Lorista ND, 100 mg+25 mg 60 pcs

hypotensive combination drug (diuretic + angiotensin II receptor antagonist)

Indications

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

· Reduced risk of associated 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 in persons under 18 years of age (efficacy and safety of use have not been established)

Patients with impaired renal function or patients on hemodialysis

Lorista® ND should not be used for initial therapy in patients with moderate renal impairment (creatinine clearance 30-50 ml/min). Lorista® ND is not recommended for use in patients on hemodialysis. The drug Lorista® ND 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

Lorista® ND should not be used for initial therapy in patients with reduced blood volume.

Patients with liver dysfunction

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

Elderly patients

Lorista® ND should not be used for initial therapy in elderly patients.

The use of Lorista® ND in patients with acute myocardial infarction is not recommended due to insufficient experience in clinical use. Also, the drug Lorista® ND should not be used to relieve a hypertensive crisis.

Drug Lorista® ND

Hypersensitivity reactions

In patients with a history of angioedema (swelling of the face, lips, pharynx/larynx and/or tongue), the use of the drug must be monitored (see section “Side effects”).

Renal and liver dysfunction

The drug Lorista® ND is contraindicated for use in patients with severely impaired liver function and severely impaired renal function (creatinine clearance less than 30 ml/min) (see section “Contraindications”).

Embryotoxicity

The use of drugs that affect the RAAS during the second and third trimester of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in neonates include calvarial hypoplasia, anuria, hypotension, renal failure and death. If pregnancy is diagnosed, Lorista® ND should be immediately discontinued (see section “Use during pregnancy and breastfeeding”).

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 ammonium accumulation in the blood serum 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 concentration 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. 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 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 are: 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

Double blockade of the RAAS

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

Arterial hypotension and decreased blood volume

In patients with reduced blood volume or sodium content in the blood plasma, which developed due to intensive diuretic therapy, a salt-restricted diet, diarrhea or vomiting, symptomatic arterial hypotension may develop, especially after taking the first dose of Lorista® ND. Correction of such conditions must be carried out before prescribing Lorista® ND.

Water-electrolyte imbalance

Fluid and electrolyte imbalance is common in patients with renal failure with or without diabetes mellitus, so careful monitoring of these patients is necessary. Careful monitoring of potassium levels in blood plasma or CK is necessary, especially in patients with heart failure and CK 30-50 ml/min.

During treatment with Lorista® ND, it is not recommended to take potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes.

Aortic or mitral stenosis, HOCM

Like all drugs that have a vasodilating effect, ARA II should be prescribed with caution to patients with aortic or mitral stenosis or HOCM.

IHD and cerebrovascular diseases

Like all drugs that have a vasodilating effect, ARA II should be prescribed with caution to patients with coronary artery disease or cerebrovascular diseases, since a pronounced decrease in blood pressure in this group of patients can lead to the development of myocardial infarction or stroke.

Chronic heart failure (CHF)

As with the use of other drugs that act on the RAAS, patients with CHF (with or without renal impairment) are at risk of developing severe hypotension or acute renal failure.

Primary hyperaldosteronism

Since patients with primary hyperaldosteronism, as a rule, do not have a positive response to therapy with antihypertensive drugs that act by inhibiting the RAAS, the use of Lorista® ND is not recommended in this group of patients.

Liver dysfunction

Data from pharmacokinetic studies indicate that the concentration of losartan in the blood plasma in patients with cirrhosis of the liver is significantly increased, therefore, patients with a history of mild or moderate impaired liver function should prescribe Lorista ND with caution. There is no experience with the use of losartan in patients with severe liver dysfunction (more than 9 points on the Child-Pugh scale), therefore Lorista® ND should not be used in this group of patients (see section “Contraindications”).

Renal dysfunction

Due to inhibition of the RAAS, changes in renal function, including the development of renal failure, have been observed in some susceptible patients. These changes in renal function may return to normal after treatment is stopped.

Some drugs that affect the RAAS may increase plasma urea and creatinine concentrations in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney. Similar effects have been reported with losartan. Such renal dysfunction may be reversible after discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or renal artery stenosis of a solitary kidney.

Special patient groups

Race

Analysis of data from the entire population of patients included in the LIFE study to study the effect of losartan on reducing the incidence of the main composite endpoint of the study in patients with arterial hypertension and left ventricular hypertrophy (n = 9193), showed that the ability of losartan, compared with atenolol, to reduce the risk of stroke and myocardial infarction, as well as reduce the rate of cardiovascular mortality in patients with arterial hypertension and left ventricular hypertrophy (by 13.0%, p = 0.021) does not apply to patients of the black race, although both treatment regimens effectively reduced blood pressure in these patients. In this study, losartan, compared with atenolol, reduced cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy of all races except blacks (n = 8660, p = 0.003). However, in this study, black patients receiving atenolol had a lower risk of the study’s primary composite endpoint (i.e., lower composite incidence of cardiovascular death, stroke, and myocardial infarction) compared with race-matched patients receiving losartan (p = 0.03).

Children and teenagers

The effectiveness and safety of the combination hydrochlorothiazide + losartan in children and adolescents under 18 years of age have not been established.

If oliguria or arterial hypotension develops in newborns whose mothers took Lorista® ND during pregnancy, symptomatic therapy aimed at maintaining blood pressure and renal perfusion is necessary. Blood transfusions or dialysis may be required to prevent hypotension and/or maintain renal function.

Elderly patients

Clinical studies have not revealed any particularities regarding the safety and effectiveness of Lorista® ND in elderly patients (over 65 years of age).

Special information on excipients

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

No studies have been conducted to assess the effect on the ability to drive vehicles and operate machines. When driving vehicles or operating machinery, you should be careful

Active ingredient

Hydrochlorothiazide, Losartan

Composition

1 film-coated tablet contains:

Core:

Active ingredients:

Hydrochlorothiazide 25.00 mg

Losartan potassium 100.00 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® ND is contraindicated during pregnancy.

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.

Medicines that act directly on the RAAS can cause serious damage and death to the developing fetus, therefore, if pregnancy is diagnosed, Lorista® ND should be immediately discontinued.

Although there is no experience with the use of Lorista® ND in pregnant women, preclinical studies in animals have shown that administration of losartan leads to the development of serious embryonic and neonatal damage and death of the fetus or offspring. It is believed that the mechanism of these phenomena is due to the effect on the RAAS.

Renal perfusion in the fetus, dependent on the development of the RAAS, appears in the second trimester, so the risk to the fetus increases if Lorista® ND is used in the second or third trimester of pregnancy.

The use of drugs that affect the RAAS during the second and third trimester of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. The development of oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in neonates include calvarial hypoplasia, anuria, hypotension, renal failure and death.

The above undesirable outcomes are usually caused by the use of drugs that affect the RAAS in the second and third trimester of pregnancy. Most epidemiological studies examining the development of fetal abnormalities following the use of antihypertensive drugs in the first trimester of pregnancy have found no differences between drugs acting on the RAAS and other antihypertensive drugs. When prescribing antihypertensive therapy to pregnant women, it is important to optimize possible outcomes for the mother and fetus.

If it is impossible to select an alternative therapy instead of therapy with drugs that affect the RAAS, it is necessary to inform the patient about the possible risk of therapy to the fetus. Periodic ultrasound examinations are necessary to assess the intra-amniotic space. If oligohydramnios is detected, it is necessary to stop taking the drug Lorista® ND, unless it is vital for the mother. Depending on the week of pregnancy, appropriate fetal tests must be carried out. Patients and physicians should be aware that oligohydramnios may not be detected until irreversible fetal damage occurs. Careful monitoring of newborns whose mothers took Lorista® ND during pregnancy is necessary to monitor arterial hypotension, oliguria and hyperkalemia.

Breastfeeding period

The use of Lorista® ND is contraindicated during breastfeeding.

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.

It is not known whether losartan is excreted in breast milk. Since many drugs are excreted in breast milk and there is a risk of developing possible adverse effects in a breastfed baby, a decision should be made to stop breastfeeding or to discontinue the drug Lorista® ND, taking into account the need for the mother to take it.

Contraindications

Lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome, since Lorista® ND contains lactose.
Hypersensitivity to losartan, hydrochlorothiazide and other excipients.
Hypersensitivity to other sulfonamide derivatives.
Anuria.
Severe renal dysfunction (creatinine clearance less than 30 ml/min).
Severe liver dysfunction.
Pregnancy and breastfeeding period.
Age up to 18 years (efficacy and safety of use have not been established).
Concomitant use with aliskiren and drugs containing aliskiren 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).
Concomitant use with ACE inhibitors in patients with diabetic nephropathy.

Side Effects

In clinical studies with the hydrochlorothiazide + losartan combination, no adverse reactions specific to this combination were observed. Adverse reactions were limited to those already reported with losartan and/or hydrochlorothiazide alone. The total incidence of adverse reactions reported with this combination was comparable to that with placebo. Treatment discontinuation rates were also comparable to those in patients receiving placebo.

In general, treatment with the hydrochlorothiazide + losartan combination was well tolerated. In most cases, adverse reactions were mild, transient and did not require discontinuation of therapy.

In controlled clinical trials for the treatment of hypertension, dizziness was the only drug-related adverse reaction that was greater than 1% greater than placebo.

As shown in controlled clinical studies, losartan in combination with hydrochlorothiazide is generally well tolerated in patients with arterial hypertension and left ventricular hypertrophy. The most common adverse reactions were systemic and non-systemic dizziness, weakness/fatigue.

During post-marketing use of this combination, clinical trials conducted and/or post-registration use of individual active ingredients of the combination, the following additional adverse reactions were reported.

Blood and lymphatic system disorders: thrombocytopenia, anemia, aplastic anemia, hemolytic anemia, leukopenia, agranulocytosis.

Immune system disorders: anaphylactic reactions, angioedema, including swelling of the larynx and vocal folds with the development of airway obstruction and/or swelling of the face, lips, pharynx and/or tongue in patients taking losartan were observed rarely (≥ 0.01% and < 0.1% of cases), some of these patients had indications of the development of angioedema in the anamnesis when using other medicines, including ACE inhibitors.

Metabolic and nutritional disorders: anorexia, hyperglycemia, hyperuricemia, imbalance of blood electrolytes, including hyponatremia and hypokalemia.

Mental disorders: insomnia, anxiety.

Nervous system disorders: dysgeusia, headache, migraine, paresthesia.

Visual disturbances: xanthopsia, transient visual impairment.

Cardiac disorders: palpitations, tachycardia.

Vascular disorders: dose-dependent orthostatic effects, necrotizing angiitis (vasculitis), cutaneous vasculitis.

Respiratory, thoracic and mediastinal disorders: cough, nasal congestion, pharyngitis, sinus disorders (sinusitis), upper respiratory tract infections, adult respiratory distress syndrome (including pneumonitis and pulmonary edema).

Digestive system disorders: dyspepsia, abdominal pain, esophageal reflux, gastrointestinal colic, diarrhea, constipation, nausea, vomiting, pancreatitis, sialadenitis.

Disorders of the liver and biliary tract: hepatitis, jaundice (intrahepatic cholestatic jaundice).

Skin and subcutaneous tissue disorders: skin rash, pruritus, purpura (including Henoch-Schönlein purpura), toxic epidermal necrolysis, urticaria, erythroderma, photosensitivity, lupus-like syndrome.

Musculoskeletal and connective tissue disorders: back pain, muscle cramps, muscle spasms, myalgia, arthralgia.

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

Genital and breast disorders: erectile dysfunction/impotence.

General disorders and disorders at the injection site: chest pain, swelling, malaise, fever, weakness.

Laboratory and instrumental data: liver dysfunction (rarely increased alanine aminotransferase activity in blood plasma).

Laboratory indicators

In controlled clinical studies, clinically significant changes in standard laboratory parameters were rarely observed while taking the combination of hydrochlorothiazide + losartan. Hyperkalemia (serum potassium > 5.5 mEq/L) was observed in 0.7% of patients, but in these studies there was no need to discontinue the hydrochlorothiazide + losartan combination due to the occurrence of hyperkalemia. Increases in plasma alanine aminotransferase activity were observed rarely and usually returned to normal after discontinuation of therapy.

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;

– antifungals: 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 level in the blood.

Drugs that can cause hypokalemia: amphotericin B (with intravenous administration), gluco- and mineralocorticosteroids (with systemic use), tetracosactide (ACTH), glycyrrhizic acid (carbenoxolone, drugs 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 potassium content 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 level in the blood 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

In clinical studies examining pharmacokinetic drug interactions, no clinically significant interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital were identified. Rifampin, being an inducer of drug metabolism, reduces the concentration of the active metabolite of losartan in the blood plasma. Clinical studies have examined the use of two inhibitors of the CYP3A4 isoenzyme: ketoconazole and erythromycin. Ketoconazole did not affect the metabolism of losartan to its active metabolite after intravenous administration of losartan. Erythromycin did not have a clinically significant effect when losartan was taken orally. Fluconazole, an inhibitor of the CYP2C9 isoenzyme, reduces the concentration of the active metabolite of losartan in the blood plasma, but the pharmacodynamic significance of the simultaneous use of losartan and inhibitors of the CYP2C9 isoenzyme has not been studied. It has been shown that patients who do not metabolize losartan into the active metabolite have a very rare and specific defect in the CYP2C9 isoenzyme. These data suggest that the metabolism of losartan to the active metabolite is carried out by the CYP2C9 isoenzyme, and not by the CYP3A4 isoenzyme.

Concomitant use of losartan, as well as other drugs that block angiotensin II or its effects, with potassium-sparing diuretics (for example, spironolactone, triamterene, amiloride, eplerenone), potassium supplements or potassium salts may lead to an increase in serum potassium.

As with other medicinal products that affect sodium excretion, losartan may decrease lithium excretion. Therefore, when using lithium preparations and ARA II simultaneously, it is necessary to carefully monitor the concentration of lithium in the blood serum.

Nonsteroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may reduce the effect of diuretics and other antihypertensive agents. As a result, the antihypertensive effect of ARA II or ACE inhibitors may be weakened when used simultaneously with NSAIDs, including selective COX-2 inhibitors.

In some patients with impaired renal function (for example, elderly or dehydrated patients, including those taking diuretics) receiving NSAID therapy, including selective COX-2 inhibitors, concomitant use of ARB II or ACE inhibitors may cause a further deterioration of renal function, including the development of acute renal failure. These effects are usually reversible, so concomitant use of these drugs should be done with caution in patients with impaired renal function.

Dual blockade of the RAAS using ARB II, ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, renal function and electrolyte levels in the blood plasma is necessary in patients taking simultaneously the drug Lorista® ND and other drugs that affect the RAAS. The simultaneous use of ARA II with aliskiren and drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or with moderate to severe renal impairment (GFR less than 60 ml/min/1.73 m2 body surface area) and is not recommended in other patients. The simultaneous use of ARB II with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Overdose

There is no data on the specific treatment of overdose with the combination of hydrochlorothiazide + losartan. Treatment is symptomatic and supportive. Taking Lorista® ND should be discontinued and the patient should be monitored. If the drug has been taken recently, it is recommended to induce vomiting, as well as eliminate dehydration, fluid and electrolyte disturbances, hepatic coma and lower blood pressure using standard methods.

Hydrochlorothiazide

Symptoms

The most common manifestation of an overdose of hydrochlorothiazide is 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, disturbances of 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 blood urea nitrogen (especially in patients with renal failure).

Treatment

In case of overdose, symptomatic and supportive therapy is provided. 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. In case of respiratory failure, 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

Information on overdose is limited.

Symptoms

The most likely manifestation of an overdose is a pronounced decrease in blood pressure and tachycardia; bradycardia can occur due to parasympathetic (vagal) stimulation.

Treatment

Symptomatic therapy; in case of development of symptomatic arterial hypotension, maintenance therapy is indicated.

Losartan and its active metabolite are not eliminated by hemodialysis.

Clinical pharmacology

Mechanism of action

Combination hydrochlorothiazide + losartan

The components of the drug Lorista® ND hydrochlorothiazide and losartan have an additive antihypertensive effect, reducing blood pressure (BP) to a greater extent than each of the components separately. It is believed that this effect is due to the complementary action of both components. Due to the diuretic effect, hydrochlorothiazide increases plasma renin activity (PRA), stimulates the secretion of aldosterone, increases the concentration of angiotensin II and reduces the potassium content in the blood serum. Taking losartan blocks all physiological effects of angiotensin II and, by suppressing the effects of aldosterone, may help reduce diuretic-associated potassium loss.

Losartan has a moderate and transient uricosuric effect. Hydrochlorothiazide causes a slight increase in plasma uric acid concentrations. The combination of losartan and hydrochlorothiazide helps reduce the severity of diuretic-induced hyperuricemia.

Hydrochlorothiazide

Thiazides usually have no effect on normal blood pressure levels.

Hydrochlorothiazide is a diuretic and antihypertensive agent. It affects the reabsorption of electrolytes in the distal tubules of the kidneys. Hydrochlorothiazide approximately equally increases the excretion of sodium and chloride ions. Natriuresis may be accompanied by a slight loss of potassium ions and bicarbonates.

Losartan

Angiotensin II is a powerful vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), as well as a decisive pathophysiological link in the development of arterial hypertension. Angiotensin II binds to AT1 receptors found in many tissues (vascular smooth muscle, adrenal glands, kidneys and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates the proliferation of smooth muscle cells. AT2 receptors are the second type of receptor to which angiotensin II binds, but its role in regulating cardiovascular function is unknown.

Losartan is a selective antagonist of angiotensin II AT1 receptors, highly effective when taken orally. Losartan and its pharmacologically active carboxylated metabolite (E-3174), both in vitro and in vivo, block all physiological effects of angiotensin II, regardless of its source or route of synthesis. Unlike some peptide angiotensin II antagonists, losartan does not have agonist properties.

Losartan selectively binds to AT1 receptors and does not bind or block receptors of other hormones and ion channels that play an important role in regulating the function of the cardiovascular system. In addition, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), which is responsible for the destruction of bradykinin. Therefore, effects not directly related to AT1 receptor blockade, such as increased bradykinin-mediated effects or the development of edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.

Pharmacodynamics

The drug Lorista® ND is a combination drug of losartan and hydrochlorothiazide. In patients with arterial hypertension and left ventricular hypertrophy, losartan, including in combination with hydrochlorothiazide, reduces the risk of cardiovascular morbidity and mortality, which was proven by assessing the combined incidence of stroke and myocardial infarction, as well as cardiovascular mortality in this category of 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 in the urine and a decrease in potassium levels in the blood (hypokalemia). Hydrochlorothiazide also increases the excretion of magnesium ions and reduces the excretion of calcium ions in the urine. Thiazide diuretics reduce the excretion of uric acid by the kidneys and increase its concentration in the blood. 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 suppresses the increase in systolic and diastolic blood pressure during angiotensin II infusion.

During the period of taking losartan, elimination of the negative feedback, which consists in the suppression of renin secretion by angiotensin II, leads to an increase in ARP. An increase in ARP leads to an increase in the concentration of angiotensin II in the blood plasma. With long-term (6-week) treatment of patients with arterial hypertension with losartan at a dose of 100 mg/day, a 2-3-fold increase in the concentration of angiotensin II in the blood plasma was observed at the time the maximum concentration (Cmax) of losartan was reached. In some patients, an even greater increase in angiotensin II concentrations was observed, especially with a short duration of treatment (2 weeks). Despite this, during treatment, an antihypertensive effect and a decrease in plasma aldosterone concentrations appeared after 2 and 6 weeks of therapy, indicating effective blockade of angiotensin II receptors. After discontinuation of losartan, ARP and angiotensin II concentrations decreased within 3 days to the values ​​observed before the start of losartan administration.

Since losartan is a specific antagonist of angiotensin II AT1 receptors, it does not inhibit ACE (kininase II), an enzyme that inactivates bradykinin. A study comparing the effects of losartan at doses of 20 mg and 100 mg with the effects of an ACE inhibitor on angiotensin I, angiotensin II and bradykinin showed that losartan blocked the effects of angiotensin I and angiotensin II without affecting the effects of bradykinin. This is due to the specific mechanism of action of losartan. The ACE inhibitor blocked responses to angiotensin I and increased the severity of the effects due to the action of bradykinin, without affecting the severity of the response to angiotensin II, demonstrating a pharmacodynamic difference between losartan and ACE inhibitors.

Concentrations of losartan and its active metabolite in blood plasma, as well as the antihypertensive effect of losartan increase with increasing dose of the drug. Since losartan and its active metabolite are ARA II, they both contribute to the antihypertensive effect.

In a study with a single dose of 100 mg losartan, which included healthy volunteers (men), oral administration of the drug under conditions of a high- and low-salt diet did not affect the glomerular filtration rate (GFR), effective renal plasma flow and filtration fraction. Losartan had a natriuretic effect that was more pronounced with a low-salt diet and did not appear to be associated with suppression of early sodium reabsorption in the proximal renal tubules. Losartan also caused a transient increase in renal excretion of uric acid.

In patients with arterial hypertension, proteinuria (at least 2 g/24 hours), without diabetes and taking losartan for 8 weeks at a dose of 50 mg with a gradual increase to 100 mg, there was a significant decrease in proteinuria (by 42%), fractional excretion of albumin and immunoglobulins (IgG). In these patients, losartan stabilized GFR and reduced the filtration fraction.

In postmenopausal women with arterial hypertension who took losartan at a dose of 50 mg/day for 4 weeks, there was no effect of therapy on the renal and systemic levels of prostaglandins.

Losartan does not affect autonomic reflexes and does not have a long-term effect on the concentration of norepinephrine in the blood plasma.

In patients with arterial hypertension, losartan in doses up to 150 mg/day did not cause clinically significant changes in serum concentrations of fasting triglycerides, total cholesterol and high-density lipoprotein cholesterol. At the same doses, losartan had no effect on fasting plasma glucose concentrations.

In general, losartan caused a decrease in serum uric acid concentrations (usually less than 0.4 mg/dL), which persisted with long-term treatment. In controlled clinical studies involving patients with arterial hypertension, no cases of drug withdrawal due to an increase in creatinine concentration or serum potassium levels were recorded.

In a 12-week parallel study, which included patients with left ventricular failure (NYHA functional class II-IV), most of whom were taking diuretics and/or cardiac glycosides, the effects of losartan at doses of 2.5 mg/day, 10 mg/day, 25 mg/day and 50 mg/day were compared with placebo. At doses of 25 mg/day and 50 mg/day, the drug exhibited positive hemodynamic and neurohormonal effects, which persisted throughout the study. Hemodynamic effects included an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, as well as a decrease in total peripheral vascular resistance, mean systemic blood pressure, and heart rate. The incidence of arterial hypotension in these patients depended on the dose of the drug. Neurohormonal effects included a decrease in plasma aldosterone and norepinephrine concentrations.

Pharmacokinetics

Hydrochlorothiazide

Action and distribution

Hydrochlorothiazide is not fully, but is absorbed quite quickly 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 groups of patients

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

When taken orally, losartan is well absorbed and undergoes first-pass metabolism through the liver to form an active carboxylated metabolite and inactive metabolites. The systemic bioavailability of losartan in tablet form is approximately 33%. The average Cmax of losartan and its active metabolite is reached after 1 hour and after 3-4 hours, respectively. When using losartan during a normal meal, no clinically significant effect on the plasma concentration profile of losartan was detected.

Distribution

Losartan and its active metabolite are bound to plasma proteins (mainly albumin) by at least 99%. The volume of distribution of losartan is 34 liters. Studies on rats have shown that losartan practically does not penetrate the blood-brain barrier.

Metabolism

Approximately 14% of a dose of losartan, when administered intravenously or taken orally, is converted into its active metabolite. After oral or intravenous administration of radioactive carbon-labeled losartan (14C losartan), the radioactivity of circulating blood plasma is primarily due to the presence of losartan and its active metabolite. Low efficiency of conversion of losartan to its active metabolite was observed in approximately 1% of patients participating in the study.

In addition to the active metabolite, biologically inactive metabolites are formed, including two major metabolites formed as a result of hydroxylation of the butyl side chain, and one minor one – N-2-tetrazole glucuronide.

Withdrawal

Plasma clearance of losartan and its active metabolite is about 600 ml/min and 50 ml/min, respectively. The renal clearance of losartan and its active metabolite is approximately 74 ml/min and 26 ml/min, respectively. When losartan is taken orally, about 4% of the dose is excreted unchanged by the kidneys and about 6% of the dose is excreted by the kidneys in the form of an active metabolite. Losartan and its active metabolite have linear pharmacokinetics when losartan is taken orally in doses up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a final T½ of approximately 2 hours and 6-9 hours, respectively. With a dosage regimen of 100 mg once a day, there is no significant accumulation of either losartan or its active metabolite in the blood plasma.

Losartan and its metabolites are excreted by the kidneys and through the intestines with bile. After oral administration of 14C losartan in men, about 35% of the radioactivity is found in the urine and 58% in the feces. After intravenous administration of 14C losartan in men, approximately 43% of radioactivity is found in urine and 50% in feces.

Pharmacokinetics in special groups of patients

Gender

It was noted that the concentration of losartan in the blood plasma in women with arterial hypertension is 2 times higher than the corresponding value in men with arterial hypertension. This pharmacokinetic difference is not clinically significant. The concentration of the active metabolite did not differ between men and women.

Liver dysfunction

When losartan was taken orally by patients with mild to moderate alcoholic cirrhosis, the concentrations of losartan and its active metabolite in the blood plasma were 5 and 1.7 times higher, respectively, than in young healthy male volunteers.

Renal dysfunction

Plasma concentrations of losartan in patients with creatinine clearance (CC) above 10 ml/min did not differ from those in patients with unchanged renal function. The area under the concentration-time curve (AUC) of losartan in patients on hemodialysis was approximately 2 times greater than the AUC of losartan in patients with normal renal function. Plasma concentrations of the active metabolite did not change in patients with impaired renal function or in patients on hemodialysis. Losartan and its active metabolite are not eliminated by hemodialysis.

Combination of losartan + hydrochlorothiazide

Pharmacokinetics in special groups of patients

Elderly patients

Concentrations of losartan and its active metabolite in blood plasma and the rate of absorption of hydrochlorothiazide in elderly patients with arterial hypertension do not differ significantly from these indicators in young patients with arterial hypertension.

Storage conditions

At a temperature not exceeding 30 ºС, in the 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