Losartan - instructions for use, dose, side effects, contraindications

Excipients: lactose monohydrate, microcrystalline cellulose, povidone K-25 (polyvinylpyrrolidone medium molecular weight), potato starch, silicon dioxide colloid (aerosil), magnesium stearate.

Shell accessories: Opadry II white [polyvinyl alcohol, talc, macrogol (polyethylene glycol), titanium dioxide].

1 tablet with a dosage of 50 mg contains:

Active substance: Losartan potassium - 50.0 mg.

Excipients: lactose monohydrate, microcrystalline cellulose, povidone K-25 (polyvinylpyrrolidone medium molecular weight), potato starch, silicon dioxide colloid (aerosil), magnesium stearate.

Shell accessories: Opadry II orange [polyvinyl alcohol, talc, macrogol (polyethylene glycol), titanium dioxide, iron oxide oxide yellow, iron oxide oxide red, lacquer aluminum based dye sunset yellow].

Description:

Tablets with a dosage of 12.5 mg. Round biconvex tablets, covered with a film coating of white color. On the cross section, the nucleus is white or almost white in color. Roughness of the surface of tablets is allowed.

Tablets with a dosage of 50 mg. Round biconvex tablets, covered with a film coat of light pinkish-orange color. On the cross section, the nucleus is white or almost white in color. Roughness of the surface of tablets is allowed.

Pharmacotherapeutic group:Drugs affecting the renin-angiotensin system. Angiotensin II antagonists. Losartan

ATX: & nbsp

C.09.C.A.01 Losartan

C.09.C.A Angiotensin II antagonists

Pharmacodynamics:

Mechanism of action

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

Losartan is a selective antagonist of angiotensin AT1 receptors II, highly effective at ingestion. Losartan and its pharmacologically active carboxylated metabolite (E-3174) as in vitro, and in vivo blocks all the physiological effects of angiotensin II regardless of its source or pathway of synthesis. Unlike some peptide angiotensin antagonists II losartan does not possess the properties of an agonist.

Losartan selectively binds to AT1receptors and does not bind or block receptors of other hormones and ion channels, which play an important role in regulating the function of the cardiovascular system. Besides, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), responsible for the destruction of the bradykinina. Consequently, effects that are not directly related to the blockade AT1-receptors, such as increased bradykinin-mediated effects or development of edema (losartan 1.7%, placebo 1.9%), are not related to the action of losartan.

Losartan suppresses an increase in systolic and diastolic blood pressure (BP) during the infusion of angiotensin II. At the moment of reaching the maximum concentration of losartan in the blood plasma (Cmah) after taking losartan in a dose of 100 mg the above-mentioned effect of angiotensin II is suppressed by approximately 85%, and 24 hours after a single and multiple doses - by 26-39%.

During the administration of losartan, the elimination of negative feedback, consisting of angiotensin inhibition II secretion of renin, leads to an increase in plasma renin activity (ARP). Increased ARP leads to an increase in the concentration of angiotensin II in blood plasma. At long-term (6-week) treatment of patients with AH losartan at a dose of 100 mg / day there was a 2-3-fold increase in the concentration of angiotensin II in blood plasma at the moment of reaching Cmah losartan.In some patients, an even greater increase in the concentration of angiotensin II was observed. especially with a short duration of treatment (2 weeks). Despite this, during the treatment, the antihypertensive effect and the decrease in the plasma aldosterone concentration were manifested after 2 and 6 weeks of therapy, which indicates an effective blockade of the angiotensin II receptors. After cancellation of losartan, ARP and angiotensin II concentration decreased for 3 days to the values observed before the start of losartan. Because the losartan is a specific antagonist of AT1 receptors of angiotensin II, it does not inhibit ACE (kininase II), an enzyme that inactivates bradykinin. A study comparing the effects of losartan in doses of 20 mg and 100 mg with the effects of an ACE inhibitor on the effect on angiotensin I. angiotensin II and bradykinin showed that losartan blocks 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 the response to angiotensin I and increased the severity of effects caused by the action of bradykinin, without affecting the severity of the response to angiotensin II. which demonstrates the pharmacodynamic difference between losartan and ACE inhibitors. The concentration of losartan and its active metabolite in the blood plasma, as well as the antihypertensive effect of losartan increase with increasing dose of the drug. As losartan and its active metabolite are antagonists of angiotensin II receptors (ARA II), they both contribute to the antihypertensive effect.

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

In patients with AH, proteinuria (not less than 2 g / 24 h), without diabetes mellitus 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 (lgG). In these patients losartan stabilized GFR and reduced the filtration fraction.

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

Losartan does not affect vegetative reflexes and does not have a lasting effect on the concentration of noradrenaline in the blood plasma.

In patients with AH losartan in doses up to 150 mg / day did not cause clinically significant changes in the concentration of fasting triglycerides, total cholesterol and high-density lipoprotein cholesterol. In the same doses losartan did not affect the concentration of glucose in the blood on an empty stomach.

In a clinical trial HEAAL the effect of high and low dose of ARA II (losartan) on the outcome of treatment of patients with chronic heart failure (CHF) included patients (n=3834) with CHF (II-IV functional class by classification NYHA) and intolerance to ACE inhibitors. Patients were observed for more than 4 years (median follow-up was 4.7 years) to compare the effects of losartan 50 mg / day and 150 mg / day for a reduction in all-cause mortality or hospitalization for heart failure. This study showed that losartan at a dose of 150 mg / day significantly reduced the risk of all-cause mortality and hospitalization for heart failure, as compared with a dose of 50 mg / day (hazard ratio [HR] 0.899, p = 0.027).

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

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

Pharmacokinetics:

Suction

Ingestion losartan is well absorbed and metabolized by "primary passage" through the liver to form an active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan in tablet form is approximately 33%. Mean maximum concentrations (Cmah) losartan and its active metabolite are achieved after 1 h and 3-4 h respectively. When losartan was taken during the usual meal, there was no clinically significant effect on the profile of losartan concentration in the blood plasma.

Distribution

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

Metabolism

Approximately 14% of losartan with intravenous administration and when ingested is converted into its active metabolite. After ingestion or intravenous administration of radiolabeled radiolabel (¹⁴With losartan) the radioactivity of circulating blood plasma is primarily due to the presence of losartan and its active metabolite in it. The low conversion efficiency of losartan in its active metabolite was observed in about 1 % patients who participated in the study.

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

Excretion

The 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 taking losartan, about 4% of the dose is excreted by the kidneys unchanged and about 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have a linear pharmacokinetics when administered to losartan in doses up to 200 mg.

After oral administration, the plasma concentrations of losartan and its active metabolite decrease polyexponentially with a finite half-life of about 2 and 6-9 hours, respectively. When the dosing regimen of the drug is 100 mg once a day, there is no significant accumulation in the blood plasma of either losartan or its active metabolite.

The excretion of losartan and its metabolites is carried out by the kidneys and through the intestine with bile. After oral administration ¹⁴With losartan in men, about 35% of radioactivity is found in urine and 58% in feces. After intravenous administration ^YWith losartan in men, approximately 43% of radioactivity is found in urine and 50% in feces.

Pharmacokinetics in specific patient groups

Elderly patients

The concentrations of losartan and its active metabolite in blood plasma in elderly male patients with AH do not significantly differ from these indices in young male patients with AH.

Floor

Values of losartan concentrations in blood plasma in women with AH were 2 times higher than the corresponding values in men with AH.The concentrations of active metabolite in men and women did not differ. This is an obvious pharmacokinetic difference, gem is no less clinically significant.

Patients with impaired hepatic function

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

Patients with impaired renal function

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

Indications:

- Arterial hypertension.

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

- Protection of the kidneys in patients with type 2 diabetes mellitus with proteinuria is a slowdown in the progression of renal failure, manifested by a decrease in the frequency of hypercreatininemia, the incidence of the terminal stage of chronic renal failure requiring hemodialysis or kidney transplantation, mortality rates, and a decrease in proteinuria.

- Chronic heart failure with ineffective treatment with ACE inhibitors or intolerance to AIF inhibitors. It is not recommended to transfer patients with heart failure and stable parameters when taking ACE inhibitors for drug therapy Losartan.

Contraindications:

- Hypersensitivity to losartan and other components of the drug.

- Simultaneous use with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic nephropathy.

- Simultaneous use with aliskiren and preparations containing aliskiren, in patients with diabetes mellitus and / or moderate or severe renal dysfunction (glomerular filtration rate (GFR) of less than 60 ml / min / 1.73 m²body surface area) (see "Interaction with Other Drugs").

- Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.

- Severe liver dysfunction (no experience of use).

- Pregnancy and the period of breastfeeding.

- Children under 18 years of age (efficacy and safety of use not established).

Carefully:

Bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney; hyperkalemia; condition after kidney transplantation (no experience of application); aortic or mitral stenosis; hypertrophic obstructive cardiomyopathy; heart failure with concomitant severe impairment of kidney function; severe heart failure (IV functional class by classification NYHA); heart failure with life-threatening arrhythmias; ischemic heart disease; cerebrovascular diseases; primary hyperaldosteronism; angioedema in history.

Patients with reduced circulating blood volume (eg, receiving treatment with large doses of diuretics) - symptomatic arterial hypotension may occur.

Pregnancy and lactation:

Medicines that directly affect RAAS can cause serious damage and death of the developing fetus, so when diagnosing a pregnancy, the drug Losartan should be immediately canceled and, if necessary, an alternative hypotensive therapy is prescribed.

Drug therapy Losartan You can not start during pregnancy. If patients planning a pregnancy continue losartan therapy is considered necessary, should be replaced losartan to alternative antihypertensive drugs that have an established safety profile when applied during pregnancy.

Although there is no experience with the drug Losartan in pregnant women, preclinical studies in animals have shown that taking the drug Losartan leads to the development of serious embryonic and neonatal lesions and death of the fetus or offspring. It is believed that the mechanism of these phenomena is due to the impact on the RAAS.

Renal perfusion in the fetus, depending on the development of RAAS, appears in the second trimester, so the risk to the fetus increases if the drug Losartan is used in the second or third trimester of pregnancy.

The use of drugs that affect RAAS in the second and third trimester of pregnancy reduces the function of the kidneys of the fetus and increases the incidence and mortality of the fetus and newborns. The development of oligohydramnion can be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include hypoplasia of the skull bones, anuria, arterial hypotension, renal failure and death.

The above undesirable outcomes are usually due to the use of drugs that affect RAAS in the second and third trimester of pregnancy. Most epidemiological studies on the development of fetal anomalies after the use of antihypertensive drugs in the first trimester of pregnancy have not revealed differences between drugs that affect RAAS and other antihypertensive drugs.When prescribing antihypertensive therapy for pregnant women, it is important to optimize the possible outcomes for the mother and fetus.

If it is impossible to choose an alternative therapy instead therapy medicinal products acting on the RAAS, it is necessary to inform the patient about the potential risks of therapy to the fetus. It is necessary to conduct periodic ultrasound examinations to assess the intra-amniotic space. When identifying oligohydramnion, it is necessary to stop taking the drug Losartan, unless it is vital to the mother. Depending on the week of pregnancy, appropriate fetal tests are necessary. Patients and physicians should be aware that the oligohydramnios may not be detected until irreversible damage to the fetus occurs. It is necessary to closely monitor the newborns whose mothers took the drug Losartan during pregnancy, in order to control arterial hypotension, oliguria and hyperkalemia.

It is not known whether losartan with breast milk. Since many drugs are excreted in breast milk and there is a risk of developing possible adverse effects in the child,breastfeeding should decide whether to stop breastfeeding or to cancel the drug, taking into account the need for its reception for the mother.

Dosing and Administration:

A drug Losartan is taken orally regardless of the meal.

The drug can be taken in combination with other antihypertensive drugs.

To ensure the necessary dosage regimen, you can take the drug Losartan in a dose of 50 mg.

Arterial hypertension

The standard initial and maintenance dose for most patients is 50 mg of the drug Losartan 1 time per day. The maximum antihypertensive effect is achieved in 3-6 weeks from the start of therapy. In some patients, to achieve a greater effect, the dose may be increased to a maximum daily dose of 100 mg of the drug Losartan 1 time per day.

In patients with a reduced volume of circulating blood (for example, when taking large doses of diuretics), the initial dose of losartan should be reduced to 25 mg once a day (see "Special instructions").

There is no need to select an initial dose for elderly patients and patients with impaired renal function, including patients on dialysis.

Patients with a history of liver disease are recommended to prescribe lower doses of the drug Losartan (see "Special instructions").

Reduced risk of associated cardiovascular morbidity and mortality the patients with hypertrophy and left ventricular hypertrophy

The standard initial dose of the drug Losartan is 50 mg once a day. It is recommended to add hydrochlorothiazide in low doses or increase the dose of the drug Losartan up to the maximum daily dose of 100 mg once a day, taking into account the degree of BP reduction.

Kidney protection the patients with diabetes mellitus 2 and proteinuria

The standard initial dose of the drug Losartan is 50 mg once a day. In the future, the dose can be increased to a maximum daily dose of 100 mg 1 time per day, taking into account the degree of decrease in blood pressure. A drug Losartan can be assigned in combination with other antihypertensive agents (for example, diuretics, blockers of "slow" calcium channels, alpha and beta adrenoblockers, central antihypertensive agents), insulin and other hypoglycemic agents (eg, sulfonylurea derivatives, glitazones and glucosidase inhibitors).

Chronic heart failure

The initial dose of losartan for patients with chronic heart failure is 12.5 mg once a day. Typically, the dose increases with a weekly interval (ie, 12.5 mg / day, 25 mg / day, 50 mg / day, 100 mg / day to the maximum (only for this indication) 150 mg dose once a day) depending on from individual tolerance.

Side effects:

To assess the incidence of adverse events (AEs), the following WHO classification is used: very often (≥ 1/10); often (≥ 1/100 and <1/10); infrequently (≥ 1/1000 and <1/100); rarely (≥ 1/10000 and <1/1000); very rarely (<1/10000), the frequency is unknown - can not be determined from the available data.

In general, the drug Losartan well tolerated by patients with AH. NEAs are light and transitory in nature and do not require withdrawal of the drug. The total frequency of AEs when taking the drug Losartan is comparable with this indicator when taking placebo. In controlled clinical trials, the frequency of discontinuation of therapy due to clinically significant AE was 2.3% in the group of patients taking the drug Losartan, and 3.7% in the group of patients taking placebo.

The following AEs were observed in controlled clinical trials of the drug in patients with AH.

Disturbances from the nervous system

Often: dizziness.

Infrequent: drowsiness, headache, sleep disturbances.

Hearing disorders and labyrinthine disorders

Often: systemic dizziness (vertigo).

Heart Disease

Infrequent: a feeling of heartbeat, angina.

Vascular disorders

Infrequently: (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with reduced circulating blood volume (BCC), for example, in patients with severe heart failure or patients receiving treatment with high doses of diuretics).

Disorders from the gastrointestinal tract

Infrequent: pain in the abdomen, constipation.

Disturbances from the skin and subcutaneous tissues

Infrequent: skin rash.

General disorders

Infrequent: weakness, fatigue, swelling.

Laboratory and instrumental data

Often: hyperkalemia.

Rarely: increased activity of alanine aminotransferase (ALT) (usually returned to normal after the abolition of therapy).

Controlled clinical studies have shown that the drug Losartan mainly well tolerated by patients with hypertrophy and left ventricular hypertrophy.The following AEs were observed in these studies.

Disturbances from the nervous system

Often: dizziness.

Hearing disorders and labyrinthine disorders

Often: systemic dizziness (vertigo).

General disorders

Infrequent: weakness, increased fatigue.

In the study LIFE in patients without diabetes mellitus, the incidence of new cases of diabetes mellitus was lower when the drug was used Losartan compared with the use of atenolol (p <0.001). Since this study did not include a group of patients taking placebo, it is not known whether this is a positive effect of the drug Losartan or an undesirable phenomenon of atenolol. Controlled clinical studies have shown that the drug Losartan mainly well tolerated by patients with type 2 diabetes and proteinuria. The following AEs were observed in these studies.

Disturbances from the nervous system

Often: dizziness.

Vascular disorders

Often: (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with reduced circulating blood volume (BCC),for example, in patients with severe heart failure or patients receiving treatment with high doses of diuretics).

General disorders

Infrequent: weakness, increased fatigue.

Laboratory and instrumental data

Often: hyperkalemia (in a clinical study involving patients with type 2 diabetes and nephropathy, hyperkalemia (> 5.5 mmol / L) was observed in 9.9% of patients taking the drug Losartan, and in 3.4% of patients taking placebo), hypoglycemia.

Controlled clinical studies have shown that the drug Losartan in the main it is well tolerated by patients with CHF. AEs observed in clinical trials were characteristic of this group of patients.

Violations of the blood and lymphatic system

Often: anemia.

Disturbances from the nervous system

Often: dizziness.

Infrequently: a headache.

Rarely: paresthesia.

Heart Disease

Rarely: fainting, atrial fibrillation, impaired cerebral circulation.

Vascular disorders

Often: (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with reduced circulating blood volume (BCC), for example,in patients with severe heart failure or patients receiving treatment with high doses of diuretics).

Disturbances from the respiratory system, chest and mediastinal organs

Infrequent: shortness of breath, cough

Disorders from the gastrointestinal tract

Infrequently: diarrhea, nausea, vomiting.

Disturbances from the skin and subcutaneous tissues

Infrequent: urticaria, skin itch, skin rash.

Disorders from the kidneys and urinary tract

Often: renal dysfunction, kidney failure.

General disorders

Infrequent: weakness, increased fatigue.

Laboratory and instrumental data

Often: increase in the concentration of creatinine, urea and potassium in the blood.

Infrequent: hyperkalemia (often in patients taking losartan in a dose of 150 mg per day than in patients taking losartan in a dose of 50 mg per day).

The following NL were observed in clinical practice during post-marketing period:

Violations of the blood and lymphatic system

The frequency is unknown: anemia, thrombocytopenia.

Immune system disorders

Rarely: hypersensitivity reactions, anaphylactic reactions,angioedema (including angioedema, swelling of the larynx, pharynx, face, lips, pharynx and / or tongue (causing airway obstruction), some of whom had a history of angioedema with other drugs, including ACE inhibitors); vasculitis (including purple Shenlaine-Genocha).

Disorders of the psyche

The frequency is unknown: depression.

Disturbances from the nervous system

The frequency is unknown: migraine, dysgeusia.

Hearing disorders and labyrinthine disorders

The frequency is unknown: tinnitus.

Disturbances from the respiratory system, the thoracic and mediastinal organs

The frequency is unknown: cough.

Disorders from the digestive system

The frequency is unknown: diarrhea, pancreatitis,

Disturbances from the liver and bile ducts

Rarely: hepatitis.

The frequency is unknown: hepatic dysfunction.

Disturbances from the skin and subcutaneous tissues

The frequency is unknown: urticaria, skin itching, rash, photosensitivity.

Disturbances from musculoskeletal and connective tissue

The frequency is unknown: myalgia, arthralgia, rhabdomyolysis.

Violations of the genitals and mammary gland

The frequency is unknown: erectile dysfunction / impotence.

General disorders

Frequency unknown: general malaise.

Laboratory and instrumental data

Frequency unknown: hyponatremia.

Overdose:

Information on overdose is limited. The most likely manifestation of an overdose is a marked decrease in blood pressure and tachycardia; Bradycardia can occur due to parasympathetic (vagal) stimulation. In the case of symptomatic arterial hypotension, maintenance therapy is indicated.

Treatment: symptomatic therapy.

Lozartan and its active metabolite are not excreted by hemodialysis.

Interaction:

In clinical studies on the pharmacokinetic interactions of drugs, clinically significant interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital have not been identified. Rifampicin, being an inducer of the metabolism of drugs, reduces the concentration of the active metabolite of losartan in the blood.

In clinical studies, the use of two inhibitors of the isoenzyme P450 3A4: ketoconazole and erythromycin has been studied. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan, Erythromycin did not have a clinically significant effect when taking losartan inside. Fluconazole, the inhibitor of the isoenzyme P450 2C9, decreases the concentration of the active metabolite of losartan, however the pharmacodynamic significance of simultaneous application of losartan and inhibitors of the isoenzyme P450 2C9 has not been studied. It was shown that in patients not metabolizing losartan in the active metabolite, there is a very rare and specific defect in the isoenzyme P450 2C9. These data suggest that the metabolism of losartan to the active metabolite is carried out by the P450 2C9 isoenzyme, rather than the P450 3A4 isoenzyme.

The simultaneous use of losartan, as well as other drugs blocking angiotensin II or its effects, with potassium-sparing diuretics (eg spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium salts can lead to an increase in potassium in the serum.

As with the use of other drugs that affect the excretion of sodium, losartan can reduce the excretion of lithium, so when lithium and ARA II are used simultaneously, the concentration of lithium in serum should be monitored carefully.

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

In some patients with impaired renal function (eg, in elderly patients or patients with dehydration, including those taking diuretics) receiving NSAID therapy, including selective COX-2 inhibitors, concomitant use of ARA II or ACE inhibitors may cause further impairment of function kidney, including the development of acute renal failure. These effects are usually reversible, so the simultaneous use of these medicines should be done with caution in patients with impaired renal function.

Double blockade of RAAS with application of ARA II,ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of developing arterial hypotension, syncope, hyperkalemia and renal dysfunction (including acute renal failure) compared with monotherapy. Regular monitoring of blood pressure, kidney function and electrolyte content in the blood in patients taking the drug simultaneously Losartan and other drugs that affect RAAS. The drug Losartan should not be used concomitantly with aliskiren or preparations containing aliskiren in patients with diabetes mellitus and / or moderate or severe renal failure (GFR less than 60 ml / min / 1.73 m² body surface area) and is not recommended in other patients. Simultaneous use of the drug Losartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Special instructions:

Hypersensitivity reactions

Patients with an angioneurotic edema in the anamnesis (edema of the face, lips, pharynx / larynx and / or tongue) need control of the drug (see "Side effect").

Embryotoxicity

Arterial hypotension and disturbance of water-electrolyte balance or decrease in the volume of circulating blood

In patients with reduced BCC (eg, receiving treatment with large doses of diuretics) symptomatic arterial hypotension may occur. Correction of such conditions should be performed prior to the appointment of the drug Losartan or start treatment with a lower dose of the drug Losartan (see "Method of administration and dose"). Violation of the water-electrolyte balance is characteristic of patients with impaired renal function withdiabetes mellitus or without diabetes mellitus, therefore careful monitoring of these patients is necessary. In clinical trials involving patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was greater in the group taking the drug Losartan, than in the group taking placebo. Several patients discontinued therapy due to hyperkalemia (see "Side effects, Laboratory indicators").

During treatment with the drug Losartan It is not recommended to take potassium-sparing diuretics, potassium preparations or potassium-containing substitutes for edible salt.

Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

Like all drugs that have a vasodilating effect, ARA II should be administered with caution to patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Ischemic heart disease and cerebrovascular disease

Like all drugs that have a vasodilating effect, ARA II should be administered with caution to patients with coronary heart disease or cerebrovascular disease,because excessive reduction in blood pressure in this group of patients can lead to the development of myocardial infarction or stroke.

Chronic heart failure

As with the use of other drugs that have an effect on RAAS, in patients with CHF and with or without renal dysfunction, there is a risk of developing severe arterial hypotension or acute renal dysfunction.

Since there is insufficient experience of the drug Losartan in patients with heart failure and concomitant severe renal dysfunction, in patients with severe heart failure (IV functional class by classification NYMA), as well as in patients with heart failure and symptomatic life-threatening arrhythmias, the drug Losartan should be administered with caution to patients in these groups.

Primary hyperaldosteronism

Since in patients with primary hyperaldosteronism, as a rule, there is no positive response to therapy with antihypertensive agents that act by inhibition of PAS, use of the drug Losartan is not recommended for this group of patients.

Impaired liver function

These pharmacokinetic studies indicate that losartan in plasma concentration in patients with cirrhosis is significantly increased, so patients with impaired liver function should be administered the drug history Losartan at a lower dose. There is no experience of using the drug Losartan in patients with severely impaired liver function, so the drug must not be used in this group of patients (see., "Pharmacological properties Pharmacokinetics", "Contraindications", "Method of administration and dose").

Impaired renal function

Due to inhibition of RAAS in some predisposed patients, renal function changes, including renal failure, were observed. These changes in renal function may return to normal after discontinuation of treatment. Some drugs that affect the RAAS may increase the concentration of urea in the blood and serum creatinine in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney. It was reported that such effects occur when taking the drug Losartan. Such changes in kidney function can be reversible after the abolition of therapy. Losartan should be used with caution in patients with bilateral stenosis of the renal arteries or stenosis of the renal artery of a single kidney.

Special patient groups

Race

Analysis of the data of the entire population of patients included in the study LIFE on the study of the effect of losartan on the reduction in the frequency of development of the main composite criterion for evaluating the study in patients with hypertrophy and left ventricular hypertrophyn = 9193), showed that the ability of losartan in comparison with atenolol to reduce the risk of stroke and myocardial infarction, as well as to reduce the cardiovascular mortality in patients with AH and left ventricular hypertrophy (by 13.0%, p = 0.021) is not covered on patients of the Negroid race, although both regimens effectively reduced blood pressure in these patients. In this study, the drug Losartan compared with atenolol reduced the incidence of cardiovascular morbidity and mortality in patients with hypertension and left ventricular hypertrophy of all races except Negroid (n = 8660, p = 0.003).However, in this study, patients of the Negroid race who received atenolol, had a lower risk of developing the main composite test evaluation criterion (ie, a lower combined rate of cardiovascular mortality, stroke, and myocardial infarction) compared to patients of the same race who took losartan (p = 0.03).

Children and teens

Efficacy and safety of the drug Losartan in children and adolescents under the age of 18 years are not established.

If the newborns whose mothers took the drug Losartan during pregnancy, there is a development of oliguria or arterial hypotension, it is necessary to carry out symptomatic therapy aimed at maintaining blood pressure and renal perfusion. You may need a blood transfusion or dialysis to prevent the development of arterial hypotension and / or maintain kidney function.

Elderly patients

Clinical studies have not revealed any specificities regarding the safety and effectiveness of losartan in elderly patients (over 65 years of age).

Effect on the ability to drive transp. cf. and fur:

There have been no studies to assess the impact on ability to drive vehicles and work with mechanisms, but care must be taken when applying antihypertensive therapy and driving or working with mechanisms, since dizziness and drowsiness may develop especially at the beginning of therapy or with increasing doses.

Form release / dosage:

Tablets, film-coated 12.5 mg and 50 mg.

Packaging:

For 10, 14 or 15 tablets per contour cell package.

1, 2, 3 contour packs of 10 tablets together with the instructions for use are placed in a pack of cardboard.

1, 2 contour packs of 14 tablets together with the instructions for use are placed in a pack of cardboard.

1, 2, 4 contour cell packs of 15 tablets together with instructions for use are placed in a pack of cardboard.

Storage conditions:

Store at a temperature not exceeding 25 ° C.

Keep out of the reach of children.

Shelf life:

3 years.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LP-004796

Date of registration:13.04.2018

Expiration Date:13.04.2023

The owner of the registration certificate:TATHIMFARMPREPARATY, JSC TATHIMFARMPREPARATY, JSC Russia

Manufacturer: & nbsp

TATHIMFARMPREPARATY, JSC Russia

Information update date: & nbsp15.05.2018

Illustrated instructions

Instructions

Losartan (Losartan)