Lorista N, 50 mg+12, 5 mg 30 pcs

hypotensive combined agent (diuretic + angiotensin II receptor antagonist).

Indications

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

· Reduced risk of cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy, manifested by a cumulative reduction in the incidence of cardiovascular mortality, stroke and myocardial infarction.

Pharmacological effect

antihypertensive combined drug (diuretic + angiotensin II receptor antagonist).

Special instructions

Bilateral renal artery stenosis or stenosis of the artery of a single kidney, hyperkalemia, conditions after kidney transplantation (no experience with use), aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy (HOCM), chronic heart failure (CHF) with concomitant severe renal impairment, severe heart failure (IV functional class according to the NYHA classification), CHF with life-threatening arrhythmias, ischemic heart disease (CHD), cerebrovascular diseases, primary hyperaldosteronism, history of angioedema, arterial hypotension, liver dysfunction, renal dysfunction, fluid and electrolyte imbalance, patients with reduced blood volume (for example, receiving treatment with large doses of diuretics) due to the possibility of symptomatic arterial hypotension, hypokalemia, hyponatremia, hypercalcemia, simultaneous the use of drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type or increase the duration of the QT interval on the ECG, the simultaneous use of drugs that can cause hypokalemia, cardiac glycosides, a history of allergic reactions to penicillin, hyperparathyroidism, hyperuricemia, gout, a history of non-melanoma skin cancer (NSC) (see. section “Special instructions”).

Contraindicated for persons under 18 years of age (efficacy and safety of use have not been established).

Patients with impaired renal function or patients on hemodialysis

In patients with moderate renal impairment (creatinine clearance 30-50 ml/min), no adjustment of the initial dose of the drug is required. Lorista® N is not recommended for patients on hemodialysis. The drug Lorista® N should not be used in patients with severely impaired renal function (creatinine clearance less than 30 ml/min) (see section “Contraindications”).

Patients with reduced blood volume

Before starting treatment with Lorista®, the blood volume and/or the content of sodium ions in the blood plasma should be restored.

Patients with liver dysfunction

Lorista® N is contraindicated in patients with severe liver dysfunction (see section “Contraindications”).

Elderly patients

No dose adjustment of Lorista® is required.

The use of Lorista® N in patients with acute myocardial infarction is not recommended due to insufficient experience in clinical use. It should also not be used to relieve a hypertensive crisis.

Hydrochlorothiazide

Renal dysfunction

In patients with impaired renal function, hydrochlorothiazide may cause azotemia. In case of renal failure, accumulation of hydrochlorothiazide is possible.

In patients with reduced renal function, periodic monitoring of CK is necessary. If renal dysfunction progresses and/or oliguria (anuria) occurs, hydrochlorothiazide should be discontinued.

Liver dysfunction

When using thiazide diuretics in patients with impaired liver function, hepatic encephalopathy may develop. In patients with severe liver failure or hepatic encephalopathy, the use of thiazides is contraindicated. In patients with mild to moderate hepatic impairment and/or progressive liver disease, hydrochlorothiazide should be used with caution, since even slight changes in fluid and electrolyte balance and serum ammonium accumulation can cause hepatic coma. If symptoms of encephalopathy occur, diuretics should be discontinued immediately.

Water-electrolyte balance and metabolic disorders

Thiazide diuretics (including hydrochlorothiazide) can cause a decrease in blood volume (hypovolemia) and disturbances in water and electrolyte balance (including hypokalemia, hyponatremia, hypochloremic alkalosis). Clinical symptoms of water and electrolyte imbalance are dryness of the oral mucosa, thirst, weakness, lethargy, fatigue, drowsiness, anxiety, 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 with long-term course treatment), clinical symptoms of water-electrolyte imbalance should be identified and the content of electrolytes in the blood plasma should be regularly monitored.

Sodium

All diuretics can cause hyponatremia, sometimes leading to severe complications. Hyponatremia and hypovolemia can lead to dehydration and orthostatic hypotension. A concomitant decrease in chlorine ions can lead to secondary compensatory metabolic alkalosis, but the frequency and severity of this effect are insignificant. It is recommended to determine the content of sodium ions in the blood plasma 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 the potassium content in the blood plasma and the development of hypokalemia (potassium content in the blood plasma less than 3.4 mmol/l). Hypokalemia increases the risk of developing heart rhythm disturbances (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 “pirouette” type, which can be fatal.

Hypokalemia poses the greatest danger to the following groups of patients: elderly people, patients simultaneously receiving therapy with antiarrhythmic and non-antiarrhythmic drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type or increase the duration of the QT interval on the ECG, patients with impaired liver function, coronary artery disease, and heart failure. In addition, patients with an increased QT interval are at increased risk. It does not matter whether this increase is caused by congenital causes or the effect of drugs.

In all the cases described above, it is necessary to avoid the risk of developing hypokalemia and regularly monitor the potassium content in the blood plasma. The first measurement of the content of potassium ions in the blood plasma should be carried out within the first week from the start of treatment. If hypokalemia occurs, appropriate treatment should be prescribed. Hypokalemia can be corrected by using potassium-containing medications or eating foods rich in potassium (dried fruits, fruits, vegetables).

Calcium

Thiazide diuretics may reduce the excretion of calcium ions by the kidneys, 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 were observed with hypercalcemia and hyperphosphatemia, but without the typical complications of hyperparathyroidism (nephrolithiasis, decreased bone mineral density, peptic ulcer). Severe hypercalcemia may be a manifestation of previously undiagnosed hyperparathyroidism.

Because of their effect on calcium metabolism, thiazides may interfere with laboratory parameters of parathyroid function. Thiazide diuretics (including hydrochlorothiazide) should be discontinued before testing parathyroid 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, it is necessary to regularly monitor the concentration of glucose in the blood plasma. Dosage adjustment of hypoglycemic medications 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 both cholesterol and triglycerides in the blood 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 loss of vision or eye pain, usually occurring within hours to weeks of starting hydrochlorothiazide therapy. If left untreated, acute angle-closure glaucoma can lead to irreversible vision loss. If symptoms appear, you should stop taking hydrochlorothiazide 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 include a history of an allergic reaction to sulfonamides or penicillin. Immune system disorders

There are reports that thiazide diuretics (including hydrochlorothiazide) may 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 about cases of the development of photosensitivity reactions when taking thiazide diuretics. If photosensitivity occurs while taking hydrochlorothiazide, treatment should be discontinued. If continued use of a diuretic is necessary, the skin should be protected from exposure to sunlight or artificial ultraviolet rays (UV rays).

Non-melanoma skin cancer (NMSC)

Two pharmacoepidemiological studies using data from the Danish National Cancer Registry demonstrated an association between hydrochlorothiazide use and an increased risk of NMSC—basal cell carcinoma and squamous cell carcinoma. The risk of developing NMSC increased with increasing total (cumulative) dose of hydrochlorothiazide. A possible mechanism for the development of NMSC is the photosensitizing effect of hydrochlorothiazide. Patients taking hydrochlorothiazide as monotherapy or in combination with other drugs should be aware of the risk of developing NMSC. It is recommended that such patients undergo regular skin examination to identify any new suspicious lesions as well as changes in existing skin lesions.

Any suspicious skin changes should be reported to your doctor immediately. Suspicious areas of skin should be examined by a specialist. To clarify the diagnosis, histological examination of skin biopsies may be required.

To minimize the risk of developing NMSC, patients should be advised to follow preventive measures, such as limiting exposure to sunlight and UV rays, and using appropriate protective equipment.

In patients with a history of NMSC, it is recommended to reconsider the use of hydrochlorothiazide.

Athletes

Hydrochlorothiazide may give a positive result during doping control in athletes.

Other

In patients with severe atherosclerosis of the cerebral and coronary arteries, hydrochlorothiazide should be used with extreme caution.

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

Losartan

Angioedema

Patients with a history of angioedema (of the face, lips, pharynx and/or larynx) should be closely monitored.

Arterial hypotension and hypovolemia (dehydration)

In patients with hypovolemia (dehydration) and/or reduced sodium content in the blood plasma, against the background of diuretic therapy, limited salt intake, diarrhea or vomiting, symptomatic arterial hypotension may develop, especially after taking the first dose of Lorista® N. Before using the drug, the BCC and/or sodium content in the blood plasma should be restored.

Water-electrolyte imbalance

Fluid and electrolyte imbalances are common in patients with impaired renal function, especially in the setting of diabetes mellitus. In this regard, it is necessary to carefully monitor the potassium content in the blood plasma and CC, especially in patients with heart failure and CC 30-50 ml/min.

Concomitant use of ARA II with aliskiren and 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 ARB II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Concomitant use with potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium, or other drugs that can increase the level of potassium in the blood plasma (for example, heparin) is not recommended.

Liver dysfunction

The concentration of losartan in the blood plasma increases significantly in patients with liver cirrhosis, so Lorista® N should be used with caution in patients with mild or moderate liver dysfunction.

Renal dysfunction

Impaired renal function, including renal failure, may occur due to inhibition of the RAAS (especially in patients whose renal function is dependent on the RAAS, such as those with severe heart failure or a history of renal dysfunction).

Renal artery stenosis

In patients with bilateral renal artery stenosis, as well as stenosis of the artery of the only functioning kidney, drugs affecting the RAAS, including ARA II, can reversibly increase the concentrations of urea and creatinine in the blood plasma.

Losartan should be used with caution in patients with bilateral renal artery stenosis or arterial stenosis of a solitary kidney.

Kidney transplant

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

Primary hyperaldosteronism

Patients with primary hyperaldosteronism are resistant to antihypertensive drugs that affect the RAAS, therefore the use of Lorista® N is not recommended for such patients.

IHD and cerebrovascular diseases

As with the treatment of any antihypertensive drugs, a pronounced decrease in blood pressure in patients with coronary artery disease or cerebrovascular diseases can lead to the development of myocardial infarction or stroke.

Heart failure

In patients whose renal function depends on the state of the RAAS (for example, with CHF III-IV functional class according to the NYHA classification, accompanied or not accompanied by impaired renal function), therapy with drugs that affect the RAAS may be accompanied by severe arterial hypotension, oliguria and/or progressive azotemia, and in rare cases, acute renal failure. It is impossible to exclude the development of these disorders due to suppression of RAAS activity while taking ARA II.

Stenosis of the aortic and/or mitral valves, HOCM

Lorista® N, like other vasodilators, should be used with caution in patients with hemodynamically significant stenosis of the aortic and/or mitral valves or with HOCM.

Ethnic characteristics

Losartan (like other drugs that affect the RAAS) has a less pronounced antihypertensive effect in patients of the Black race compared to representatives of other races, possibly due to the higher incidence of hyporeninemia in these patients with arterial hypertension.

Special information on excipients

The drug Lorista® N contains lactose, therefore the drug is contraindicated in patients with lactase deficiency, lactose intolerance, and glucose-galactose malabsorption syndrome.

At the beginning of therapy, Lorista® N may cause a decrease in blood pressure, dizziness or drowsiness, thus indirectly affecting the psycho-emotional state. For safety reasons, patients should first assess their response to treatment before engaging in activities requiring increased alertness.

Active ingredient

Hydrochlorothiazide, Losartan

Composition

1 film-coated tablet contains:

Core:

Active ingredients:

Hydrochlorothiazide 12.50 mg

Losartan potassium 50.00 mg

Excipients:

Pregelatinized starch, microcrystalline cellulose, lactose monohydrate, magnesium stearate

Film shell:

Hypromellose, macrogol-4000, quinoline yellow dye (E104), titanium dioxide (E171), talc

Pregnancy

Pregnancy

The use of Lorista® N is contraindicated during pregnancy. When planning pregnancy, it is recommended that the patient be transferred to alternative antihypertensive therapy, taking into account the safety profile. If pregnancy is confirmed, you should stop taking Lorista® N and, if necessary, switch to alternative antihypertensive therapy.

The drug Lorista® N, like other drugs that have a direct effect on the RAAS, can cause adverse effects in the fetus (impaired renal function, delayed ossification of fetal skull bones, oligohydramnios) and neonatal toxic effects (renal failure, arterial hypotension, hyperkalemia). If, nevertheless, the drug Lorista® N was used in the II-III trimesters of pregnancy, then it is necessary to conduct an ultrasound examination of the kidneys and bones of the fetal skull.

There is limited experience with the use of hydrochlorothiazide during pregnancy (especially in the first trimester). Preclinical data regarding safety are insufficient. Hydrochlorothiazide penetrates the placental barrier and is detected in umbilical cord blood. Taking into account the mechanism of pharmacological action of hydrochlorothiazide, its use in the second and third trimesters of pregnancy can disrupt fetoplacental perfusion and lead to the development of complications such as jaundice, water-electrolyte imbalance and thrombocytopenia in the fetus and newborn. Cases of the development 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 gestosis in the second half of pregnancy (edema, arterial hypertension or preeclampsia), as it increases the risk of a decrease in 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 gestosis.

Breastfeeding period

The drug Lorista® N is contraindicated during breastfeeding, as there is no experience with its use. The use of other antihypertensive drugs is recommended based on the safety profile. It is not known whether losartan is excreted in breast milk.

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

Contraindications

· Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome, since Lorista® N contains lactose.

· Hypersensitivity to losartan, hydrochlorothiazide and other sulfonamide derivatives, as well as to excipients.

· Age under 18 years (efficacy and safety of use have not been established).

· Pregnancy, breastfeeding period.

Hypokalemia or hypercalcemia resistant to therapy.

· Refractory hyponatremia.

· Anuria, severe renal failure (creatinine clearance less than 30 ml/min).

· Severe liver failure (more than 9 points on the Child-Pugh scale), cholestasis and obstructive diseases of the biliary tract.

· Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate or severe renal impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m2 body surface area).

· Concomitant use with ACE inhibitors in patients with diabetic nephropathy.

Interaction

Hydrochlorothiazide

Not recommended drug combinations

Lithium preparations

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

Combinations of drugs requiring special attention

Drugs that can cause polymorphic ventricular tachycardia of the “pirouette” type

Hydrochlorothiazide should be used with extreme caution concomitantly with drugs such as:

· class IA antiarrhythmic drugs (quinidine, hydroquinidine, disopyramide, procainamide);

Class III antiarrhythmic drugs (dofetilide, ibutilide, bretylium tosylate, sotalol, dronedarone, amiodarone);

other (non-antiarrhythmic) medicines such as:

– neuroleptics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine, fluphenazine), benzamides (amisulpride, sultopride, sulpride, tiapride), butyrophenones (droperidol, haloperidol), pimozide, sertindole;

– antidepressants: tricyclic antidepressants, selective serotonin reuptake inhibitors (citalopram, escitalopram);

– antibacterial agents: fluoroquinolones (levofloxacin, moxifloxacin, sparfloxacin, ciprofloxacin), macrolides (erythromycin for intravenous administration, azithromycin, clarithromycin, roxithromycin, spiramycin), co-trimoxazole;

– antifungal agents: azoles (voriconazole, itraconazole, ketoconazole, fluconazole);

– antimalarials (quinine, chloroquine, mefloquine, halofantrine, lumefantrine);

– antiprotozoal drugs (pentamidine for parenteral administration);

– antianginal drugs (ranolazine, bepridil);

– antitumor agents (vandetanib, arsenic trioxide, oxaliplatin, tacrolimus);

– antiemetics (domperidone, ondansetron);

– drugs affecting gastrointestinal motility (cisapride);

– antihistamines (astemizole, terfenadine, mizolastine);

– other medicines (anagrelide, vasopressin, difemanil methyl sulfate, ketanserin, probucol, propofol, sevoflurane, terlipressin, terodiline, cilostazol).

Due to the increased risk of ventricular arrhythmias, especially polymorphic ventricular tachycardia of the “pirouette” type (risk factor – hypokalemia), the potassium content in the blood plasma should be determined and, if necessary, adjusted before starting combination therapy with hydrochlorothiazide with the above drugs. It is necessary to monitor the patient’s clinical condition, blood plasma electrolyte levels and ECG parameters. In patients with hypokalemia, it is necessary to use drugs that do not cause polymorphic ventricular tachycardia of the “pirouette” type.

Medicines that can prolong the QT interval

The simultaneous use of hydrochlorothiazide with drugs that can prolong 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 developing torsade de pointes (TdP). When using such combinations, it is necessary to regularly record an ECG (to detect prolongation of the QT interval), as well as monitor the potassium content in the blood plasma.

Drugs that can cause hypokalemia: amphotericin B (with intravenous administration), gluco- and mineralocorticosteroids (with systemic use), tetracosactide (ACTH), glycyrrhizic acid (carbenoxolone, preparations containing licorice root), laxatives that stimulate intestinal motility. Increased risk of hypokalemia when used simultaneously with hydrochlorothiazide (additive effect). Regular monitoring of the potassium content in the blood plasma is necessary, and, if necessary, its correction. During therapy with hydrochlorothiazide, it is recommended to use laxatives that do not stimulate intestinal motility.

Cardiac glycosides

Hypokalemia and hypomagnesemia caused by the action of thiazide diuretics increase the toxicity of cardiac glycosides. When using hydrochlorothiazide and cardiac glycosides simultaneously, you should regularly monitor the concentration of potassium in the blood plasma, ECG readings, and, if necessary, adjust therapy.

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 concomitantly prescribed antihypertensive drugs.

It is recommended to stop taking 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 (neuroleptics), antidepressants, anxiolytics, narcotic analgesics and general anesthesia

It is possible to enhance the antihypertensive effect of hydrochlorothiazide and potentiate orthostatic hypotension (additive effect).

Non-depolarizing muscle relaxants (eg, tubocurarine)

The effect of non-depolarizing muscle relaxants may be enhanced.

Adrenergic agonists (pressor amines)

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

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (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 effects of high doses of salicylates on the central nervous system.

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 concomitantly with caution due to the risk of lactic acidosis due to 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 as hydrochlorothiazide increases serum uric acid concentrations. Thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Amantadine

Thiazide diuretics (including hydrochlorothiazide) may reduce the clearance of amantadine, lead to increased plasma concentrations of amantadine and increase the risk of adverse effects.

Anticholinergic drugs (cholinergic blockers)

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

Cytotoxic (antitumor) drugs

Thiazide diuretics reduce the renal excretion of cytotoxic drugs (for example, cyclophosphamide and methotrexate) and potentiate their myelosuppressive effects.

Methyldopa

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

Antiepileptic drugs (carbamazepine, oxcarbazepine, topiramate)

Risk of developing symptomatic hyponatremia. When using hydrochlorothiazide and carbamazepine simultaneously, it is necessary to monitor the patient’s condition and monitor the sodium level in the blood serum. When using hydrochlorothiazide and topiramate simultaneously, the level of topiramate in the blood serum should also be monitored, and if necessary, prescribe potassium supplements or adjust the dose of topiramate.

Selective serotonin reuptake inhibitors

When used simultaneously with thiazide diuretics, hyponatremia may be potentiated. Monitoring of sodium levels in blood plasma is necessary.

Cyclosporine

With simultaneous use of thiazide diuretics and cyclosporine, the risk of developing 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 developing acute renal failure, especially when using high doses of iodinated contrast agents. Before using iodinated contrast agents, it is necessary to compensate for fluid loss.

Calcium preparations

With simultaneous use, it is possible to increase the calcium content in the blood plasma and develop hypercalcemia due to a decrease in the excretion of calcium ions by the kidneys. If simultaneous administration of calcium-containing drugs is necessary, the calcium level in the blood plasma should be monitored and the dose of calcium supplements 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 in the gastrointestinal tract by 85% and 43%, respectively.

Losartan

Rifampicin and fluconazole reduced the concentration of the active metabolite. The clinical significance of this interaction has not been studied.

Concomitant use of losartan, as well as other drugs acting on the RAAS, with potassium-sparing diuretics (spironolactone, triamterene, amiloride, eplerenone), potassium supplements or salt substitutes containing potassium may lead to an increase in serum potassium levels. Simultaneous use is not recommended.

The rate of excretion of lithium ions may be reduced. Therefore, when using ARA II concomitantly with lithium salts, serum lithium concentrations should be carefully monitored.

With simultaneous use of ARA II with NSAIDs (for example, selective inhibitors of cyclooxygenase 2 (COX-2) and non-selective NSAIDs, acetylsalicylic acid in doses that have an anti-inflammatory effect), a decrease in the antihypertensive effect is possible. The simultaneous use of ARB II or diuretics with NSAIDs is accompanied by an increased risk of developing renal dysfunction, including acute renal failure, and an increase in serum potassium levels (especially in patients with a history of renal dysfunction). Concomitant use with NSAIDs should be done with caution, especially in elderly patients. In this case, it is necessary to adequately replenish blood volume and periodically monitor renal function from the moment of initiation of therapy and subsequently.

In some patients with impaired renal function who are using NSAIDs, including selective COX-2 inhibitors, concomitant use of ARB II may cause further reversible deterioration of renal function.

Double blockade of the RAAS

Concomitant use of ARA II with aliskiren and 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 ARB II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

In patients with atherosclerosis, heart failure or diabetes mellitus with target organ damage, double blockade of the RAAS (with simultaneous use of ARB II and ACE inhibitors) is accompanied by an increased incidence of arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with the use of a drug from one of the listed groups as monotherapy.

When used simultaneously with other drugs that cause arterial hypotension, including tricyclic antidepressants, antipsychotics (neuroleptics), baclofen, amifostine, the risk of developing arterial hypotension increases.

Overdose

Combination hydrochlorothiazide + losartan

There is no information about overdose with the combination of hydrochlorothiazide + losartan.

Treatment: symptomatic and supportive therapy. Lorista® N should be discontinued and the patient should be carefully monitored. If necessary: ​​induce vomiting (if the patient has recently taken the drug), replenish blood volume, correct disturbances in water-electrolyte metabolism and a pronounced decrease in blood pressure.

Hydrochlorothiazide

Symptoms: the most common manifestations of an overdose of hydrochlorothiazide are an increase in diuresis, accompanied by acute loss of fluid (dehydration) and electrolyte disturbances (hypokalemia, hyponatremia, hypochloremia). An overdose of hydrochlorothiazide may be manifested by the following symptoms:

· from the cardiovascular system: tachycardia, decreased blood pressure, shock;

· from the nervous system: weakness, confusion, dizziness and spasms of the calf muscles, 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 indicators: hypokalemia, hyponatremia, hypochloremia, alkalosis, increased urea nitrogen in the blood (especially in patients with renal failure).

Treatment: in case of overdose, symptomatic and supportive therapy is carried out. If the drug has been taken recently, induction of vomiting or gastric lavage is indicated to remove hydrochlorothiazide. The absorption of hydrochlorothiazide can be reduced by oral administration of activated charcoal. In case of a decrease in blood pressure or shock, the volume of blood volume (by introducing plasma-substituting fluids) and the deficiency of electrolytes (potassium, sodium) should be replenished. For respiratory problems, oxygen inhalation or artificial ventilation is indicated. Water and electrolyte balance (especially serum potassium levels) and renal function should be monitored until they return to normal. There is no specific antidote. Hydrochlorothiazide is eliminated by hemodialysis, but the extent of its elimination has not been established.

Losartan (data limited)

Symptoms: marked decrease in blood pressure, tachycardia, possible bradycardia caused by parasympathetic (vagal) stimulation.

Treatment: symptomatic therapy, hemodialysis is ineffective.

Clinical pharmacology

Pharmacodynamics

Combination hydrochlorothiazide + losartan

Lorista® N is a combination drug, the components of which have an additive antihypertensive effect and cause a more pronounced decrease in blood pressure (BP) compared to their separate use. Due to its diuretic effect, hydrochlorothiazide increases plasma renin activity, aldosterone secretion, reduces serum potassium levels and increases the concentration of angiotensin II in blood plasma. Losartan blocks the physiological effects of angiotensin II and, by inhibiting aldosterone secretion, can neutralize the loss of potassium ions caused by the diuretic.

Losartan has a uricosuric effect. Hydrochlorothiazide causes a moderate increase in the concentration of uric acid; when losartan is used simultaneously with hydrochlorothiazide, hyperuricemia caused by the diuretic is reduced.

The antihypertensive effect of the combination of hydrochlorothiazide + losartan lasts for 24 hours. Despite a significant reduction in blood pressure, the use of the combination of hydrochlorothiazide + losartan does not have a clinically significant effect on heart rate (HR).

The combination of hydrochlorothiazide + losartan is effective in men and women, as well as in younger (under 65 years of age) and elderly (65 years of age and older) patients.

Hydrochlorothiazide

The mechanism of action of thiazide diuretics (thiazides) has not been fully studied. Thiazides block the reabsorption of sodium and chloride ions at the beginning of the renal tubules. Thus, they increase the excretion of sodium and chlorine and therefore the excretion of water from the body.

As a result of the diuretic effect of hydrochlorothiazide, the volume of circulating fluid (CVF) decreases, as a result of which the activity of renin and the content of aldosterone in the blood plasma increases. This leads to an increase in the excretion of potassium ions by the kidneys and a decrease in the potassium content in the blood plasma (hypokalemia). Hydrochlorothiazide also increases the excretion of magnesium ions and reduces the excretion of calcium ions by the kidneys. Thiazide diuretics reduce the excretion of uric acid by the kidneys and increase its concentration in the blood plasma. Thiazide diuretics also reduce carbonic anhydrase activity by increasing the excretion of bicarbonate ions. But this effect is usually weak and does not affect the pH of the urine.

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 after approximately 4 hours. The duration of the diuretic effect of hydrochlorothiazide ranges from 6 to 12 hours.

Hydrochlorothiazide has an antihypertensive effect. Thiazide diuretics have no effect on normal blood pressure.

Losartan

Losartan is an angiotensin II receptor antagonist (ARA II) for oral administration, of a non-protein nature.

Angiotensin II is a powerful vasoconstrictor and the main hormone of the renin-angiotensin-aldosterone system (RAAS). Angiotensin II binds to AT1 receptors, which are found in many tissues (eg, vascular smooth muscle, adrenal gland, kidney, and myocardium) and mediate various biological effects of angiotensin II, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates the proliferation of smooth muscle cells.

Losartan selectively blocks AT1 receptors. Under invivo and invitro conditions, losartan and its biologically active carboxyl metabolite (EXP-3174) block all physiologically significant effects of angiotensin II on AT1 receptors, regardless of the route of its synthesis. Losartan is not agonistic and does not block other hormonal receptors or ion channels important in the regulation of the cardiovascular system. Losartan does not inhibit the activity of angiotensin-converting enzyme (ACE) (kininase II), an enzyme that is involved in the metabolism of bradykinin. Accordingly, it does not cause an increase in the incidence of bradykinin-mediated adverse effects.

Losartan indirectly causes activation of AT2 receptors by increasing the concentration of angiotensin II in the blood plasma.

Suppression of the regulation of renin secretion under the influence of angiotensin II by the “negative feedback” mechanism during treatment with losartan causes an increase in plasma renin activity, which leads to an increase in the concentration of angiotensin II in the blood plasma. However, the antihypertensive effect and suppression of aldosterone secretion persist, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, plasma renin activity and angiotensin II concentration decrease to initial values ​​within 3 days.

Losartan and its main active metabolite have a significantly higher affinity for AT1 receptors compared to AT2 receptors. The active metabolite is 10-40 times more active than losartan.

The incidence of cough is comparable with the use of losartan or hydrochlorothiazide and significantly lower than with the use of an ACE inhibitor.

In patients with arterial hypertension, proteinuria and without diabetes mellitus, treatment with losartan significantly reduces proteinuria, albumin and immunoglobulin G (IgG) excretion. Losartan supports glomerular filtration and reduces the filtration fraction. Losartan reduces serum uric acid concentrations (usually less than 0.4 mg/dL) throughout therapy. Losartan has no effect on autonomic reflexes and does not affect the concentration of norepinephrine in the blood plasma.

In patients with left ventricular failure, losartan in doses of 25 mg and 50 mg has positive hemodynamic and neurohumoral effects, characterized by an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, total peripheral vascular resistance (TPVR), mean blood pressure, heart rate and a decrease in plasma concentrations of aldosterone and norepinephrine. The risk of developing arterial hypotension in patients with heart failure depends on the dose of losartan.

Once daily use of losartan in patients with mild to moderate essential hypertension causes a significant reduction in systolic and diastolic blood pressure. The antihypertensive effect continues for 24 hours while maintaining the natural circadian rhythm of blood pressure. The degree of blood pressure reduction at the end of the dosing interval is 70-80% compared with the antihypertensive effect 5-6 hours after taking losartan.

Losartan is effective in men and women, as well as in older patients (65 years of age and older) and younger patients (under 65 years of age). Discontinuation of losartan in patients with arterial hypertension does not lead to a sharp increase in blood pressure (there is no drug withdrawal syndrome). Losartan does not have a clinically significant effect on heart rate.

Pharmacokinetics

The pharmacokinetics of losartan and hydrochlorothiazide when taken simultaneously does not differ from that when they are used separately.

Hydrochlorothiazide

Action and distribution

Hydrochlorothiazide is incompletely, but rather quickly absorbed from the gastrointestinal tract (GIT). After oral administration at a dose of 100 mg, the maximum concentration (Cmax) of hydrochlorothiazide in the blood plasma is reached after 1.5-2.5 hours. At maximum diuretic activity (approximately 4 hours after administration), the concentration of hydrochlorothiazide in the blood plasma is 2 mcg/ml. The connection with blood plasma proteins is 40%.

Hydrochlorothiazide crosses the placental barrier and is excreted into breast milk, but does not cross the blood-brain barrier.

Metabolism

Hydrochlorothiazide is not metabolized in the human body.

Withdrawal

The primary route of excretion is through the kidneys (filtration and secretion) unchanged. Approximately 61% of an oral dose is eliminated within 24 hours. In patients with normal renal function, the half-life (T½) ranges from 5.6 to 14.8 hours (average 6.4 hours).

Pharmacokinetics in special patient groups

Renal dysfunction

In patients with moderate renal failure, T½ of hydrochlorothiazide averages 11.5 hours, and in patients with creatinine clearance (CC) less than 30 ml/min it averages 20.7 hours.

Losartan

Suction

After oral administration, losartan is well absorbed and undergoes first-pass metabolism through the liver to form an active carboxyl metabolite (EXP-3174) and inactive metabolites. Systemic bioavailability is approximately 33%. Average Cmax levels in the blood plasma of losartan and its active metabolite are achieved after 1 hour and 3-4 hours, respectively.

Distribution

More than 99% of losartan and EXP-3174 are bound to plasma proteins, predominantly albumin. The volume of distribution of losartan is 34 liters. Penetrates the blood-brain barrier very poorly.

Metabolism

Approximately 14% of a dose of losartan administered intravenously or taken orally is metabolized to form an active metabolite. After oral and/or intravenous administration of 14C-losartan potassium, circulating plasma radioactivity was mainly determined by losartan and its active metabolite. In addition to the active metabolite, inactive metabolites are formed, including two main metabolites formed by hydroxylation of the butyl group of the chain, and a minor metabolite – N-2-tetrazole glucuronide.

Taking the drug with food does not have a clinically significant effect on its serum concentrations.

Withdrawal

Plasma clearance of losartan and its active metabolite is 600 ml/min and 50 ml/min, respectively, renal clearance of losartan and its active metabolite is 74 ml/min and 26 ml/min, respectively. After oral administration, only about 4% of the dose taken is excreted unchanged by the kidneys and about 6% as an active metabolite. The pharmacokinetic parameters of losartan and its active metabolite when taken orally (in doses up to 200 mg) are linear.

T½ in the terminal phase of losartan and the active metabolite is 2 hours and 6-9 hours, respectively. There is no accumulation of losartan and its active metabolite when used at a dose of 100 mg once a day.

Excreted mainly through the intestines with bile (58%), kidneys – 35%.

Pharmacokinetics in special patient groups

Liver dysfunction

In patients with mild to moderate alcoholic cirrhosis after oral administration of losartan, plasma concentrations of losartan and the active metabolite were 5 and 1.7 times higher than in young male volunteers, respectively.

Losartan and its active metabolite are not removed by hemodialysis.

Elderly patients

Plasma concentrations of losartan, its active metabolite and hydrochlorothiazide in elderly patients with arterial hypertension did not differ significantly from those in young patients.

Storage conditions

At a temperature not exceeding 25°C, in original packaging.

Keep out of the reach of children.

Shelf life

5 years.

Do not use the drug after the expiration date.

Manufacturer

KRKA-RUS, Russia