Losartan, 12.5mg 30 pcs.

Pharmacotherapeutic group

Drugs affecting the renin-angiotensin system. Angiotensin II antagonists. Lozartan.

ATC code

C09CA01

Pharmacological properties

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Pharmacodynamics

Mechanism of action

Angiotensin II is a potent vasoconstrictor, the principal active hormone of the renin-angiotensin-aldosterone system (RAAS), and a crucial pathophysiological link in the development of arterial hypertension (AH). Angiotensin II binds to AT₁ receptors located in many tissues (vascular smooth muscle tissues, adrenal, kidney and heart) and performs several important biological functions, including vasoconstriction and aldosterone release. In addition, angiotensin II stimulates smooth muscle cell overgrowth. AT₂ receptors are the second type of receptors that angiotensin II binds to, but its role in the regulation of cardiovascular function is unknown.

Lozartan is a selective AT₁-receptor antagonist of angiotensin II that is 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 synthesis pathway. Unlike some peptide angiotensin II antagonists, losartan has no agonist properties.

Lozartan selectively binds to AT₁ receptors and does not bind to or block receptors for other hormones and ion channels that play an important role in the regulation of cardiovascular function. In addition, losartan does not inhibit angiotensin-converting enzyme (ACE, kininase II), which is responsible for bradykinin degradation. Consequently, 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 relevant to the effects of losartan.

Lozartan suppresses systolic and diastolic blood pressure (BP) elevations with angiotensin II infusion. At the time of reaching the maximum plasma concentration of losartan (C_max) after a 100 mg dose of losartan, the above effect of angiotensin II is suppressed by approximately 85%, and by 26-39% after 24 hours of single and multiple doses.

While taking losartan, the elimination of the negative feedback of angiotensin II suppression of renin secretion leads to an increase in plasma renin activity (ARP). Increase of ARP leads to increase of angiotensin II concentration in blood plasma. During long-term (6-week) treatment of patients with AH with losartan at a dose of 100 mg/day, a 2-3-fold increase in plasma angiotensin II concentrations at the time of reaching C_max of losartan was observed. In some patients, even greater increases in angiotensin II concentrations were observed, especially with a short duration of treatment (2 weeks). Despite this, during treatment, the antihypertensive effect and decrease in plasma aldosterone concentration were evident 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 values observed before starting losartan. Because losartan is a specific AT₁-receptor antagonist of angiotensin II, 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 those of an ACE inhibitor for effects 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 the bradykinin-dependent effects without affecting the severity of the response to angiotensin II, demonstrating the pharmacodynamic difference between losartan and ACE inhibitors. Plasma concentrations of losartan and its active metabolite, as well as the antihypertensive effect of losartan, increase with increasing drug dose. Because losartan and its active metabolite are angiotensin II receptor antagonists (ARA II), they both contribute to the antihypertensive effect.

In a study with a single dose of 100 mg of losartan that included healthy volunteers (men), oral administration of the drug on a high-salt and low-salt diet had no effect on glomerular filtration rate (GFR), effective renal plasma flow, or filtration fraction. Losartan had a natriuretic effect that was more pronounced on the 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 uric acid excretion.

In patients with AH, proteinuria (at least 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 reduction in proteinuria (by 42%), fractional albumin excretion and immunoglobulin (IgG). In these patients, losartan stabilized FFR and decreased filtration fraction.

In postmenopausal women with AH taking losartan at a dose of 50 mg for 4 weeks, there was no effect of therapy on renal and systemic prostaglandin levels.

Lozartan has no effect on autonomic reflexes and no lasting effect on plasma norepinephrine concentrations.

In patients with AH, losartan at doses up to 150 mg daily did not cause clinically significant changes in fasting triglyceride, total cholesterol, and high-density lipoprotein cholesterol concentrations. At similar doses, losartan had no effect on fasting blood glucose concentration.

The HEAAL clinical trial evaluating the effect of high and low dose ARA II (losartan) on treatment outcome in patients with chronic heart failure (CHF) included patients (n = 3834) with CHF (NYHA functional class II-IV) and ACE inhibitor intolerance. Patients were followed more than 4 years (median follow-up was 4.7 years) to compare the effects of losartan at a dose of 50 mg/day and at a dose of 150 mg/day on reducing 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 or hospitalization for heart failure compared with a dose of 50 mg/day (hazard ratio [OR] 0.899, p = 0.027).

In general, losartan caused a decrease in serum uric acid concentrations (generally less than 0.4 mg/dL) that persisted with long-term treatment. In controlled clinical trials with patients with AH, there have been no reported cases of withdrawal of losartan due to increased serum creatinine or potassium concentrations.

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

Pharmacokinetics

Intake

In oral administration, losartan is well absorbed and metabolized at

“primary passage” through the liver to form the active carboxylated metabolite and inactive metabolites. Systemic bioavailability of losartan in tablet form is approximately 33%. Mean maximum concentrations (C_max) of losartan and its active metabolite are reached after 1 h and 3-4 h, respectively. No clinically significant effect on the plasma concentration profile of losartan has been identified when losartan is taken with a normal meal.

Distribution

Lozartan and its active metabolite bind to plasma proteins (mainly to albumin) by more than 99%. The volume of distribution of losartan is 34 liters. Studies in rats have shown that losartan has almost no penetration through the blood-brain barrier.

Metabolism

About 14% of losartan is converted to its active metabolite when administered intravenously and when taken orally. After ingestion 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 conversion efficiency 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 by hydroxylation of the side butyl chain and one minor metabolite, N-2-tetrazol-glucuronide.

Elimation

Plasma clearance of losartan and its active metabolite is approximately 600 ml/min and 50 ml/min, respectively. Renal clearance of losartan and its active metabolite is approximately 74 mL/min and 26 mL/min, respectively.

In oral administration of losartan, approximately 4% of the dose is excreted unchanged by the kidneys and approximately 6% of the dose is excreted by the kidneys as an active metabolite. Losartan and its active metabolite have linear pharmacokinetics with oral administration of losartan at doses up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal elimination half-life of approximately 2 and 6-9 hours, respectively. There is no significant plasma accumulation of either losartan or its active metabolite when the drug is dosed 100 mg once daily.

The excretion of losartan and its metabolites is by the kidneys and through the intestine with bile. After oral administration of ¹⁴C losartan in men about 35% radioactivity is detected in urine and 58% in feces. After intravenous administration of ¹⁴C losartan in men, approximately 43% of radioactivity is detectable in urine and 50% in feces.

Pharmacokinetics in special patient groups

Elderly patients

Plasma concentrations of losartan and its active metabolite in elderly male patients with arterial hypertension are not significantly different from those in younger male patients with AH.

Gender

The values of plasma concentrations of losartan in women with AH were 2-fold higher than those in men with AH. Concentrations of the active metabolite did not differ between men and women. This apparent pharmacokinetic difference, however, has no clinical significance.

Patients with impaired liver function

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

Patients with impaired renal function

Plasma concentrations of losartan in patients with a creatinine clearance (CK) above 10 mL/min were not different 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-fold greater compared to the AUC of losartan in patients with normal renal function. Plasma concentrations of the active metabolite were not altered in patients with impaired renal function or patients on hemodialysis. Losartan and its active metabolite are not excreted by hemodialysis procedures.

Indications

Hypertension (high blood pressure), Prevention of heart attacks and strokes, Heart failure

• arterial hypertension;
• chronic heart failure with ineffectiveness of treatment with ACE inhibitors or intolerance to ACE inhibitors. It is not recommended to transfer patients with heart failure and stable values while taking ACE inhibitors to losartan therapy.

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Active ingredient

Losartan

Composition

Dosage 12.5 mg

active ingredient: lozartan potassium – 12.5 mg;

helpers: lactose monohydrate, 58.6 mg; microcrystalline cellulose, 20.0 mg; croscarmellose sodium, 4.0 mg; povidone K-17 (polyvinylpyrrolidone low molecular weight) – 3.2 mg; colloidal silica – 0.7 mg; magnesium stearate – 1.0 mg;

film coating: [hypromellose, 1.8 mg, talc, 0.6 mg, titanium dioxide, 0.33 mg, macrogol 4000 (polyethylene glycol 4000), 0.27 mg] or [dry film coating mixture containing hypromellose (60%), talc (20%), titanium dioxide (11%), macrogol 4000 (polyethylene glycol 4000) (9%)] – 3.0 mg.

How to take, the dosage

Ingestion, regardless of the time of meals.

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

Arterial hypertension

The standard starting and maintenance dose for most patients is 50 mg once daily. Maximum antihypertensive effect is achieved 3 to 6 weeks after initiation of therapy.

In some patients the dose may be increased to a maximum daily dose of 100 mg once daily for greater effect.

In patients with reduced circulating blood volume (RBC) (e.g., when taking high-dose diuretics), the starting dose of losartan should be reduced to 25 mg once daily (see section “Special Precautions”).

There is no need to adjust the starting dose in elderly patients and in patients with impaired renal function, including patients on hemodialysis.

Patients with a history of liver disease are recommended to be prescribed lower doses of losartan (see section “Special Precautions”).

Risk reduction of associated cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophyThe standard starting dose of the drug is 50 mg once daily. Subsequently, it is recommended to add a low dose of hydrochlorothiazide or to increase the drug dose to a maximum daily dose of 100 mg once daily, taking into account the degree of BP reduction. Kidney protection in patients with type 2 diabetes mellitus and proteinuria

The standard initial dose of the drug is 50 mg once daily. Thereafter, the dose may be increased to a maximum daily dose of 100 mg once daily, taking into account the degree of BP reduction. The drug may be prescribed in combination with other hypotensive agents (e.g., diuretics, slow calcium channel blockers, alpha- and beta-adrenoblockers, hypotensive agents of central action), insulin and other hypoglycemic agents (e.g., sulfonylurea derivatives, glitazones and glucosidase inhibitors).

Chronic Heart Failure

The starting dose of losartan for patients with chronic heart failure is 12.5 mg once daily. Generally, the dose is increased at weekly intervals (i.e., 12.5 mg/day, 25 mg/day, 50 mg/day, 100 mg/day to a maximum (for this indication only) dose of 150 mg once daily) depending on individual tolerance.

Interaction

In clinical studies on pharmacokinetic drug interactions, no clinically significant interactions of losartan with hydrochlorothiazide, digoxin, warfarin, cimetidine and phenobarbital have been identified.

Rifampicin, as an inducer of drug metabolism, reduces the blood concentration of the active metabolite losartan.

The use of two P450 ZA4 isoenzyme inhibitors, ketoconazole and erythromycin, has been studied in clinical trials. Ketoconazole did not affect the metabolism of losartan to the active metabolite after intravenous administration of losartan; erythromycin had no clinically significant effect when losartan was ingested. Fluconazole, a P450 2C9 isoenzyme inhibitor, reduces the concentration of the active metabolite of losartan, but the pharmacodynamic significance of concomitant use of losartan and P450 2C9 isoenzyme inhibitors has not been studied. Patients who do not metabolize losartan to the active metabolite have been shown to have a very rare and specific defect in the P450 2C9 isoenzyme. These data suggest that the metabolism of losartan to the active metabolite is by the P450 2C9 isoenzyme rather than the P450 3A4 isoenzyme.

The concomitant use of losartan, as well as other drugs that block angiotensin II or its effects, with potassium-saving diuretics (e.g., spironolactone, eplerenone, triamterene, amiloride), potassium supplements or potassium salts may result in increased serum potassium levels.

As with other drugs that affect sodium excretion, losartan may decrease lithium excretion, so serum lithium concentrations should be monitored closely when lithium and ARA II drugs are used concomitantly.

Non-steroidal anti-inflammatory drugs (NSAIDs), including selective cyclooxygenase-2 (COX-2) inhibitors, may decrease the effect of diuretics and other hypotensive agents. Consequently, 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 (e.g., 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 renal function, including development of acute renal failure. These effects are usually reversible, therefore concomitant use of these drugs should be conducted with caution in patients with impaired renal function.

Double RAAS blockade with ARA II, ACE inhibitors or aliskiren (renin inhibitor) is associated with an increased risk of arterial hypotension, syncope, hyperkalemia and impaired renal function (including acute renal failure) compared to monotherapy. Blood pressure, renal function and electrolytes should be monitored regularly in patients taking losartan concomitantly with other drugs that affect the RAAS. Losartan should not be used concomitantly with aliskiren or drugs containing aliskiren in patients with diabetes mellitus and/or moderate to severe renal impairment (FFR less than 60 ml/min/1.73 m² body surface area) and is not recommended in other patients. Concomitant use of losartan with ACE inhibitors is contraindicated in patients with diabetic nephropathy and is not recommended in other patients.

Special Instructions

Hypersensitivity reactions

In patients with a history of angioedema (edema of the face, lips, pharynx/larynx and/or tongue), monitoring of the drug is required (see section “Adverse effects”).

Embryotoxicity

The use of drugs acting on the RAAS in the second and third trimesters 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 skull bone hypoplasia, anuria, arterial hypotension, renal failure, and death. If pregnancy is diagnosed, the drug should be discontinued immediately (see section

“Use in pregnancy and during breastfeeding”).

Arterial hypotension and water-electrolyte imbalance or decreased circulating blood volume

Patients with decreased blood circulation (e.g., those treated with high-dose diuretics) may have symptomatic arterial hypotension. These conditions should be corrected prior to prescribing losartan or treatment should be initiated with a lower dose of losartan (see section “Dosage and administration”).

Electrolyte disturbances are common in patients with impaired renal function with or without diabetes mellitus, so close monitoring of these patients is required. In clinical trials with patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was greater in the group taking losartan than in the group taking placebo. Several patients discontinued therapy due to hyperkalemia (see sections “Side effects” and “Laboratory and instrumental data”).

Potent potassium-saving diuretics, potassium preparations, or potassium-containing salt substitutes are not recommended during treatment with losartan.

Aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy

. As with all drugs with vasodilatory effects, ARA II should be prescribed with caution in patients with aortic or mitral stenosis or hypertrophic obstructive cardiomyopathy.

Ischemic heart disease and cerebrovascular disease

. As with all drugs with a vasodilator effect, APA II should be prescribed with caution in patients with ischemic heart disease or cerebrovascular disease, because excessive lowering of BP in this group of patients may lead to myocardial infarction or stroke.

Chronic Heart Failure

As with other drugs acting on the RAAS, patients with CHF and with or without impaired renal function are at risk for severe arterial hypotension or acute renal impairment.

As there is insufficient experience with losartan in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA functional class IV), and in patients with heart failure and symptomatic life-threatening arrhythmias, losartan should be prescribed with caution.

Primary hyperaldosteronism

Because patients with primary hyperaldosteronism generally have no positive response to therapy with hypotensive agents that act by inhibiting RAS, the use of losartan is not recommended in this patient group.

Hepatic dysfunction

The data from pharmacokinetic studies indicate that plasma concentrations of losartan are significantly increased in patients with cirrhosis, so a lower dose of losartan should be administered in patients with a history of hepatic dysfunction. There is no experience of using losartan in patients with severe hepatic impairment; therefore, the drug should not be used in this group of patients (see sections “Pharmacological properties”, “Pharmacokinetics”,

“Contraindications”, “Dosage and administration”).

Renal function impairment

Renal function changes, including the development of renal failure, have been observed in some predisposed patients due to RAAS inhibition. These changes in renal function may return to normal after discontinuation of treatment.

Some drugs that affect the RAAS may increase blood urea and serum creatinine concentrations in patients with bilateral renal artery stenosis or artery stenosis of the sole kidney. Similar effects have been reported with losartan. Such changes in renal function may be reversible after discontinuation of therapy. Caution should be exercised with losartan in patients with bilateral renal artery stenosis or renal artery stenosis of the sole kidney.

Special patient groups. Race.

. An analysis of data from the entire patient population enrolled in the LIFE study of the effect of losartan on reducing the incidence of the main composite criterion of the study evaluation in patients with AH and left ventricular hypertrophy (n = 9193) showed that the ability of losartan compared with atenolol to reduce the risk of stroke and myocardial infarction and reduce cardiovascular mortality in patients with AH and left ventricular hypertrophy (by 13.0%, p = 0.021) did not extend to non-Hispanic patients, although both therapies effectively reduced BP levels in these patients. In this study, losartan compared with atenolol reduced cardiovascular morbidity and mortality in patients with AH and left ventricular hypertrophy of all races except the non-Hispanic race (n = 8660, p = 0.003). However, in this study, patients of the non-Hispanic race receiving atenolol had a lower risk of developing the main composite criterion of the study evaluation (that is, a lower combined incidence of cardiovascular mortality, stroke, and myocardial infarction) compared with patients of the same race taking losartan (p = 0.03).

Children and adolescents

The efficacy and safety of losartan in children and adolescents under 18 years of age have not been established.

If neonates whose mothers have taken losartan during pregnancy develop oliguria or arterial hypotension, symptomatic therapy to maintain BP and renal perfusion is necessary. Blood transfusion or dialysis may be required to prevent the development of arterial hypotension and/or to maintain renal function.

Elderly patients

Clinical studies have not demonstrated any specific findings regarding the safety and efficacy of losartan in elderly patients (>65 years).

Influence on driving and operating machinery

There have been no studies to evaluate the effect on driving and operating machinery, but caution should be exercised when using hypotensive therapy and driving or operating machinery as dizziness and somnolence may occur, especially at the start of therapy or when increasing the dose.

Contraindications

• high sensitivity to losartan and other drug components;
• current use with angiotensin-converting enzyme (ACE) inhibitors in patients with diabetic nephropathy;
• .concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate to severe renal function impairment (glomerular filtration rate (GFR) less than 60 ml/min/1.73 m² body surface area) (see “Interaction with Other Drugs “Interaction with other drugs”);
• hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome;
• pregnancy and breastfeeding period;
• children under 18 years of age (efficacy and safety of use not established).

With caution

• bilateral renal artery stenosis or artery stenosis of the sole renal artery; hyperkalemia;
• post renal transplant conditions (no experience with use);
• aortic or mitral stenosis;
• hypertrophic obstructive cardiomyopathy;
• heart failure with concomitant severe renal impairment;
• heart failure with life-threatening arrhythmias;
• ischemic heart disease;
• cerebrovascular disease;
• primary hyperaldosteronism;
• anhyoneurotic edema in history;
• patients with reduced circulating blood volume (such as those treated with high doses of diuretics) – symptomatic arterial hypotension may occur.

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Side effects

Classification of the frequency of side effects according to the recommendations of the World Health Organization (WHO):
very frequently ≥ 1/10;
frequently ≥ 1/100 to < 1/10; infrequently ≥ 1/1000 to < 1/100; rarely ≥ 1/10000 to < 1/1000;
very rarely < 1/10000, including individual reports;
frequency unknown – based on available data it is impossible to determine the incidence.
In general, losartan is well tolerated in patients with AH. Adverse events (AEs) are mild and transient and do not require drug withdrawal. The cumulative incidence of NIH when taking losartan is comparable to that of placebo. In controlled trials, the quit rate due to clinically significant NPS was 2.3% in losartan and 3.7% in placebo.
The following NPS were observed in controlled trials of losartan in patients with AH.
Nervous system disorders:
often – dizziness;
infrequently – drowsiness, headache, sleep disturbances.

Hearing and labyrinth organ disorders:
often – systemic dizziness (vertigo).
Heart disorders:
infrequently – palpitations, angina pectoris.
Vascular disorders:
infrequent – (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with decreased blood circulation, e.g., in patients with severe heart failure or in patients treated with high doses of diuretics).
Gastrointestinal disorders:
Infrequent – abdominal pain, constipation.
Skin and subcutaneous tissue disorders:
infrequent – skin rash.
General disorders and reactions at the place of administration:
infrequent – weakness, fatigue, edema.
Laboratory and instrumental data:
often – hyperkalemia;
rarely – increased alanine aminotransferase (ALT) activity (usually returning to normal after discontinuation of therapy).
Controlled clinical trials have shown that losartan is generally well tolerated in patients with AH and left ventricular hypertrophy. The following NNDs were observed in these studies:
Nervous system disorders:
often – dizziness.
Hearing and labyrinth disorders:
often – systemic vertigo (vertigo).
General disorders and reactions at the site of administration:
infrequent – weakness, increased fatigue.
In the LIFE study in patients without a history of diabetes mellitus, the incidence of new cases of diabetes was lower with losartan compared with atenolol administration (p < 0.001). Because this study did not include a group of patients taking placebo, it is unknown whether this is a beneficial effect of losartan or an adverse event of atenolol. Controlled clinical trials have shown that losartan is generally well tolerated in patients with type 2 diabetes mellitus and proteinuria. The following NNDs were observed in these studies:
Nervous system disorders:
often dizziness.
Vascular disorders:
often – (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with decreased BOD, such as patients with severe heart failure or patients treated with high doses of diuretics).
General disorders and reactions at the site of administration:
infrequently – weakness, increased fatigue.
Laboratory and instrumental data:
often – hyperkalemia (in a clinical study involving patients with type 2 diabetes and nephropathy hyperkalemia (over 5.5 mmol/l) was observed in 9.9% of patients taking losartan, and in 3.4% of patients taking placebo), hypoglycemia.

Controlled clinical trials have shown that losartan is generally well tolerated in patients with CHF. NIs observed in clinical studies were common in this group of patients.
Blood and lymphatic system disorders:
often – anemia.
Nervous system disorders:
frequently – dizziness; infrequently – headache; rarely – paresthesia.
Cardiac disorders:
rarely – syncope, atrial fibrillation, stroke.
Vascular disorders:
often – (orthostatic) hypotension (including dose-mediated orthostatic effects) (especially in patients with decreased blood circulation, e.g. in patients with severe heart failure or in patients treated with high-dose diuretics).
Respiratory system, thorax and mediastinum disorders: infrequent – shortness of breath, cough.
Gastrointestinal disorders:
infrequent – diarrhea, nausea, vomiting.
Skin and subcutaneous tissue disorders:
infrequent – urticaria, itching, skin rash.
Renal and urinary tract disorders:
often – renal dysfunction, renal failure.
General disorders and reactions in the place of administration:
infrequently – weakness, increased fatigue.
Laboratory and instrumental data:
often – increased concentration of creatinine, urea and potassium in the blood; infrequently – hyperkalemia (often in patients who took losartan at a dose of 150 mg per day than in patients who took losartan at a dose of 50 mg per day).
The following NIs have been observed in clinical practice in the post-registration period.
Blood and lymphatic system disorders:
frequency unknown – anemia, thrombocytopenia.
Immune system disorders:
rare – hypersensitivity reactions, anaphylactic reactions, angioedema (including angioedema of the larynx, pharynx, face, lips, pharynx and/or tongue (causing airway obstruction); some of these patients had a history of angioedema while taking other drugs (including ACE inhibitors), vasculitis (including Schoenlein-Henoch purpura).
Mental disorders:
frequency unknown – depression.
Nervous system disorders:
frequency unknown – migraine, dysgeusia.
Hearing and labyrinth disorders:
frequency unknown – tinnitus.
Respiratory system, thoracic and mediastinal organs:
frequency unknown – cough.
Gastrointestinal disorders:
frequency unknown – diarrhea, pancreatitis.
Disorders of the liver and biliary tract:
rarely – hepatitis;
frequency unknown – liver function disorders.
Skin and subcutaneous tissue disorders:
frequency unknown – urticaria, skin itching, rash, photosensitization. Muscular, skeletal and connective tissue disorders: frequency unknown – myalgia, arthralgia, rhabdomyolysis.
Reproductive system and breast disorders:
frequency unknown – erectile dysfunction/impotence.
General disorders and reactions at the injection site:
frequency unknown – general malaise.
Laboratory and instrumental data:
frequency unknown – hyponatremia.

Overdose

There is limited information about overdose.

The most likely manifestations of overdose

A marked decrease in BP and tachycardia; bradycardia may occur due to parasympathetic (vagus) stimulation. If symptomatic arterial hypotension develops, supportive therapy is indicated.

Treatment

Symptomatic therapy.

Lozartan and its active metabolite are not excreted by hemodialysis.

Pregnancy use

Medications acting directly on the RAAS can cause serious damage and death to the developing fetus, so the drug should be withdrawn immediately upon diagnosis of pregnancy and, if necessary, alternative hypotensive therapy should be prescribed.

Pregnancy

Lozartan therapy should not be started during pregnancy. If continued therapy with losartan is deemed necessary in patients planning to become pregnant, losartan should be replaced with alternative hypotensive agents that have an established safety profile for use during pregnancy.

While there is no experience with the use of losartan in pregnant women, preclinical animal studies have shown that administration of losartan causes serious fetal and neonatal damage and fetal or offspring death. The mechanism of these events is thought to be due to effects on the RAAS.

Fetal renal perfusion dependent on the development of RAAS appears in the second trimester, so the risk to the fetus is increased if losartan is used in the second or third trimester of pregnancy.

The use of drugs affecting the RAAS in the second and third trimesters of pregnancy reduces fetal renal function and increases fetal and neonatal morbidity and mortality. Oligohydramnios may be associated with fetal lung hypoplasia and skeletal deformities. Possible adverse events in newborns include skull bone hypoplasia, anuria, arterial hypotension, renal failure, and death.

The above adverse outcomes are usually due to the use of drugs affecting the RAAS in the second and third trimesters of pregnancy. Most epidemiologic studies of fetal abnormalities after the use of hypotensive drugs in the first trimester of pregnancy have found no differences between RAAS-acting drugs and other hypotensive agents. When prescribing hypotensive therapy to pregnant women, it is important to optimize possible outcomes for the mother and fetus.

If no alternative therapy can be selected to replace therapy with drugs acting on the RAAS, the patient should be informed about the possible risks of therapy for the fetus. Periodic ultrasound examinations should be performed to assess the intraamniotic space. If oligohydramnios is detected, losartan should be discontinued unless it is vital for the mother. Depending on the week of pregnancy, appropriate fetal tests should be performed. Patients and physicians should be aware that oligohydramnios may not be detected until irreversible fetal damage has occurred. Newborns whose mothers have taken losartan during pregnancy should be closely monitored for arterial hypotension, oliguria, and hyperkalemia.

Breastfeeding

It is not known whether losartan is excreted with breast milk. Because many medications are excreted with breast milk and there is a risk of possible adverse effects in the breastfed infant, a decision should be made to discontinue breastfeeding or to discontinue the medication, taking into account the need for it for the mother.

Similarities

Lozap, Lorista, Presartan, Bloctran, Lozartan, Lozartan Canon