Losartan

Pharmacological properties

potassium losartan is an antagonist of angiotensin ii receptors (type at1). angiotensin ii, formed from angiotensin i in the reaction involving apf (kininase ii), is a powerful vasoconstrictor, the primary vasoactive hormone of the renin-angiotensin system and an important component of the pathophysiological mechanisms of ag. angiotensin ii also binds to the at1 receptor, which is found in many tissues (vascular smooth muscle, adrenal gland, kidney, and heart), determining a number of important biological effects, including vasoconstriction and aldosterone release. angiotensin ii also stimulates the proliferation of smooth muscle cells.

Losartan and its active metabolite carboxylic acid block all physiologically significant effects of angiotensin II, regardless of the source or route of synthesis.

Losartan selectively binds to the AT receptor₁, does not bind or block other hormone receptors or ion channels.

Moreover, losartan does not inhibit ACE (kininase II), an enzyme that promotes the breakdown of bradykinin. As a consequence, effects not directly related to AT receptor blockade₁, such as an increase in influence, mediated by bradykinin, are not associated with the use of losartan.

When using losartan, the elimination of the negative reversible reaction of angiotensin II to renin secretion leads to an increase in renin activity in blood plasma. Such an increase in activity leads to an increase in the level of angiotensin II in blood plasma. Although such an increase occurs, antihypertensive activity and suppression of the concentration of aldosterone in plasma remain, which indicates an effective blockade of angiotensin II receptors. After discontinuation of losartan, plasma renin activity and angiotensin II levels for 3 days return to their original values.

Both losartan and its main metabolite have a higher affinity for AT₁receptors than AT₂. The active metabolite is 10–40 times more active than losartan.

Pharmacokinetics After oral administration, losartan is well absorbed and undergoes metabolic transformations of the first passage. Systemic bioavailability is about 33%. Almost 14% of an oral dose of losartan is converted into an active carboxy metabolite. C_max losartan and its active metabolite is reached after 1 and 3-4 hours, respectively. Losartan and the active metabolite intensely bind to plasma proteins, mainly with albumin. T_½ losartan is 2 hours, the active metabolite is 6–9 hours. The pharmacokinetics of losartan and the active metabolite is linear for oral doses of losartan up to 200 mg and does not change with time. Losartan and the active metabolite accumulate in blood plasma in the event of a repeated dose once a day. About 4% of the dose is excreted unchanged in the urine and about 6% in the form of an active metabolite. Biliary excretion of the drug is a certain part of the elimination of losartan and its active metabolite - about 35% of the dose enters the urine and almost 58% into the feces.

Elderly patients. Significant changes in pharmacokinetic characteristics in elderly patients with hypertension compared with young patients were not detected.

Floor. Plasma losartan concentrations in women with hypertension were 2 times higher than in men. Dependence of the concentration of the active metabolite on gender has not been identified.

Impaired liver and kidney function. Concentrations of losartan and its active metabolite in blood plasma in patients with impaired liver function are 1.7–5 times higher than those in patients with unchanged liver function.

The plasma concentrations of losartan in patients with creatinine clearance of 10 ml / min did not differ from those in healthy patients.AUC in patients with severe renal impairment was 2 times higher than the AUC of losartan in patients with normal renal function. The plasma concentrations of the active metabolite of losartan remained unchanged. Losartan and its active metabolite cannot be excreted by hemodialysis.

Pharmacokinetics in children. The active metabolite of losartan is formed in patients of all age groups. The pharmacokinetics of losartan after oral administration are similar in newborns and children over the age of 2 years, children of preschool, school age and adolescents. The pharmacokinetic parameters of the metabolite depend more on the age group, especially when comparing preschool children and adolescents. Exposure in infants and children under 2 years of age is relatively high.

Indications

• Treatment of essential hypertension in adults, as well as in children from the age of 6 years. treatment of kidney disease in adult patients with ag and type II diabetes mellitus with proteinuria ≥0.5 g / day - as part of hell. treatment of chronic heart failure (in patients over the age of 60) in cases where the use of APF inhibitors is considered impossible due to intolerance (especially when coughing) or if there are contraindications. patients with heart failure, whose condition is stable when taking APF inhibitors, the appointment of the drug Closart is impractical. in the patient, the ejection fraction of the left ventricle should be ≤40%, the condition should be clinically stable, and the patient should adhere to the established treatment regimen for chronic heart failure. reduced risk of stroke in adult patients with ag and left ventricular hypertrophy, which is confirmed by ecg.

Application

Take the tablets regardless of the meal with 1 glass of water.

AH. For most patients, the initial and maintenance dose of Closart is 50 mg once a day. The maximum antihypertensive effect is achieved at 3-6 weeks after the start of treatment. For some patients, it may be beneficial to increase the dose of the drug to 100 mg once a day (in the morning).

Closart can be used in combination with other antihypertensive drugs, especially with diuretics (e.g. hydrochlorothiazide).

Patients with hypertension, type II diabetes mellitus and proteinuria (≥0.5 g / day). Typically, the initial dose of Closart is 50 mg 1 time per day. The dose can be increased to 100 mg once a day, depending on what the blood pressure readings are 1 month after the start of treatment. Closart can be used together with other antihypertensive agents (diuretics, calcium channel blockers, α- or β-receptor blockers, centrally acting drugs), as well as with insulin and other hypoglycemic agents (e.g. sulfonylurea, glitazone and glucosidase inhibitors).

Heart failure. Typically, the initial dose of losartan in patients with chronic heart failure is 12.5 mg once daily. As a rule, the dose is titrated with a weekly interval (i.e. 12.5; 25; 50 mg / day) to the usual maintenance dose of 50 mg (1 Closart 50 mg tablet) once a day, depending on individual tolerance.

Reducing the risk of stroke in patients with hypertension and left ventricular hypertrophy has been documented using an ECG. Usually the initial dose is 50 mg 1 time per day. Depending on changes in blood pressure, it may be necessary to prescribe a low dose of hydrochlorothiazide and / or a dose of losartan should be increased to 100 mg once a day.

Individual patient groups

Use in patients with reduced BCC. In patients with reduced BCC (for example, due to the use of high doses of diuretics), therapy should be started with a dose of 25 mg once a day.

Use in patients with renal failure and patients on hemodialysis. When prescribing Closart to patients with impaired renal function, as well as to patients who undergo hemodialysis, an initial dose adjustment is not required.

The use in patients with impaired liver function in history. For patients with a history of liver dysfunction, consideration should be given to the appointment of the drug in the lowest dose. There is no experience in treating patients with severely impaired liver function, therefore, Closart is contraindicated in this group of patients.

Use in children over the age of 6 years. For children who can swallow tablets and who have a body weight of 20 kg and 50 kg, the recommended dose is 25 mg once a day. In exceptional cases, the dose can be increased to a maximum of 50 mg once a day. The dose should be adjusted depending on changes in blood pressure.

In patients with a body weight of 50 kg, the recommended dose is 50 mg 1 time per day. In exceptional cases, the dose can be increased to a maximum of 100 mg once a day. The use of doses exceeding 1.4 mg / kg (or more than 100 mg) per day in children has not been studied.

Closart is not recommended for use in children with impaired liver function.

Closart is also not recommended for children with a glomerular filtration rate (GFR) of 30 ml / min / 1.73 m²as there is no relevant data regarding the application.

Use in patients over the age of 75 years. Therapy should be started with a dose of 25 mg once a day. Dose adjustment is usually not required.

Contraindications

• Hypersensitivity to the active substance and any excipient that is part of the drug. severe dysfunction of the liver. pregnant women or women planning a pregnancy (see use during pregnancy and lactation). the simultaneous use of losartan and aliskiren in patients with diabetes mellitus or with impaired renal function (SCF 60 ml / min / 1.73 m2) is contraindicated (see use, special instructions, interactions).

Side effects

From the nervous system: dizziness, drowsiness, headache, insomnia, muscle cramps, paresthesia, stroke, migraine, dysgeusia.

From the side of the organ of hearing and the labyrinth: vertigo, ringing in the ears.

From the psyche: depression.

From the side of the heart: palpitation, syncope, angina pectoris, tachycardia, atrial fibrillation.

From the vascular system: symptomatic hypotension (especially in patients with intravascular dehydration, for example, patients with severe heart failure or in the treatment of diuretics in high doses), dose-dependent orthostatic effect.

From the digestive system: abdominal pain, dyspepsia, constipation, diarrhea, pancreatitis, nausea, vomiting.

From the hepatobiliary system: hepatitis, impaired liver function.

From the respiratory system: cough, shortness of breath, rhinorrhea, sinusitis, pharyngitis, upper respiratory tract infection.

From the side of the kidneys and urinary tract: changes in kidney function, including renal failure in patients at risk (such changes in kidney function may be reversible when therapy is discontinued), urinary tract infections.

From the blood system and lymphatic system: anemia, thrombocytopenia.

General condition and disorders associated with the method of use of the drug: asthenia / weakness, malaise, swelling, flu-like symptoms.

From the skin and subcutaneous tissue: urticaria, pruritus, rash, photosensitivity, erythroderma.

From the musculoskeletal system and connective tissue: back pain, myalgia, arthralgia, rhabdomyolysis.

From the reproductive system and mammary glands: erectile dysfunction / impotence.

On the part of the immune system: hypersensitivity reactions (anaphylactic reactions, angioedema, including swelling of the larynx and glottis, which leads to obstruction of the respiratory tract and / or swelling of the face, lips, pharynx and / or tongue); some patients had a history of angioedema associated with the use of other drugs, including ACE inhibitors; vasculitis, including purpure of Shenlein - Genoch.

Laboratory indicators: hypoglycemia, hyperkalemia, hyponatremia, increased levels of AlAT, increased levels of urea in the blood, creatinine in blood plasma.

special instructions

Pregnancy. during pregnancy, the use of angiotensin receptor antagonists is contraindicated ii. patients receiving angiotensin ii receptor antagonists and planning a pregnancy should switch to antihypertensive drugs that have an established safety profile for use during pregnancy. when pregnancy is established, treatment with angiotensin ii receptor antagonists must be stopped urgently and, if necessary, alternative treatment should be started (see contraindications and use during pregnancy and lactation).

Hypersensitivity. Angioneurotic edema. While taking the drug in patients with a history of angioedema (swelling of the face, lips, throat and / or tongue), the general condition should be constantly monitored.

Arterial hypotension and water-electrolyte imbalance. Symptomatic arterial hypotension, especially after applying the first dose or increasing it, can occur in patients with reduced BCC or sodium deficiency caused by the use of strong diuretics, dietary restriction of salt intake, diarrhea or vomiting. Such conditions require correction before starting treatment with losartan or lowering the initial dose of the drug. The same recommendations apply to children over 6 years old.

Electrolyte imbalance. Electrolyte imbalance is often noted in patients with impaired renal function (with / without diabetes mellitus), which should be taken into account. It should also carefully monitor the concentration of potassium (the possibility of hyperkalemia) in the blood plasma, as well as creatinine clearance indicators, especially in patients with heart failure and creatinine clearance of 30-50 ml / min.

The simultaneous use of losartan and potassium-sparing diuretics, potassium supplements and salt substitutes containing potassium is not recommended.

Impaired liver function. Considering the pharmacokinetic data indicating a significant increase in the concentration of losartan in the blood plasma of patients with cirrhosis of the liver, consideration should be given to reducing the dose for patients with a history of impaired liver function. There is no experience with the use of the drug in patients with severely impaired liver function.

The drug is not recommended for use in children with impaired liver function.

Impaired renal function. Changes in kidney function, including renal failure, have been reported that are associated with suppression of the renin-angiotensin system (especially in patients with renal-angiotensin-aldosterone system (RAAS) dependence, i.e. patients with severe cardiac impairment or pre-existing disorders kidney function).

Drugs that affect RAAS can cause an increase in plasma urea and creatinine levels in patients with bilateral renal artery stenosis, with renal artery stenosis, or with a single kidney artery stenosis.

These changes in kidney function may be reversible after discontinuation of therapy. Closart should be used with caution in patients with bilateral renal artery stenosis or with stenosis of a single kidney artery.

Use in children with impaired renal function. The drug is not recommended for use in children with GFR 30 ml / min / 1.73 m², since there is no relevant application data.

During the period of use of the drug, Closart should regularly check kidney function, since its deterioration is possible. This is especially true in situations where Closart is used in the presence of other pathological conditions (fever, dehydration), which can affect kidney function.

The simultaneous use of the drug Closart and ACE inhibitors worsens renal function, so this combination is not recommended.

Kidney transplantation. There is no experience regarding the safety of losartan in patients who have only had a kidney transplant.

Primary hyperaldosteronism. In patients with primary hyperaldosteronism, as a rule, there is no effect when using drugs that act by inhibiting the renin-angiotensin system. Therefore, Closart is not recommended for this group of patients.

Coronary artery disease and cerebrovascular disease. As with other antihypertensive drugs, an excessive decrease in blood pressure in patients with coronary artery disease and cerebrovascular disease can lead to the development of myocardial infarction or stroke.

Heart failure. As with other drugs that affect RAAS, in patients with heart failure with / without impaired renal function, there is a risk of severe arterial hypotension and (often acute) impaired renal function.

There is insufficient therapeutic experience with the use of losartan in patients with heart failure and concomitant severe renal impairment, patients with severe heart failure (NYHA class IV), as well as in patients with heart failure and symptomatic life-threatening cardiac arrhythmia. Therefore, losartan should be used with caution in this group of patients. With caution, losartan and β-adrenoreceptor blockers should be used simultaneously.

Stenosis of aortic and mitral valves, obstructive hypertrophic cardiomyopathy. As with other vasodilators, Closart should be prescribed with extreme caution to patients with aortic and mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Cautions. It has been established regarding ACE inhibitors that losartan and other angiotensin antagonists are less effective in patients of the Negroid race than in other patients, possibly due to the low renin activity in patients with hypertension who are representatives of the Negroid race.

Double blockade of RAAS. Hypertension, fainting, stroke, hyperkalemia, as well as changes in the kidneys (including acute renal failure) have been reported in susceptible individuals, especially when combining drugs that affect this system (see INTERACTIONS). Therefore, double blockade of RAAS by combining angiotensin II receptor blockers (ARBs) with ACE inhibitors or aliskiren is not recommended.

The combination with aliskiren is contraindicated in patients with diabetes mellitus or renal failure (GFR 60 ml / min / 1.73 m²).

Use during pregnancy and lactation

Pregnancy. The drug is contraindicated for pregnant women or women planning a pregnancy (see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS). If pregnancy is confirmed during treatment, the use of the drug should be stopped immediately and replaced with another drug approved for use in pregnant women.

It is known that the use of angiotensin II receptor antagonists in the II and III trimester induces fetotoxicity (impaired renal function, oligohydramnios, delayed ossification of the bones of the skull) and neonatal toxicity (renal failure, hypotension, hyperkalemia).

If angiotensin II receptor antagonists were used in the second trimester of pregnancy, it is recommended to perform an ultrasound scan to check kidney function and the condition of the skull bones.

The condition of newborns whose mothers used angiotensin II receptor antagonists should often be checked for the development of arterial hypotension.

Lactation.Since there is no information on the use of losartan during lactation, it is not recommended to prescribe this drug. An alternative treatment with drugs with a better-studied safety profile during breastfeeding is desirable, especially during the neonatal period or if the baby is premature.

Children. Safety and effectiveness of the use of the drug Closart for children under 6 years of age have not been established.

The ability to influence the reaction rate when driving vehicles or working with other mechanisms. Data on the effect of losartan on the ability to drive vehicles or work with other mechanisms is limited. The possibility of developing adverse reactions such as dizziness and drowsiness should be taken into account, especially at the beginning of treatment and with an increase in the dose of the drug.

Interactions

Other antihypertensive agents may enhance the hypotensive effect of losartan. simultaneous use with other drugs that can induce side effects such as arterial hypotension (tricyclic antidepressants, antipsychotics, baclofen and amifostine) can increase the risk of hypotension.

Losartan is predominantly metabolized by the cytochrome P450 (CYP) 2C9 of the active metabolite - carboxylic acid. It was found that fluconazole reduces the exposure of the active metabolite by about 50%, and simultaneous treatment with losartan and rifampicin (an inducer of metabolic enzymes) leads to a 40% decrease in the concentration of the active metabolite in blood plasma. The clinical significance of this effect is unknown. There are differences in exposure with the simultaneous use of losartan and fluvastatin (a weak inhibitor of CYP 2C9).

As with other drugs that block angiotensin II or its effects, the simultaneous use of drugs that inhibit potassium in the body (for example, potassium-sparing diuretics: spironolactone, triamteren, amiloride), or can increase the level of potassium (e.g. heparin), potassium supplements, or Potassium-containing salt substitutes can increase plasma potassium levels. The simultaneous use of such funds is not recommended.

A reversible increase in plasma lithium concentrations, as well as toxicity, have been reported with the simultaneous use of lithium with ACE inhibitors. The simultaneous use of lithium and losartan preparations should be carried out with caution. If the use of such a combination is considered necessary, it is recommended to control the level of lithium in blood plasma during the treatment period.

With the simultaneous use of angiotensin II antagonists and NSAIDs (for example, selective COX-2 inhibitors, acetylsalicylic acid in doses that have anti-inflammatory effects, non-selective NSAIDs), the antihypertensive effect may be weakened. The simultaneous use of angiotensin II antagonists or diuretics with NSAIDs can lead to an increased risk of impaired renal function, including the possible development of acute renal failure, as well as increased levels of potassium in the blood plasma, especially in patients with existing impaired renal function. This combination should be prescribed with caution, especially in elderly patients. Patients should undergo appropriate dehydration, should also consider monitoring renal function after initiation of concomitant therapy, then periodically.

Double blockade (for example, by adding an ACE inhibitor or aliskiren to angiotensin II receptor antagonists) should be limited to individually defined cases with close monitoring of blood pressure, kidney function, and electrolytes. In separate studies, it has been shown that in patients with established atherosclerosis, heart failure or diabetes mellitus with organ damage, the double blockade of RAAS is associated with a higher incidence of hypotension, fainting, hyperkalemia, as well as changes in kidney function (including acute renal failure) drug acting on RAAS. The combined administration of aliskiren with losartan is not recommended in patients with diabetes mellitus or in individuals with renal failure (GFR 60 ml / min) (see CONTRAINDICATIONS).

Overdose

Symptoms of an overdose.losartan overdose data is limited. the most likely manifestations of an overdose are hypotension and tachycardia; bradycardia may be due to parasympathetic (vagal) stimulation.

Treatment. Treatment depends on the length of time elapsed after taking the drug, as well as the nature and severity of the symptoms. The priority measure should be stabilization of the function of the cardiovascular system. After oral administration of losartan, the use of activated carbon in the appropriate dose is indicated. Later, you should often monitor the basic vital signs of the body and adjust if necessary. Losartan and its active metabolites are not excreted during hemodialysis.

Storage conditions

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