Co-Diroton tablets 10mg/12.5mg №10×3

Name:
Co-Diroton tablets 10mg/12.5mg in bl. in pack. No. 10×3
Description:
Tablets 10 mg / 12.5 mg: tablets are round, flat on both sides, chamfered, light blue in color with a few patches of a darker color. On one side – engraving “C 43”. Diameter about 8 mm. Tablets 20 mg / 12.5 mg: tablets are round, flat on both sides, chamfered, light green in color with a few patches of a darker color. On one side – engraving “C 44”. Diameter about 8 mm. The main active ingredient Lisinopril + hydrochlorothiazide Release form Tablets Dosage 10 mg / 12.5 mg Pharmacological properties Pharmacodynamics Co-Diroton® is a combination drug containing lisinopril, an angiotensin-converting enzyme (ACE) inhibitor, and hydrochlorothiazide, a thiazide diuretic. The components complement each other’s action, enhancing the antihypertensive effect. Lisinopril is a peptidyl dipeptidase inhibitor. Lisinopril inhibits the angiotensin-converting enzyme (ACE), which catalyzes the conversion of angiotensin I to the vasoconstrictor peptide, angiotensin II. Angiotensin II also stimulates the secretion of aldosterone by the adrenal cortex. Suppression of ACE leads to a decrease in angiotensin II concentrations, which leads to a decrease in vasoconstrictor activity and a decrease in aldosterone secretion. A decrease in the level of the latter can lead to an increase in the content of potassium in the blood plasma. Despite the fact that the main mechanism of the antihypertensive effect of lisinopril is considered to be suppression of the renin-angiotensin-aldosterone system, lisinopril also has an effect in patients with arterial hypertension with low renin content. ACE is identical to kininase II, an enzyme that catalyzes the breakdown of bradykinin. Whether elevated levels of bradykinin, a potent vasodilator peptide, contribute to the therapeutic effects of lisinopril remains unclear. Hydrochlorothiazide is a diuretic and antihypertensive agent. Hydrochlorothiazide affects the distal tubular mechanism of electrolyte reabsorption and increases the excretion of sodium and chloride ions in approximately equivalent amounts. Natriuresis may be accompanied by some loss of potassium and bicarbonate ions. The mechanism of the antihypertensive action of thiazides is not fully understood. Thiazides usually do not affect normal blood pressure. Two large randomized controlled clinical trials (ONTARGET (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial) and VA NEPHRON-D (The Veterans Affair Nephropathy in Diabetes) investigated the combination of an ACE inhibitor with an angiotensin II receptor blocker. ONTARGET included Patients with cardiovascular or cerebrovascular disease or type II diabetes with signs of end organ damage The VA NEPHRON-D trial studied patients with type II diabetes and diabetic nephropathy These studies did not show a significant benefit in terms of renal and/or cardiovascular -vascular outcomes and mortality and, at the same time, revealed an increased risk of hyperkalemia, acute renal failure and / or hypotension compared with monotherapy with these drugs.Based on the similarity of pharmacodynamics, these results are also applicable to other ACE inhibitors and angina blockers type II iotensin receptors. Thus, ACE inhibitors and type II angiotensin receptor blockers should not be co-administered in patients with diabetic nephropathy. The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardiovascular and Renal Disease Endpoints) study examined the benefit of adding aliskiren to standard therapy with an ACE inhibitor or an angiotensin II receptor blocker in patients with type 2 diabetes mellitus with chronic kidney disease, cardiovascular disease, or both. another. The study was terminated early due to an increased risk of adverse outcomes. Cardiovascular death and stroke were more common in the aliskiren group than in the placebo group. Serious adverse reactions such as hyperkalemia, hypotension and renal failure were also more common in the aliskiren group than in the placebo group. Pharmacokinetics The combined use of lisinopril and hydrochlorothiazide has little or no effect on the bioavailability of both drugs. There were no clinically significant pharmacokinetic interactions between the two components when taken as a single tablet. Lisinopril Absorption After oral administration of lisinopril, peak plasma concentration is reached within 7 hours, in patients with acute myocardial infarction, there is a tendency to increase the time required to reach peak serum concentration. Based on renal excretion, the mean absorption of lisinopril is approximately 25% with inter-individual variability of 6-60% over the dose range (5-80 mg). Absolute bioavailability is reduced by 16% in patients with chronic heart failure. Eating does not affect the absorption of lisinopril. Distribution Lisinopril does not bind to plasma proteins, except for circulating angiotensin-converting enzyme (ACE). Studies in rats have shown that lisinopril hardly crosses the blood-brain barrier. Excretion Lisinopril is not metabolized and is excreted unchanged by the kidneys. The elimination half-life after repeated administration is 12.6 hours. The clearance of lisinopril in healthy volunteers is approximately 50 ml/min. A decrease in plasma concentrations of lisinopril indicates a prolonged terminal phase, which does not contribute to the accumulation of the active substance. This terminal phase is possibly saturable ACE binding and is not dose proportional. Chronic heart failure In patients with chronic heart failure, compared with healthy volunteers, a greater exposure of lisinopril was observed (an increase in the area under the concentration-time curve (AUC) by an average of 125%), but based on the renal excretion of lisinopril, it can be concluded that absorption is reduced lisinopril by approximately 16% compared with healthy volunteers. Elderly Elderly patients have higher plasma concentrations of lisinopril and an increase in AUC (approximately 60%) compared to younger patients. Impaired renal function With impaired renal function, the excretion of lisinopril is reduced (because the excretion of lisinopril is carried out by the kidneys), but this is of clinical importance only if the glomerular filtration rate is less than 30 ml / min. In mild to moderate renal insufficiency (creatinine clearance (CC) from 30 to 79 ml / min), the average AUC value increases by only 13%, while in severe renal insufficiency, an increase in the average AUC value of 4.5 times (CC 5 to 29 ml/min). Lisinopril can be removed from the body by hemodialysis. During a 4-hour hemodialysis procedure, plasma concentrations of lisinopril are reduced by an average of 60% with a dialysis clearance of 40 to 55 ml / min. Impaired liver function Impaired liver function in patients with cirrhosis of the liver resulted in a decrease in the absorption of lisinopril (about 30%, based on renal excretion), but an increase in exposure (approximately 50%) was observed compared with healthy volunteers due to a decrease in clearance. Hydrochlorothiazide When monitoring the concentration of hydrochlorothiazide in blood plasma for at least 24 hours, its half-life varied from 5.6 to 14.8 hours. At least 61% of the substance is excreted unchanged within 24 hours. After taking hydrochlorothiazide orally, the diuretic effect occurs within the first 2 hours, reaches a maximum after about 4 hours and lasts about 6-12 hours. Hydrochlorothiazide penetrates the placental barrier, but does not penetrate the blood-brain barrier. Indications for use Treatment of mild to moderate arterial hypertension in patients whose condition is already adequately controlled by the simultaneous administration of lisinopril and hydrochlorothiazide in the same doses as in Co-Diroton®. Route of administration and doses Route of administration For oral administration Arterial hypertension Doses Adults The use of a fixed dose combination preparation is not suitable for initiating therapy. The fixed dose combination may replace the combination of 10 mg or 20 mg of lisinopril and 12.5 mg of hydrochlorothiazide in patients already adequately controlled by co-administration of lisinopril and hydrochlorothiazide at the same doses as Co-Diroton®. The usual dose is one tablet 1 time per day. As with other once-daily medications, Co-Diroton® should be taken at about the same time each day. In general, if the expected therapeutic effect cannot be achieved with this dose within 2-4 weeks, it can be increased to two tablets once a day. Prior diuretic therapy Symptomatic hypotension may develop after the initial dose of Co-Diroton®; the development of this condition is most likely in patients with reduced circulating blood volume (CBV) and / or salt deficiency as a result of previous diuretic therapy. Therapy with diuretics should be discontinued 2-3 days before the start of therapy with Co-Diroton®. If this is not possible, treatment should be started with lisinopril monotherapy at a dose of 5 mg. Patients with renal insufficiency Thiazides are not suitable for use in patients with renal insufficiency, are they not effective in CC? 30 ml / min (i.e. with moderate or severe renal insufficiency). Co-Diroton® should not be used as initial therapy in patients with renal insufficiency. In patients with CC> 30 ml / min and < 80 ml / min, Co-Diroton® can only be used after titration of the dose of individual components. In this case, the recommended dose of lisinopril, prescribed as monotherapy for mild renal failure, is 5-10 mg. Children and adolescents (< 18 years) Safety and efficacy in children and adolescents (< 18 years) have not been established. Elderly patients In elderly patients, dose adjustment is not required. In clinical studies, the efficacy and tolerability of lisinopril and hydrochlorothiazide, with their simultaneous use, were the same in both elderly and younger patients with arterial hypertension. In the dose range of 20-80 mg, the efficacy of lisinopril was similar in elderly patients (65 years and older) and younger patients suffering from arterial hypertension. In elderly hypertensive patients, lisinopril monotherapy was as effective in lowering diastolic blood pressure as either hydrochlorothiazide or atenolol monotherapy. According to the results of clinical studies, age does not affect the tolerability of lisinopril. Use during pregnancy and lactation Pregnancy ACE inhibitors The use of ACE inhibitors is not recommended during the 1st trimester of pregnancy. The use of ACE inhibitors is contraindicated during the 2nd and 3rd trimesters of pregnancy (see section "Contraindications"). Epidemiological data regarding the risk of developing teratogenic effects as a result of exposure to ACE inhibitors during the first trimester of pregnancy are not informative; however, a slight increase in risk cannot be ruled out. If continued therapy with ACE inhibitors is not necessary, patients planning pregnancy should be switched to alternative antihypertensive therapy with an acceptable safety profile. When pregnancy is established, treatment with ACE inhibitors should be stopped immediately and, if necessary, alternative therapy should be started. It is known that taking ACE inhibitors during the second and third trimesters of pregnancy has a fetotoxic effect (decrease in kidney function, oligohydramnios, slowing of the ossification of the skull bones) and has a toxic effect on newborns (renal failure, arterial hypotension, hyperkalemia). If ACE inhibitors are taken in the second trimester of pregnancy, an ultrasound examination of the function of the kidneys and skull is recommended. Infants exposed to ACE inhibitors in utero should be closely monitored for hypotension (see also the Contraindications handout). Lisinopril, which crosses the placental barrier, can be removed from the neonatal circulation by peritoneal dialysis and, theoretically, by exchange transfusion. There is no experience of removing hydrochlorothiazide, which also crosses the placental barrier, from the systemic circulation of the newborn. Hydrochlorothiazide Routine use of diuretics in otherwise healthy pregnant women is not recommended because both mother and fetus are exposed to unnecessary risks, including fetal and neonatal jaundice, thrombocytopenia, and possibly other side effects similar to those seen in adult patients. Experience with hydrochlorothiazide during pregnancy is limited, particularly during the first trimester of pregnancy. Animal studies are not enough. Hydrochlorothiazide crosses the placental barrier. Based on the pharmacological mechanism of action of hydrochlorothiazide, its use during the second and third trimesters of pregnancy may create a risk of impaired fetal perfusion and cause fetal and neonatal manifestations such as jaundice, electrolyte imbalance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational edema, hypertension in pregnancy or preeclampsia, due to the risk of a decrease in blood plasma volume and the development of placental hypoperfusion and the absence of any positive effects on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnancy, except in rare situations where there are no therapeutic alternatives. Breastfeeding period ACE inhibitors Due to the lack of information regarding the use of the combination lisinopril / hydrochlorothiazide during breastfeeding, the use of the drug Co-Diroton® is not recommended, it is preferable to prescribe an alternative treatment with a well-established safety profile, especially when feeding newborns or premature babies . Hydrochlorothiazide Hydrochlorothiazide passes into breast milk in small amounts. Large doses of thiazides that cause severe diuresis inhibit milk production. The use of Co-Diroton® during breastfeeding is not recommended. If Co-Diroton® is used during breastfeeding, the dose should be minimal. Precautions Symptomatic hypotension In rare cases, patients with uncomplicated hypertension may experience symptomatic hypotension. The risk of lowering blood pressure is most likely in patients with a decrease in circulating blood volume, for example, during diuretic therapy, while following a diet with salt restriction, after hemodialysis, with diarrhea or vomiting, with severe renin-dependent arterial hypertension (see sections "Interaction with other medicinal products" and "Side effects"), In such patients, the content of electrolytes in the blood serum should be regularly monitored. The selection of doses and treatment of patients with an increased risk of developing clinically significant arterial hypotension begins under close medical supervision. In patients with ischemic heart disease or cerebrovascular diseases, the drug should be used with extreme caution, since an excessive decrease in blood pressure can lead to the development of myocardial infarction or acute cerebrovascular accident. With the development of arterial hypotension, the patient should be laid on his back and, if necessary, an intravenous infusion of saline should be started. A transient hypotensive reaction is not a contraindication to continuing therapy. After the restoration of the effective volume of circulating blood and blood pressure, it is possible to resume therapy with a reduced dose, or any of the components of the drug Co-Diroton® can be used separately. In some patients with heart failure, but with normal or low blood pressure, against the background of the use of lisinopril, a decrease in systemic blood pressure may be observed. This effect is expected and is usually not a reason to stop the drug. With the development of clinically pronounced arterial hypotension, it may be necessary to reduce the dose or cancel lisinopril and (or) hydrochlorothiazide. Aortic and mitral valve stenosis/hypertrophic cardiomyopathy As with other ACE inhibitors, lisinopril should be used with caution in patients with mitral valve stenosis and left ventricular outflow tract obstruction (aortic stenosis or hypertrophic cardiomyopathy). Dual blockade of the penin-angiotensin-aldosterone system It is known that with the simultaneous use of ACE inhibitors, angiotensin II receptor blockers or aliskiren, the risk of arterial hypotension, hyperkalemia and impaired renal function (including acute renal failure) increases. Thus, a double blockade of the RAAS by the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is not recommended (see sections "Interaction with other drugs" and "Pharmacodynamics"). If double blockade is absolutely necessary, then it should be carried out under the supervision of a specialist and with regular monitoring of renal function, electrolytes and blood pressure. ACE inhibitors and angiotensin II receptor blockers should not be co-administered in patients with diabetic nephropathy. Impaired renal function Thiazide diuretics are not recommended for use in patients with impaired renal function; thiazides are ineffective at creatinine clearance values of 30 ml / min or below (corresponding to moderate or severe renal insufficiency). The combination of lisinopril and hydrochlorothiazide should not be administered to a patient with renal insufficiency (creatinine clearance < 80 ml/min) until doses of the individual components have been adjusted to match the doses in the combined preparation. Hypotension that occurs after initiation of treatment with ACE inhibitors in patients with heart failure may lead to further deterioration of renal function. In some cases, the development of acute renal failure (usually reversible) has been reported. In some patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney treated with ACE inhibitors, there was an increase in serum urea and creatinine, usually reversible after discontinuation of therapy. This is especially true for patients with renal insufficiency. If renovascular hypertension also occurs, there is an increased risk of severe hypotension and renal failure. In such patients, treatment should be initiated at low doses under close medical supervision; careful dose titration is required. Since treatment with diuretics may contribute to the development of the above situations, during the first few weeks of therapy with Co-Diroton®, renal function should be monitored. Some patients with arterial hypertension without a history of kidney disease, with the simultaneous use of lisinopril and a diuretic, developed, as a rule, a slight transient increase in the concentration of blood urea and plasma creatinine. Such changes are most likely in patients with previous renal impairment. Dose reduction or discontinuation of diuretic and/or lisinopril therapy may be necessary. Prior diuretic therapy Prior diuretic therapy should be discontinued 2-3 days prior to initiation of Co-Diroton® therapy. If this is not possible, treatment should be started with individually selected low doses of individual components (lisinopril at a dose of 5 mg). Dose reduction or discontinuation of diuretic and/or lisinopril therapy may be necessary. Condition after kidney transplantation Since there are no data on the use of lisinopril in patients in the early period after kidney transplantation, Co-Diroton® should not be used in this group of patients. Anaphylactoid reactions in patients on hemodialysis The combination of lisinopril and hydrochlorothiazide is not indicated for the treatment of patients with renal insufficiency requiring hemodialysis. There are reports of the development of anaphylactoid reactions in patients receiving ACE inhibitors during certain types of hemodialysis (for example, using high-permeability AN69 membranes and when performing low-density lipoprotein (LDL) apheresis using dextran sulfate). In such cases, a different type of dialysis membrane or other classes of antihypertensive agents should be used. Anaphylactic reactions during low-density lipoprotein (LDL) apheresis (LDL) procedures In rare cases, patients receiving ACE inhibitors have experienced life-threatening anaphylactic reactions during low-density lipoprotein (LDL) apheresis using dextran sulfate. To prevent the development of anaphylactic reactions, ACE inhibitor therapy should be temporarily discontinued before each apheresis procedure. Liver disease In patients with impaired liver function or with progressive liver disease, thiazide diuretics should be used with caution, since minor changes in the water and electrolyte balance can provoke the development of hepatic coma (see section "Contraindications"). In rare cases, against the background of taking ACE inhibitors, a syndrome of development of cholestatic jaundice was observed with a transition to fulminant liver necrosis, sometimes with a fatal outcome. The mechanism by which this syndrome develops is unclear. In the event that against the background of the use of a combination of lisinopril and hydrochlorothiazide, the appearance of jaundice or a significant increase in the level of liver enzymes is noted, the drug should be discontinued; The patient must be under close medical supervision. Surgery / General Anesthesia In patients whose condition requires major surgery or general anesthesia with drugs that cause arterial hypotension, lisinopril may block the formation of angiotensin II with compensatory renin release. A pronounced decrease in blood pressure, which is considered a consequence of this mechanism, can be eliminated by increasing the volume of circulating blood. Metabolic and endocrine effects During the use of ACE inhibitors and thiazides, impaired glucose tolerance may occur. Doses of antidiabetic drugs, including insulin, may need to be adjusted. In diabetic patients receiving oral antidiabetic drugs or insulin, during the first month of treatment with an ACE inhibitor, glycemic levels should be carefully monitored. Against the background of the use of thiazide diuretics, a transition from a latent form of diabetes mellitus to a manifest one is possible. Against the background of therapy with thiazide diuretics, the concentration of cholesterol and triglycerides may increase. In some patients, thiazide therapy may provoke the development of hyperuricemia and/or gout. However, lisinopril accelerates the excretion of uric acid by the kidneys, thereby weakening the hyperuricemic effect of hydrochlorothiazide. Violation of the electrolyte balance In the treatment of diuretics, patients are shown regular determination of the content of electrolytes in the blood serum. When using thiazides, including hydrochlorothiazide, it is possible to develop a violation of the water or electrolyte balance (hypokalemia, hyponatremia, hypochloremic alkalosis). Signs of a violation of the water or electrolyte balance include: dry mouth, thirst, weakness, lethargy, drowsiness, muscle pain or spasms, muscle fatigue, arterial hypotension, oliguria, tachycardia, disorders of the gastrointestinal tract (nausea, vomiting). Patients with edema in hot weather may develop hypervolemic hyponatremia. Chloride deficiency is usually minor and does not require treatment. Thiazides are known to increase urinary excretion of magnesium, which can lead to hypomagnesemia. Thiazides can reduce urinary calcium excretion and cause a slight periodic increase in serum calcium. Severe hypercalcemia may be a sign of latent hyperparathyroidism. Before the study of the function of the parathyroid glands, thiazide diuretics should be discontinued. Hyperkalemia An increase in serum potassium has been observed in some patients receiving ACE inhibitors, including lisinopril. Risk factors for the development of hyperkalemia are: renal failure, diabetes mellitus, concomitant use of potassium-sparing diuretics, use of potassium-containing supplements or salt substitutes, and drugs that can increase serum potassium levels (eg, heparin). If necessary, the simultaneous use of the above-mentioned drugs is recommended to regularly monitor the content of potassium in the blood serum (see section "Interaction with other drugs"). Hypersensitivity/angioneurotic edema With the use of angiotensin-converting enzyme inhibitors, including lisinopril, angioedema of the face, extremities, lips, tongue, pharynx and/or larynx may develop in rare cases. Angioedema can develop at any time during treatment. With the development of such a reaction, lisinopril should be immediately canceled; the patient should receive appropriate therapy and be under medical supervision until the symptoms disappear completely. Even in cases where there is only swelling of the tongue (without impaired respiratory function), the patient is indicated for long-term observation, since the use of antihistamines and corticosteroids may be ineffective. In very rare cases, angioedema of the larynx or tongue can be fatal. Swelling of the tongue, vocal cords, or larynx may lead to airway obstruction, especially in patients who have undergone respiratory surgery. In such cases, urgent therapy is indicated. Adrenaline solution and/or airway management may be required. The patient should be under close medical supervision until the symptoms disappear completely and permanently. In patients of the Black race taking angiotensin-converting enzyme inhibitors, angioedema is observed more often than in patients of other races. Patients with a history of angioedema, not associated with the use of ACE inhibitors, may be at greater risk of developing angioedema during therapy with ACE inhibitors (see section "Contraindications"). In patients receiving thiazides, hypersensitivity reactions may develop regardless of the presence of allergies or bronchial asthma in history. Cases of occurrence or exacerbation of systemic lupus erythematosus against the background of the use of thiazide diuretics are described. Patients with diabetes In patients with diabetes receiving oral antidiabetic drugs or insulin, during the first month of treatment with an ACE inhibitor, the level of glycemia should be carefully monitored (see the section "Interaction with other drugs"), Desensitization In patients taking inhibitors ACE against the background of desensitizing therapy (for example, with intoxication with hymenoptera venom), prolonged anaphylactoid reactions develop. If such patients abstained from taking ACE inhibitors for the duration of desensitization, no reactions were observed, however, accidental administration of ACE provoked an anaphylactoid reaction. Neutropenia, agranulocytosis Cases of neutropenia (agranulocytosis), thrombocytopenia and anemia have been reported in patients receiving ACE inhibitors. In patients with normal renal function and in the absence of other aggravating factors, neutropenia rarely develops. Neutropenia and agranulocytosis are reversible and disappear after discontinuation of the ACE inhibitor. Lisinopril is used with extreme caution in patients with systemic connective tissue disease, on the background of immunosuppressant therapy, in allopurinol or procainamide therapy, especially in patients with impaired renal function. In some cases, this category of patients developed serious infections, including those that did not respond to intensive antibiotic therapy. When prescribing lisinopril in such patients, it is recommended to periodically monitor the content of leukocytes in the blood. Patients should be instructed to report any signs of infection to their physician immediately. Race In patients of black race taking angiotensin-converting enzyme inhibitors, angioedema is observed more often than in patients of other races. Like other ACE inhibitors, lisinopril is less effective in lowering blood pressure in blacks than in patients of other races. This is probably due to the predominantly low renin content in black patients with arterial hypertension. Cough Cough has been reported with the use of ACE inhibitors. Cough dry, prolonged, which disappears after discontinuation of treatment with an ACE inhibitor. In the differential diagnosis of cough, it is necessary to take into account the cough caused by the use of an ACE inhibitor. Lithium preparations Simultaneous use of ACE inhibitors and lithium preparations should be avoided (see section "Interaction with Other Drugs"). Doping controls This medicinal product contains hydrochlorothiazide, which may cause a positive doping test result. Pregnancy The use of ACE inhibitors during pregnancy is not recommended. Patients planning pregnancy should be given an alternative antihypertensive therapy with a proven safety profile during pregnancy, unless the use of ACE inhibitors is necessary. If pregnancy occurs during treatment, the ACE inhibitor should be immediately discontinued and, if possible, an alternative treatment should be prescribed (see sections "Contraindications" and "Use during pregnancy and during breastfeeding"). Interaction with other drugs Antihypertensive drugs When used simultaneously with other antihypertensive drugs, there may be an increase in the antihypertensive effect. Simultaneous use with nitroglycerin, other nitrates or vasodilators enhances the antihypertensive effect. The appointment of lisinopril in combination with drugs containing aliskiren should be avoided (see sections "Contraindications" and "Precautions"). Data from clinical studies have shown that dual blockade of the renin-angiotensin-aldosterone system (RAAS) with the combined use of ACE inhibitors, angiotensin II receptor blockers or aliskiren is associated with a higher incidence of adverse events such as arterial hypotension, hyperkalemia and decreased renal function (including acute renal failure), compared with the use of a single drug that affects the RAAS (see sections "Contraindications", "Precautions" and "Pharmacodynamics"). Lithium preparations With the simultaneous use of lithium preparations and ACE inhibitors, there have been cases of a reversible increase in the level of lithium in the blood serum and the appearance of signs of toxicity. Diuretics and ACE inhibitors reduce the renal clearance of lithium, which increases the risk of its toxicity. Thus, the use of lisinopril and hydrochlorothiazide in combination with lithium preparations is not recommended. If the use of this combination is necessary, the level of lithium in the blood serum should be carefully monitored (see section "Precautions"). Potassium-sparing diuretics, potassium-containing supplements or salt substitutes Due to the potassium-sparing effect of lisinopril, potassium excretion is reduced when taking thiazide diuretics. The use of potassium-sparing drugs, potassium-containing supplements and salt substitutes can lead to a significant increase in serum potassium, especially in patients with impaired renal function and diabetes mellitus. If the simultaneous use of a combination of lisinopril and hydrochlorothiazide and any of the above agents is necessary, treatment should be carried out with caution against the background of regular monitoring of the content of potassium in the blood serum (see section "Precautions"). Drugs that can cause torsades de pointes Because of the risk of hypokalemia, caution should be exercised when hydrochlorothiazide is used concomitantly with drugs that can cause torsades de pointes (certain antiarrhythmic, antipsychotic, and other drugs). Tricyclic antidepressants, antipsychotics (neuroleptics), anesthetics When ACE inhibitors are used together with some anesthetics, tricyclic antidepressants and neuroleptics, an increase in the antihypertensive effect may be observed (see section "Precautions"). Non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid Long-term use of NSAIDs (selective cyclooxygenase-2 inhibitors, acetylsalicylic acid at a dose of> 3 g / day, non-selective NSAIDs) may weaken the antihypertensive and diuretic effect of ACE inhibitors and thiazide diuretics. The simultaneous use of NSAIDs and ACE inhibitors can lead to an increase in the content of potassium in the blood serum and a deterioration in kidney function. As a rule, these phenomena are reversible. In rare cases, renal failure may develop, especially in patients with impaired renal function, such as elderly patients or patients with dehydration. Gold Preparations Patients receiving ACE inhibitors were more likely to experience nitritoid (vasomotor) reactions against the background of the use of injectable forms of gold preparations (for example, sodium aurothiomalate). Nitritoid reactions are characterized by the appearance of symptoms of vasodilation (reddening of the skin), nausea, dizziness and arterial hypotension. Sympathomimetic