiazide. Pulmonary edema usually develops within a few minutes or hours after taking hydrochlorothiazide. At the onset of the disease, symptoms include shortness of breath, fever, worsening lung condition and arterial hypotension. If ARDS is suspected, the drug Co-Diroton^® should be discontinued and appropriate treatment should be carried out. Hydrochlorothiazide should not be prescribed to patients who have previously experienced acute respiratory distress syndrome after taking hydrochlorothiazide or another thiazide diuretic.

Other

Hydrochlorothiazide should be used with particular caution in patients with severe atherosclerosis of the cerebral and coronary arteries.

Thiazide diuretics may reduce the amount of iodine bound to plasma proteins without showing signs of thyroid dysfunction.

Lisinopril

Symptomatic arterial hypotension

Most often, a marked decrease in blood pressure is associated with hypovolemia caused by the use of diuretics, a reduced amount of salt in the diet, dialysis, diarrhea or vomiting (see sections “Drug Interactions”, “Adverse Reactions”). In patients with CHF, regardless of whether it is associated with renal failure, arterial hypotension may develop. It has been found that in patients with severe heart failure, this condition occurs more often in connection with the prescription of high doses of diuretics, hyponatremia or impaired renal function. Such patients require careful medical supervision (it is necessary to carefully select the doses of lisinopril and diuretics). The same instructions apply to patients with coronary artery disease and cerebrovascular insufficiency, in whom a sharp decrease in blood pressure can lead to myocardial infarction or stroke.

In case of a significant decrease in blood pressure, the patient should be placed in a supine position, and if necessary, intravenous 0.9% sodium chloride solution should be administered.

A transient hypotensive reaction is not a contraindication for taking the next dose of lisinopril.

In patients with CHF but with normal or low blood pressure, the use of lisinopril may lead to a decrease in blood pressure; this is usually not a reason to discontinue the drug. If arterial hypotension becomes symptomatic, a dose reduction or discontinuation of treatment with the drug is necessary. In patients at risk of developing symptomatic arterial hypotension (on a low-salt or salt-free diet), regardless of the presence of hyponatremia, as well as in patients receiving high doses of diuretics, hypovolemia or sodium deficiency must be compensated before starting treatment.

Blood pressure should be monitored when taking the first dose of lisinopril.

Acute Myocardial Infarction

Standard treatment (thrombolytics, acetylsalicylic acid, beta-blockers) is recommended. Lisinopril can be used concomitantly with intravenous nitroglycerin or transdermal nitroglycerin. The use of the drug Co-Diroton^® in patients with acute myocardial infarction is not recommended due to insufficient clinical experience.

Renal Impairment

In patients with CHF, a significant decrease in blood pressure during ACE inhibitor therapy may lead to worsening renal function. Cases of acute renal failure have been reported.

In patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney during ACE inhibitor use, an increase in serum urea and creatinine levels has been observed; usually, these disturbances were transient and resolved after discontinuation of therapy. They occurred more frequently in patients with renal insufficiency. The drug should be prescribed with caution in renovascular hypertension.

Hypersensitivity, Angioedema

In rare cases, during the use of ACE inhibitors, including Lisinopril, angioedema of the face, extremities, lips, tongue, glottis, and/or larynx has been observed. In such cases, immediate discontinuation of lisinopril is required; patient monitoring is indicated until symptoms completely resolve. Usually, angioedema of the face and lips is temporary and does not require treatment; however, antihistamines may be prescribed.

Laryngeal angioedema can be fatal. Swelling of the tongue, glottis, or larynx can lead to secondary airway obstruction. In such a case, it is necessary to immediately administer 0.3-0.5 ml of 1:1000 adrenaline solution subcutaneously and ensure airway patency.

In rare cases, intestinal angioedema has developed during therapy with ACE inhibitors. In these patients, abdominal pain was noted as an isolated symptom or in combination with nausea or vomiting, in some cases without preceding facial angioedema and with normal C1-esterase levels. The diagnosis was established using computed tomography of the abdomen, ultrasound, or during surgery. Symptoms resolved after discontinuation of ACE inhibitors. Therefore, in patients with abdominal pain receiving ACE inhibitors, the possibility of intestinal angioedema should be considered in the differential diagnosis.

In patients with a history of angioedema not associated with ACE inhibitor use, the risk of its development when using ACE inhibitors is higher (see “Contraindications”).

Anaphylactic Reactions in Patients on Hemodialysis

The use of the HCT/linisopril combination is not indicated in patients with renal failure undergoing hemodialysis.

Anaphylactic reactions have occurred in patients undergoing hemodialysis using high-flux dialysis membranes (e.g., AN69) and during LDL apheresis with dextran sulfate, who were simultaneously receiving ACE inhibitors. In such patients, the use of other dialysis membranes or other antihypertensive drugs is indicated.

Anaphylactic Reactions Associated with LDL Apheresis

In very rare cases, life-threatening anaphylactic reactions have developed during ACE inhibitor use in patients who were also undergoing LDL apheresis with dextran sulfate. Such complications can be avoided by temporarily discontinuing ACE inhibitors before each apheresis procedure.

Anaphylactic Reactions Associated with Desensitization to Hymenoptera Venom

In very rare cases, life-threatening anaphylactic reactions may develop in patients taking ACE inhibitors during desensitization to hymenoptera venom, so ACE inhibitors should be temporarily discontinued before desensitization is performed.

Cough

ACE inhibitor therapy may cause a cough, which should be considered during differential diagnosis. A persistent dry cough usually resolves after discontinuation of ACE inhibitors. When conducting a differential diagnosis of the causes of a dry cough, cough caused by ACE inhibitor use should also be considered.

Surgical Interventions/General Anesthesia

The use of antihypertensive drugs during major surgery or general anesthesia may lead to suppression of angiotensin II formation due to compensatory renin secretion.

A significant decrease in blood pressure associated with this effect can be prevented by increasing the circulating blood volume.

Patients taking ACE inhibitors should inform the surgeon/anesthesiologist before undergoing surgery (including dental procedures).

Serum Potassium

Cases of hyperkalemia have been reported.

Risk factors for hyperkalemia include renal failure, diabetes mellitus, therapy with potassium-sparing diuretics (spironolactone, triamterene, and amiloride), use of potassium preparations and potassium-based salt substitutes, especially in patients with impaired renal function.

If combined use of lisinopril and these drugs is necessary, regular monitoring of serum potassium concentration is indicated.

Dual Blockade of the RAAS

Concomitant use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren has been shown to increase the risk of arterial hypotension, hyperkalemia, and impaired renal function (including acute renal failure). Therefore, combined use of ACE inhibitors, angiotensin II receptor blockers, or aliskiren for dual blockade of the RAAS is not recommended.

If there are absolute indications for dual blockade of the RAAS, it should be carried out under the close supervision of a specialist with frequent monitoring of renal function, electrolyte levels, and blood pressure.

Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Neutropenia/Agranulocytosis/Thrombocytopenia/Anemia

Neutropenia/agranulocytosis, thrombocytopenia, and anemia may occur during ACE inhibitor use. In patients with normal renal function and no other complicating factors, neutropenia is rare. Co-Diroton^® should be prescribed with particular caution to patients with systemic connective tissue diseases, those taking immunosuppressants, allopurinol, or procainamide, or with a combination of these risk factors, especially patients with impaired renal function. Some patients have developed severe infections, in some cases resistant to intensive antibiotic therapy. When prescribing Co-Diroton^® to such patients, periodic monitoring of the white blood cell count in plasma is recommended. Patients should report any signs of infectious diseases (e.g., sore throat, fever) to their doctor.

Mitral Stenosis/Aortic Stenosis/Hypertrophic Cardiomyopathy

ACE inhibitors should be prescribed with caution to patients with mitral stenosis, as well as to patients with left ventricular outflow tract obstruction (aortic stenosis, hypertrophic cardiomyopathy).

Hepatic Failure

Very rarely, cholestatic jaundice has occurred during ACE inhibitor use. With the progression of this syndrome, fulminant liver necrosis develops, sometimes with a fatal outcome. The mechanism of development of this syndrome is unclear. If jaundice or a significant increase in liver enzyme activity occurs during ACE inhibitor use, Co-Diroton^® should be discontinued and the patient carefully monitored.

Diabetes Mellitus

When using lisinopril in patients with diabetes mellitus receiving oral hypoglycemic agents or insulin, blood glucose concentration should be regularly monitored during the first month of therapy.

Kidney Transplantation

There is no experience with the use of lisinopril in patients who have recently undergone kidney transplantation.

Elderly Patients

In elderly patients, the use of standard doses leads to a higher concentration of lisinopril in the blood, so special caution is required when determining the dose, despite the fact that no differences in the antihypertensive effect of lisinopril between elderly and young patients have been identified.

Ethnic Differences

In patients of Black race, angioedema develops more frequently during ACE inhibitor use compared to other races. ACE inhibitors may have a less pronounced antihypertensive effect in patients of Black race compared to other races. This difference may be due to the fact that Black patients with arterial hypertension more often have low renin activity.

Effect on the Ability to Drive and Operate Machinery

During treatment with Co-Diroton^®, a slight or moderate effect on the ability to drive vehicles and operate machinery may be observed. Difficulties in driving or operating machinery are individual and occur more often at the beginning of treatment or when changing the drug dose. The possibility of dizziness and fatigue should also be taken into account.

Overdose

Lisinopril

Data on overdose in humans are limited.

Symptoms arterial hypotension, circulatory shock, electrolyte imbalance, renal failure, hyperventilation, tachycardia, palpitations, bradycardia, dizziness, anxiety, cough, increased diuresis, depression of consciousness (up to coma), convulsions, paresis, cardiac arrhythmias, renal failure. Hypokalemia may exacerbate arrhythmias in patients receiving digoxin.

Treatment infusion of saline solution. If arterial hypotension develops, the patient should be placed on their back. If necessary, infusion of angiotensin II and/or intravenous administration of catecholamines is indicated. If the drug was taken recently, measures aimed at removing lisinopril (e.g., induction of vomiting, gastric lavage, administration of adsorbents and sodium sulfate) are indicated. Lisinopril can be removed from the systemic circulation by hemodialysis (see the “Special Instructions” section). For the correction of bradycardia or pronounced vagal reactions, atropine administration is indicated. If bradycardia resistant to therapy develops, the installation of a pacemaker is indicated. Vital signs, electrolyte levels, and serum creatinine should be carefully monitored.

Hydrochlorothiazide

Symptoms. The most common manifestations of hydrochlorothiazide overdose are increased diuresis, accompanied by acute fluid loss (dehydration) and electrolyte disturbances (hypokalemia, hyponatremia, hypochloremia). Hydrochlorothiazide overdose may manifest with the following symptoms

• from the cardiovascular system – tachycardia, decreased blood pressure, shock;
• from the nervous system – weakness, confusion, dizziness and calf muscle cramps, paresthesia, impaired consciousness, fatigue;
• from the gastrointestinal tract – nausea, vomiting, thirst;
• from the kidneys and urinary tract – polyuria, oliguria or anuria (due to hemoconcentration);
• laboratory parameters – hypokalemia, hyponatremia, hypochloremia, alkalosis, increased blood urea nitrogen (especially in patients with renal failure).

Treatment. In case of overdose, symptomatic and supportive therapy is performed. If the drug was taken recently, induction of vomiting or gastric lavage is indicated to remove hydrochlorothiazide. Absorption of hydrochlorothiazide can be reduced by oral administration of activated charcoal. In case of decreased blood pressure or shock, the circulating blood volume should be replenished by administration of plasma-substituting fluids and electrolyte deficits (potassium, sodium). For respiratory disturbances, oxygen inhalation or mechanical ventilation is indicated. Water-electrolyte balance (especially serum potassium levels) and renal function should be monitored until they normalize.

There is no specific antidote. Hydrochlorothiazide is removed by hemodialysis, but the extent of its removal has not been established.

Drug Interactions

Hydrochlorothiazide

Not Recommended Drug Combinations

Lithium preparations

With simultaneous use of hydrochlorothiazide and lithium preparations, the renal clearance of lithium decreases, which can lead to an increase in plasma lithium concentration and an increase in its toxicity. If concomitant use of hydrochlorothiazide is necessary, the dose of lithium preparations should be carefully selected, plasma lithium concentration should be regularly monitored, and the drug dose should be adjusted accordingly.

Drug Combinations Requiring Special Attention

Drugs that can cause polymorphic ventricular tachycardia of the “torsades de pointes” type

Due to the increased risk of ventricular arrhythmias, especially polymorphic ventricular tachycardia of the “torsades de pointes” type (risk factor – hypokalemia), Hydrochlorothiazide should be used with particular caution simultaneously with such drugs as

• class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide. procainamide);
• class III antiarrhythmic drugs (dofetilide, ibutilide, bretylium tosilate), sotalol, dronedarone, amiodarone;
• Other (non-antiarrhythmic) drugs such as:
  • antipsychotics – phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpiride, tiapride), butyrophenones (droperidol, haloperidol); pimozide, sertindole;
  • antidepressants – tricyclic antidepressants, selective serotonin reuptake inhibitors (citalopram, escitalopram);
  • antibacterial agents – fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin); macrolides (erythromycin with intravenous administration, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole;
  • antifungal agents – azoles (voriconazole, itraconazole, ketoconazole, fluconazole);
  • antimalarial agents (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);
  • antiprotozoal agents (pentamidine with parenteral administration);
  • antianginal agents (ranolazine, bepridil);
  • antineoplastic agents (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus);
  • antiemetics (domperidone, ondansetron);
  • agents affecting gastrointestinal motility (cisapride);
  • antihistamines (astemizole; terfenadine; mizolastine);
  • other drugs (anagrelide, vasopressin, diphemanil metilsulfate, ketanserin, probucol, propofol, sevoflurane, terlipressin, terodiline, cilostazol).

Plasma potassium levels should be determined and, if necessary, corrected before starting combined therapy with hydrochlorothiazide and the drugs listed above. Monitoring of the patient’s clinical condition, plasma electrolyte levels, and ECG parameters is necessary. In patients with hypokalemia, drugs that do not cause polymorphic ventricular tachycardia of the “torsades de pointes” type should be used.

Drugs that can increase the QT interval

Concomitant use of hydrochlorothiazide with drugs that can increase the QT interval should be based on a careful assessment for each patient of the expected benefit versus the potential risk (possible increased risk of polymorphic ventricular tachycardia of the “torsades de pointes” type). When using such combinations, regular ECG recording (to detect QT interval prolongation) and monitoring of blood potassium levels are necessary.

Drugs that can cause hypokalemia: amphotericin B (with intravenous administration), gluco- and mineralocorticoids (with systemic use), tetracosactide (ACTH), glycyrrhizic acid (carbenoxolone, preparations containing licorice root), laxatives stimulating intestinal motility

Increased risk of hypokalemia with simultaneous use with hydrochlorothiazide (additive effect). Regular monitoring of plasma potassium levels is necessary, and correction if needed. During hydrochlorothiazide therapy, it is recommended to use laxatives that do not stimulate intestinal motility.

Cardiac glycosides

Hypokalemia and hypomagnesemia caused by the action of thiazide diuretics enhance the toxicity of cardiac glycosides. With simultaneous use of hydrochlorothiazide and cardiac glycosides, plasma potassium concentration and ECG parameters should be regularly monitored, and therapy should be adjusted if necessary.

Drug Combinations Requiring Attention

Other antihypertensive drugs

Potentiation of the antihypertensive effect of hydrochlorothiazide (additive effect). It may be necessary to adjust the dose of concurrently prescribed antihypertensive drugs.

It is recommended to discontinue hydrochlorothiazide 2-3 days before starting ACE inhibitor therapy to prevent the development of symptomatic arterial hypotension. If this is not possible, then the initial dose of ACE inhibitors should be reduced.

Ethanol, barbiturates, antipsychotics, antidepressants, anxiolytics, narcotic analgesics, and general anesthetics

Possible enhancement of the antihypertensive effect of hydrochlorothiazide and potentiation of orthostatic hypotension (additive effect).

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

Possible enhancement of the effect of non-depolarizing muscle relaxants.

Adrenergic agonists (pressor amines)

Hydrochlorothiazide may reduce the effect of adrenergic agonists such as epinephrine and norepinephrine.

NSAIDs, including selective COX-2 inhibitors and high doses of acetylsalicylic acid (≥3 g/day)

NSAIDs may reduce the diuretic and antihypertensive effects of hydrochlorothiazide. With simultaneous use, there is a risk of developing acute renal failure due to a decrease in GFR.

Hydrochlorothiazide may enhance the toxic effect of high doses of salicylates on the CNS.

Oral Hypoglycemic Agents and Insulin

Thiazide diuretics affect glucose tolerance (hyperglycemia may develop) and reduce the effectiveness of hypoglycemic agents (dose adjustment of hypoglycemic agents may be required).

Hydrochlorothiazide and metformin should be used together with caution due to the risk of lactic acidosis against the background of renal impairment caused by hydrochlorothiazide.

Beta-blockers, Diazoxide

Concomitant use of thiazide diuretics (including Hydrochlorothiazide) with beta-blockers or diazoxide may increase the risk of hyperglycemia.

Medicines Used to Treat Gout (Probenecid, Sulfinpyrazone, Allopurinol)

Dose adjustment of uricosuric drugs may be required because Hydrochlorothiazide increases serum uric acid concentration.

Thiazide diuretics may increase the frequency of hypersensitivity reactions to allopurinol.

Amantadine

Thiazide diuretics (including Hydrochlorothiazide) may reduce the clearance of amantadine, lead to an increase in amantadine plasma concentration and increase the risk of its adverse effects.

Anticholinergic Drugs (Cholinoceptor Blockers)

Anticholinergic drugs (e.g., atropine, biperiden) increase the bioavailability of thiazide diuretics by reducing gastrointestinal motility and gastric emptying rate.

Cytotoxic (Antineoplastic) Drugs

Thiazide diuretics reduce the renal excretion of cytotoxic drugs (e.g., cyclophosphamide and methotrexate) and potentiate their myelosuppressive effect.

Methyldopa

Cases of hemolytic anemia have been described with the simultaneous use of hydrochlorothiazide and methyldopa.

Carbamazepine

Risk of symptomatic hyponatremia. With simultaneous use of hydrochlorothiazide and carbamazepine, patient monitoring and control of plasma sodium levels are necessary.

Cyclosporine

With simultaneous use of thiazide diuretics and cyclosporine, the risk of hyperuricemia and exacerbation of gout increases.

Oral Anticoagulants

Thiazide diuretics may reduce the effect of oral anticoagulants.

Iodinated Contrast Agents

Dehydration while taking thiazide diuretics increases the risk of acute renal failure, especially when using high doses of iodinated contrast agents. Fluid loss must be compensated before using iodinated contrast agents.

Calcium Preparations

With simultaneous use, an increase in blood calcium levels and the development of hypercalcemia are possible due to reduced renal excretion of calcium ions. If concomitant use of calcium-containing drugs is necessary, plasma calcium levels should be monitored and the dose of calcium preparations should be adjusted.

Anion Exchange Resins (Cholestyramine and Colestipol)

Anion exchange resins reduce the absorption of hydrochlorothiazide. Single doses of cholestyramine and colestipol reduce the absorption of hydrochlorothiazide from the gastrointestinal tract by 85% and 43%, respectively.

Lisinopril

Dual Blockade of the RAAS

In patients with atherosclerotic disease, heart failure, or diabetes with target organ damage, concomitant therapy with an ACE inhibitor and angiotensin II receptor antagonists (ARBs) is associated with a higher incidence of arterial hypotension, syncope, hyperkalemia, and worsening renal function (including acute renal failure) compared with the use of only one drug affecting the RAAS.

Dual blockade (e.g., combining an ACE inhibitor with an ARB) should be limited to individual cases with careful monitoring of renal function, potassium levels, and regular BP control.

Concomitant use of ACE inhibitors with drugs containing aliskiren is contraindicated in patients with diabetes and/or with moderate or severe renal impairment (GFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients.

Concomitant use of ACE inhibitors with angiotensin II receptor antagonists (ARBs) is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Potassium-Sparing Diuretics, Potassium Preparations, Potassium-Containing Salt Substitutes and Other Drugs That Can Increase Serum Potassium Levels

When lisinopril is used concomitantly with potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium preparations or potassium-containing salt substitutes and other drugs that can increase serum potassium levels (including angiotensin II receptor antagonists, heparin, tacrolimus, cyclosporine; drugs containing co-trimoxazole [sulfamethoxazole+trimethoprim]), the risk of hyperkalemia increases (especially in patients with renal impairment). Therefore, these combinations are prescribed with caution, under the control of plasma potassium levels and renal function.

In elderly patients and patients with impaired renal function, concomitant use of ACE inhibitors with sulfamethoxazole/trimethoprim was accompanied by severe hyperkalemia, which is thought to be caused by trimethoprim, so Lisinopril should be used with caution with drugs containing trimethoprim, regularly monitoring plasma potassium levels.

Non-Potassium-Sparing Diuretics

When lisinopril is used concomitantly with non-potassium-sparing diuretics, the hypokalemia caused by their use may be reduced.

Other Antihypertensive Drugs

When used concomitantly with vasodilators, beta-blockers, slow calcium channel blockers, diuretics and other antihypertensive drugs, the severity of the antihypertensive effect of lisinopril is enhanced.

Lithium Preparations

When lisinopril is used concomitantly with lithium preparations, the elimination of lithium from the body is slowed (risk of increased cardiotoxic and neurotoxic effects of lithium). Concomitant use of lisinopril with lithium preparations is not recommended. If it is necessary to use this combination, plasma lithium concentration should be regularly monitored.

NSAIDs, Including Selective COX-2 Inhibitors and Acetylsalicylic Acid in High Doses (≥3 g/day)

NSAIDs (including selective COX-2 inhibitors) and acetylsalicylic acid in doses greater than 3 g/day reduce the antihypertensive effect of lisinopril.

In some patients with impaired renal function (e.g., elderly patients or patients with dehydration, including those taking diuretics) receiving NSAID therapy (including selective COX-2 inhibitors), concomitant use of ACE inhibitors or ARBs may cause further deterioration of renal function, including the development of acute renal failure, and hyperkalemia. These effects are usually reversible. Concomitant use of ACE inhibitors and NSAIDs should be carried out with caution (especially in elderly patients and patients with impaired renal function). Patients should receive adequate amounts of fluid. It is recommended to carefully monitor renal function, both at the beginning and during treatment.

The use of lisinopril in combination with acetylsalicylic acid as an antiplatelet agent is not contraindicated.

Hypoglycemic Drugs

Concomitant use of lisinopril and insulin, as well as oral hypoglycemic agents, may lead to the development of hypoglycemia. The greatest risk of development is observed during the first weeks of concomitant use, as well as in patients with impaired renal function.

Tricyclic Antidepressants/Antipsychotics/General Anesthetics/Narcotic Drugs

When used concomitantly with tricyclic antidepressants, antipsychotics, general anesthetics, barbiturates, and muscle relaxants, the antihypertensive effect of lisinopril is enhanced.

Alpha- and Beta-Adrenergic Agonists

Alpha- and beta-adrenergic agonists (sympathomimetics), such as epinephrine (adrenaline), isoproterenol, dobutamine, dopamine, may reduce the antihypertensive effect of lisinopril.

Baclofen

Enhances the antihypertensive effect of ACE inhibitors. Blood pressure should be carefully monitored and, if necessary, the dose of antihypertensive drugs should be adjusted.

Ethanol

With simultaneous use, ethanol enhances the antihypertensive effect of lisinopril.

Estrogens

Estrogens weaken the antihypertensive effect of lisinopril due to fluid retention.

Allopurinol, Procainamide, Cytostatics, Immunosuppressants, Systemic Corticosteroids

Concomitant use of ACE inhibitors with allopurinol, procainamide, and cytostatics increases the risk of developing neutropenia/agranulocytosis.

Gold Preparations

With simultaneous use of lisinopril and intravenous gold preparations (sodium aurothiomalate), a symptom complex including facial flushing, nausea, vomiting, and decreased blood pressure has been described.

Selective Serotonin Reuptake Inhibitors

Concomitant use of lisinopril with selective serotonin reuptake inhibitors may lead to severe hyponatremia.

mTOR (mammalian Target of Rapamycin) Inhibitors (e.g., Temsirolimus, Sirolimus, Everolimus)

In patients taking ACE inhibitors and mTOR inhibitors (temsirolimus, sirolimus, everolimus) simultaneously, an increased frequency of angioedema was observed.

Dipeptidyl Peptidase Type IV (DPP-IV) Inhibitors (Gliptins), e.g., Sitagliptin, Saxagliptin, Vildagliptin, Linagliptin

In patients taking ACE inhibitors and DPP-IV inhibitors (gliptins) simultaneously, an increased frequency of angioedema was observed.

Estramustine

Increased frequency of angioedema when used concomitantly with ACE inhibitors.

Neutral Endopeptidase (NEP) Inhibitors

An increased risk of angioedema has been reported with the concomitant use of ACE inhibitors and racecadotril (an enkephalinase inhibitor used to treat acute diarrhea).

When ACE inhibitors are used concomitantly with drugs containing sacubitril (a neprilysin inhibitor), the risk of angioedema increases, therefore the concomitant use of these drugs is contraindicated. ACE inhibitors should be prescribed no earlier than 36 hours after discontinuation of drugs containing sacubitril. Prescribing drugs containing sacubitril to patients receiving ACE inhibitors is contraindicated, as well as within 36 hours after discontinuation of ACE inhibitors.

Tissue Plasminogen Activators

Observational studies have revealed an increased frequency of angioedema in patients taking ACE inhibitors after using alteplase for thrombolytic therapy of ischemic stroke.

Pharmacokinetic Interaction

Antacids and cholestyramine reduce the absorption of lisinopril from the gastrointestinal tract.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

The shelf life is 2 years. Do not use after the expiration date stated on the packaging.

Dispensing Status

Dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.