Lorista, 12,5mg 30 pcs.

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

• Arterial hypertension.
• Risk reduction in associated cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy, manifested by a combined reduction in cardiovascular mortality, stroke and myocardial infarction.
• Kidney protection in patients with type 2 diabetes mellitus with proteinuria – slowing the progression of renal failure, manifested by decreased incidence of hypercreatininemia, incidence of terminal chronic renal failure requiring hemodialysis or renal transplantation, mortality rates, and decreased proteinuria.
• Cronic heart failure with ineffective treatment with ACE inhibitors or intolerance to ACE inhibitors. It is not recommended to transfer patients with heart failure and stable hemodynamic parameters while taking ACE inhibitors to therapy with losartan.

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Indications

Arterial hypertension.
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.
Kidney protection in patients with type 2 diabetes mellitus with proteinuria – slowing the progression of renal failure, manifested by a decrease in the incidence of hypercreatininemia, the incidence of end-stage chronic renal failure requiring hemodialysis or kidney transplantation, mortality rates, as well as a decrease in proteinuria.
Chronic heart failure with ineffective treatment with ACE inhibitors or intolerance to ACE inhibitors. It is not recommended to transfer patients with heart failure and stable hemodynamic parameters while taking ACE inhibitors to losartan therapy.

Pharmacological effect

angiotensin II receptor antagonist (ARA II)

Special instructions

Bilateral renal artery stenosis or stenosis of the artery of a single kidney, hyperkalemia, condition after kidney transplantation (no experience with use), aortic or mitral stenosis, hypertrophic obstructive cardiomyopathy (HOCM), heart failure with concomitant severe renal impairment, severe heart failure (NYHA functional class IV), heart failure with life-threatening arrhythmias, coronary artery disease (IHD), cerebrovascular diseases, primary hyperaldosteronism, history of angioedema.

In patients with reduced circulating blood volume (CBV) (for example, patients receiving treatment with large doses of diuretics) symptomatic arterial hypotension may develop.

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

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

Contraindicated in patients with severe liver dysfunction (no experience with use).

For patients with a history of liver disease, it is recommended to use lower doses of Lorista® (see section “Special Instructions”).

Hypersensitivity reactions

Patients with a history of angioedema (swelling of the face, lips, pharynx/larynx and/or tongue) should be under strict medical supervision when using Lorista® (see section “Side Effects”).

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 pulmonary hypoplasia and skeletal deformities. Possible AEs in newborns include calvarial hypoplasia, anuria, hypotension, renal failure and death. If pregnancy is diagnosed, Lorista® should be discontinued immediately (see section “Use during pregnancy and breastfeeding”).

Arterial hypotension and water-electrolyte imbalance or decreased blood volume

In patients with reduced blood volume (for example, those receiving treatment with large doses of diuretics), symptomatic arterial hypotension may develop. Correction of such conditions must be carried out before using the drug Lorista® or treatment must begin with a lower dose of the drug Lorista® (see section “Method of administration and dosage”). Fluid and electrolyte imbalance is common in patients with impaired renal function with or without diabetes mellitus, so careful monitoring of these patients is necessary. In clinical trials in patients with type 2 diabetes mellitus with proteinuria, the incidence of hyperkalemia was greater in the losartan group than in the placebo group. Several patients discontinued therapy due to hyperkalemia (see section “Side effects”, subsection “Laboratory and instrumental data”).

During treatment with Lorista®, 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 used with caution in patients with aortic or mitral stenosis or HOCM.

IHD and cerebrovascular diseases

Like all drugs that have a vasodilating effect, ARA II should be used with caution in 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.

CHF

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

Since there is insufficient experience with the use of Lorista® in patients with heart failure and concomitant severe renal impairment, in patients with severe heart failure (NYHA functional class IV), as well as in patients with heart failure and symptomatic life-threatening arrhythmias, Lorista® should be used with caution in patients in these groups.

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 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 impaired liver function should use the drug Lorista® at a lower dose. There is no experience with the use of losartan in patients with severe liver dysfunction, so Lorista® should not be used in this group of patients (see sections “Pharmacological properties” [subsection “Pharmacokinetics”], “Contraindications”, “Dosage and Administration”).

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 serum 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

Ethnic characteristics

Analysis of data from the entire population of patients included in a clinical trial to study the effect of losartan on reducing the incidence of the main composite criterion for evaluating the study in patients with hypertension and left ventricular hypertrophy showed that the ability of losartan, compared with atenolol, to reduce the risk of stroke and myocardial infarction, as well as to reduce cardiovascular mortality in patients with hypertension and left ventricular hypertrophy (by 13.0%) does not apply to patients 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 hypertension and left ventricular hypertrophy of all races except blacks. However, in this study, black patients receiving atenolol had a lower risk of the study’s primary composite endpoint (i.e., lower combined incidence of cardiovascular death, stroke, and myocardial infarction) compared with race-matched patients receiving losartan.

Children and teenagers

The effectiveness and safety of 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 losartan 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 losartan in elderly patients (over 65 years of age).

No studies have been conducted to evaluate the effect of losartan on the ability to drive vehicles and operate machines, however, caution should be exercised when using antihypertensive therapy and driving or operating machines, since dizziness and drowsiness may develop, especially at the beginning of therapy or when increasing the dose of Lorista®.

Active ingredient

Losartan

Composition

per 1 tablet 12.5 mg/25 mg/50 mg/100 mg

Core:

Active ingredient:

Losartan potassium 12.50 mg/25.00 mg/50.00 mg/100.00 mg

Excipients:

Cellactose 801, pregelatinized starch, corn starch, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate

Film shell:

Hypromellose, talc, propylene glycol, quinoline yellow dye (E104) (for tablets 12.5 mg and 25 mg), titanium dioxide (E171)

1 Cellactose 80: lactose monohydrate, cellulose.

Pregnancy

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

Therapy with Lorista® should not be started during pregnancy. If continued antihypertensive therapy with losartan is considered necessary in patients planning pregnancy, losartan should be replaced with alternative antihypertensive agents that have an established safety profile for use in pregnancy.

Although there is no experience with the use of losartan in pregnant women, preclinical studies in animals have shown that administration of losartan leads to the development of serious fetal 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® 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 pulmonary hypoplasia and skeletal deformities. Potential adverse events (AEs) 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 using antihypertensive therapy in 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, unless it is vital for the mother. Depending on the stage of pregnancy, appropriate tests on the fetus are necessary. 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 during pregnancy is necessary to monitor arterial hypotension, oliguria and hyperkalemia.

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 possible adverse effects in a breastfed baby, a decision should be made to stop breastfeeding or discontinue the drug, taking into account the need for the mother.

Contraindications

Hypersensitivity to any of the components of this drug.
Severe liver dysfunction (no experience with use).
Concomitant use with aliskiren and drugs containing aliskiren in patients with diabetes mellitus and/or moderate to severe renal impairment (glomerular filtration rate [GFR] less than 60 ml/min/1.73 m2 body surface area) (see section “Interaction with other drugs”).
Concomitant use with ACE inhibitors in patients with diabetic nephropathy.
Hereditary lactose intolerance, lactase deficiency, glucose-galactose malabsorption syndrome.
Pregnancy and breastfeeding period.
Age up to 18 years (efficacy and safety of use have not been established).

Interaction

Other antihypertensive drugs may enhance the antihypertensive effect of losartan. Concomitant use with other drugs that can cause arterial hypotension (such as tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of developing arterial hypotension.

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. In clinical studies, the use of two inhibitors of the CYP3A4 isoenzyme was studied: 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, eplerenone, triamterene, amiloride), potassium supplements or potassium salts may lead to an increase in serum potassium.

As with the use of other drugs that affect the excretion of sodium ions, losartan can reduce the excretion of lithium, therefore, when using lithium preparations and ARA II simultaneously, it is necessary to carefully monitor the lithium content 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. The simultaneous use of these drugs should be carried out 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 Lorista® and other drugs that affect the RAAS at the same time. The simultaneous use of ARA II with drugs containing aliskiren is contraindicated in patients with diabetes mellitus and/or moderate to severe renal failure (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

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. In case of development of symptomatic arterial hypotension, maintenance therapy is indicated.

Treatment: symptomatic therapy. Losartan and its active metabolite are not eliminated by hemodialysis.

Clinical pharmacology

Mechanism of action

Angiotensin II is a powerful vasoconstrictor, the main active hormone of the renin-angiotensin-aldosterone system (RAAS), and also a decisive pathophysiological link in the development of arterial hypertension (AH). Angiotensin II binds to AT1 receptors in many tissues (vascular smooth muscle, adrenal glands, kidneys and heart) and has 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 their 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), in both in vitro and in vivo conditions, 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 to 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

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

When taking losartan, elimination of the negative feedback, which consists in the suppression of renin secretion by angiotensin II, leads to an increase in plasma renin activity (PRA). An increase in ARP leads to an increase in the concentration of angiotensin II in the blood plasma.

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.

Losartan therapy in postmenopausal women with hypertension does not affect 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 hypertension, losartan in doses up to 150 mg/day does not cause clinically significant changes in serum concentrations of fasting triglycerides, total cholesterol and high-density lipoprotein cholesterol. At the same doses, losartan has no effect on fasting blood glucose concentrations.

In patients with chronic heart failure (CHF) functional class II-IV according to the NYHA classification and intolerance to ACE inhibitors, losartan at a dose of 150 mg/day significantly reduces the risk of mortality from all causes or the risk of hospitalization for heart failure compared with a dose of 50 mg/day.

In patients with left ventricular failure (II-IV functional class according to the NYHA classification), most of whom are taking diuretics and/or cardiac glycosides, losartan in doses of 25 and 50 mg/day exhibits positive hemodynamic and neurohormonal effects. Hemodynamic effects include an increase in cardiac index and a decrease in pulmonary capillary wedge pressure, as well as a decrease in total peripheral vascular resistance (TPVR), mean systemic blood pressure and heart rate (HR). The incidence of arterial hypotension in such patients depends on the dose of losartan. Neurohormonal effects include decreased serum aldosterone and norepinephrine concentrations.

Pharmacokinetics

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 the dosage form of film-coated tablets is approximately 33%. The average Cmax of losartan and its active metabolite in blood plasma is reached after 1 hour and after 3-4 hours, respectively. When taking losartan with a normal meal, there was no clinically significant effect on the plasma concentration profile of losartan.

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 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 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 terminal half-life of approximately 2 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 certain groups of patients

Elderly patients

Concentrations of losartan and its active metabolite in blood plasma in elderly male patients with hypertension do not differ significantly from these indicators in young male patients with hypertension.

Gender

Concentrations of losartan in blood plasma in women with hypertension were 2 times higher than the corresponding values ​​in men with hypertension. Concentrations of the active metabolite in blood plasma did not differ between men and women. This apparent pharmacokinetic difference is, however, not clinically significant.

Patients with 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.

Patients with impaired renal function

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 patients on hemodialysis. Losartan and its active metabolite are not removed by hemodialysis.

Storage conditions

At a temperature not exceeding 25 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