Lorista H100 film-coated tablets. Visitor report on side effects. Release form and composition

Compound

Active ingredients: losartan, hydrochlorothiazide;

1 coated tablet contains 100 mg of losartan potassium and 12.5 mg of hydrochlorothiazide;

Excipients: corn starch, microcrystalline cellulose, lactose, magnesium stearate, hypromellose, macrogol 4000, titanium dioxide (E 171), talc.

Dosage form. Film-coated tablets.

Basic physical and chemical properties: oval, biconvex tablets, film-coated, white.

Pharmacological group

Angiotensin II antagonists and diuretics. Losartan and diuretics.

ATX code C09D A01.

pharmacological properties.

Pharmacological.

Losartan and hydrochlorothiazide

It has been proven that the hypotensive effect of the components of the drug is additive, thus, the use of the components of the drug together lowers blood pressure to a greater extent than taking them separately. It is believed that the effect is the result of the concomitant action of both components. In addition, as a result of the diuretic effect, hydrochlorothiazide increases the activity of renin in the blood plasma and the release of aldosterone, reduces the concentration of potassium and increases the level of angiotensin II in the blood plasma. Taking losartan blocks all physiological effects of angiotensin II and, due to the inhibition of the effects of aldosterone, can reduce the loss of potassium associated with the use of a diuretic.

Losartan has a moderate and transient uricosuric effect. Hydrochlorothiazide slightly increases the level of uric acid in the blood The combination of losartan and hydrochlorothiazide attenuates diuretic-induced hyperuricemia.

The antihypertensive effect of the drug persists for 24 hours, and also persists with prolonged use. In addition to a significant decrease in blood pressure, drug therapy had no clinically significant effect on heart rate.

The combination of losartan and hydrochlorothiazide is effective in lowering blood pressure in men and women, patients of black and Caucasian races, patients of average (<65 лет) и пожилого возраста (≥ 65 лет), а также эффективная на всех стадиях артериальной гипертензии.

Losartan

Losartan is a synthetic angiotensin II receptor antagonist (type AO 1) for oral administration. Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to AO 1 receptors found in many tissues (eg, vascular smooth muscle, adrenals, kidneys, and heart) and exhibits several important biological effects, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells.

Losartan selectively blocks the AT 1 receptor. Under in vitro and in vivo conditions, losartan and its pharmacologically active metabolite, carboxylic acid (E 3174), block all physiologically significant effects of angiotensin II, regardless of the source or route of synthesis.

Losartan does not bind or block other hormone receptors and ion channels that are important for the regulation of the cardiovascular system. In addition, losartan does not affect the action of ACE (kinase II), which is responsible for the breakdown of bradykinin. Therefore, undesirable reactions associated with an increased concentration of bradykinin do not differ. With the introduction of losartan, the negative effect of angiotensin II on the formation of renin is inhibited, which leads to an increase in the activity of renin in the blood plasma. An increase in renin activity leads to an increase in the level of angiotensin II in the blood plasma. Despite this, antihypertensive activity and a decrease in plasma aldosterone levels persist, indicating effective blocking of the angiotensin II receptor. After discontinuation of losartan therapy, plasma renin activity and angiotensin II concentration returned to normal within three days.

Losartan and its major active metabolite are more capable of binding to the AT 1 prescription than to the AT 2 receptor. The active metabolite is 10 to 40 times more effective than losartan by volume percentage.

Losartan does not affect autonomic reflexes and has no long-term effect on plasma norepinephrine levels.

Hydrochlorothiazide

Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive action of the thiazide diuretic is not fully understood. Thiazides affect the renal tubular mechanism of electrolyte reabsorption, thereby directly increasing the excretion of sodium and chloride in approximately equal amounts. The diuretic effect of hydrochlorothiazide reduces plasma volume, increases plasma renin activity, increases aldosterone secretion, followed by an increase in urinary potassium and loss of bicarbonate and a decrease in serum potassium. Perhaps due to the blockade of the renin-aldosterone system, the simultaneous administration of angiotensin II receptor antagonists contributes to the reversible loss of potassium associated with a thiazide diuretic.

After ingestion, diuresis begins within two hours, peaks at 4:00, and continues for 6-12 hours. The antihypertensive effect lasts no more than 24 hours.

Pharmacokinetics.

Suction.

Losartan

After oral administration, losartan is well absorbed and undergoes primary metabolism with the formation of one active carboxyl metabolite and other pharmacologically inactive metabolites. The systemic bioavailability of losartan is approximately 33%. The maximum concentration of losartan and its active metabolite is reached one hour and 3-4 hours after administration, respectively. Eating does not have clinically significant deviations in the pharmacokinetic profile.

Distribution

Losartan

99% of losartan and its active metabolite are bound to plasma proteins, predominantly to albumin. The volume of distribution of losartan is 34 liters. In an animal study, little or no losartan crossed the blood-brain barrier.

Hydrochlorothiazide

Hydrochlorothiazide crosses the placental barrier, does not cross the blood-brain barrier; passes into breast milk.

Metabolism

Losartan

Approximately 14% of an oral or administered dose of losartan is metabolized to its active metabolite. After ingestion or administration of radioactively labeled (14 C) potassium losartan, plasma radioactivity is mainly caused by losartan and its active metabolite. In 1% of the studied individuals, losartan is only slightly converted into an active metabolite.

In addition to the active metabolite, inactive metabolites are formed, including two major metabolites formed by hydroxylation of the butyl chain and a minor N-2 metabolite, tetrazole glucuronide.

Losartan

The plasma clearance of losartan and its active metabolite is approximately 600 ml/min and 50 ml/min, respectively. The clearance of losartan and its active metabolite from the kidneys is 74 ml/min and 26 ml/min, respectively. When administered orally, 4% of the dose of losartan is excreted in the urine unchanged and 6% as the active metabolite.

The pharmacokinetic properties of losartan and its active metabolite change linearly with oral doses of losartan potassium up to 200 mg.

After taking the concentration of losartan and its active metabolite in blood plasma decrease polyexponentially; the half-life is approximately 2:00 and 6-9 hours, respectively. With a single dose of 100 mg, neither losartan nor its active metabolite significantly accumulate in plasma.

Both biliary and renal excretion play a role in the elimination of losartan and its active metabolites. After ingestion of radioactively labeled (14 C) losartan, about 35% of the radioactivity is found in the urine, and 58% in the feces.

Hydrochlorothiazide

Hydrochlorothiazide is not metabolized but is rapidly excreted by the kidneys. According to observations lasting at least 24 hours, the blood half-life of hydrochlorothiazide was 5.6-14.8 hours. At least 61% of an oral dose is excreted unchanged within 24 hours.

Characteristics in Patients

Losartan and hydrochlorothiazide

Plasma concentrations of losartan and its active metabolite and absorption of hydrochlorothiazide in elderly patients with arterial hypertension do not differ significantly from those in young patients with arterial hypertension.

Losartan

After oral administration in patients with mild to moderate alcoholic cirrhosis, plasma concentrations of losartan and its active metabolites were 5 and 1.7 times higher, respectively, than in young volunteers.

Neither losartan nor its active metabolite can be removed by hemodialysis.

Indications

Treatment of hypertension in patients whose blood pressure is not adequately controlled with losartan or hydrochlorothiazide alone.

Reducing the risk of cardiovascular disease and death in hypertensive patients with left ventricular hypertrophy.

Contraindications.

Hypersensitivity to losartan, sulfonamide derivatives (such as hydrochlorothiazide) or any of the excipients.
Hypokalemia or hypercalcemia resistant to therapy.
Severe liver dysfunction cholestasis and obstruction of the biliary tract.
Refractory hyponatremia.
Symptomatic hyperuricemia/gout.
Pregnant women and women who plan to become pregnant (see section "Use during pregnancy or lactation").
breastfeeding period.
Severe renal impairment (creatinine clearance<30 мл / мин).
Anuria.
Simultaneous use with aliskiren in case of diabetes mellitus or impaired renal function (GFR<60 мл / мин / 1,73 м 2) (см. Разделы «Особенности применения» и «Взаимодействие с другими лекарственными средствами и другие виды взаимодействий»).

Interaction with other medicinal products and other forms of interaction

Losartan

There have been reports that rifampicin and fluconazole reduce the level of the active metabolite. The clinical consequences of these interactions have not been evaluated.

As with other drugs that block angiotensin II receptors or their effects, concomitant use of potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride), potassium supplements, or salt substitutes containing potassium may lead to an increase in serum potassium levels. Simultaneous use is not recommended.

As with the use of other drugs that affect the excretion of sodium, a decrease in the excretion of lithium is possible. Therefore, serum lithium levels should be carefully monitored if lithium salts are used in conjunction with angiotensin II receptor antagonists.

Non-steroidal anti-inflammatory drugs (acetylsalicylic acid in the anti-inflammatory dosing regimen, selective COX-2 inhibitors) and non-selective non-steroidal anti-inflammatory drugs can reduce the antihypertensive effect of angiotensin II receptor antagonists. Concomitant use of angiotensin II receptor antagonists or diuretics and non-steroidal anti-inflammatory drugs may lead to deterioration of renal function, including possible acute renal failure, and an increase in serum potassium levels, especially in patients with impaired renal function. This combination should be taken with caution, especially in elderly patients. Patients require adequate hydration and close monitoring of renal function at the start of concomitant therapy and periodically thereafter.

In some patients with impaired renal function, concomitant use of angiotensin II receptor antagonists and drugs that inhibit COX 2 may lead to further deterioration of renal function. These effects are usually reversible.

Arterial hypotension as a main or side effect is typical for tricyclic antidepressants, antipsychotics, baclofen, amifostine. The simultaneous use of these drugs may increase the risk of arterial hypotension.

Studies have shown that as a result of dual blockade of the RAAS with the simultaneous use of ACE inhibitors, angiotensin II receptor antagonists or aliskiren, the risk of adverse reactions, such as arterial hypotension, hyperkalemia and changes in kidney function, including acute renal failure, is increased compared with the use of a single agent of renin- angiotensin of the aldosterone system (see sections "Contraindications", "Peculiarities of use".

Hydrochlorothiazide

With simultaneous use, the following drugs may interact with thiazide diuretics.

Alcohol, barbiturates, drugs or antidepressants

Orthostatic hypotension may worsen.

Antidiabetic drugs (oral drugs and insulin)

The use of thiazides may affect glucose tolerance. It may be necessary to change the dose of antidiabetic agents. Metformin should be used with caution, as there is a risk of lactic acidosis caused by possible renal failure associated with the use of hydrochlorothiazide.

Other antihypertensives

additive effect.

Resins of cholestyramine and colestipol

The absorption of hydrochlorothiazide is impaired in the presence of anion exchange resins. Single doses of cholestyramine or colestipol bind hydrochlorothiazide and reduce its absorption from the gastrointestinal tract to 85% and 43%, respectively;

Corticosteroids, ACTH

The loss of electrolytes increases, especially the risk of hypokalemia.

Pressor amines (e.g. adrenaline)

Possible decreased response to pressor amines. The degree of this decrease is insignificant, therefore, the use of these funds is not excluded.

Non-depolarizing musculoskeletal relaxants (eg tubocurarine)

An increased reaction to the use of muscle relaxants is possible.

lithium preparations

Diuretics reduce renal clearance and increase the risk of lithium intoxication; simultaneous use is not recommended.

Medicines used to treat gout (probenecid, sulfinpyrazone, and allopurinol)

It may be necessary to adjust the dose of drugs that promote the excretion of uric acid, since hydrochlorothiazide can increase the level of uric acid in the blood serum. An increase in the dose of probenecid or sulfinpyrazone may be required. Concomitant use of thiazides may increase the frequency of hypersensitivity reactions to allopurinol.

Anticholinergics (eg atropine, biperidene)

An increase in the bioavailability of thiazide diuretics is associated with a decrease in the motor activity of the gastrointestinal tract and the rate of gastric emptying.

Cytotoxic drugs (eg, cyclophosphamide, methotrexate)

Thiazides can reduce the excretion of cytotoxic drugs by the kidneys and increase their myelosuppressive effect.

salicylates

When using large doses of salicylates, hydrochlorothiazide can increase the toxic effect of salicylates on the central nervous system.

methyldopa

In some cases, with the simultaneous use of hydrochlorothiazide and methyldopa, hemolytic anemia was noted.

cyclosporine

With the simultaneous use of cyclosporine, the risk of hyperuricemia and complications such as gout increases.

cardiac glycosides

Thiazide-induced hypokalemia or hypomagnesemia can induce the development of cardiac arrhythmias caused by cardiac glycosides.

Medicinal products affected by impaired serum potassium levels

It is necessary to periodically monitor the concentration of potassium in the blood serum and conduct ECG monitoring when using the drug losartan / hydrochlorothiazide with drugs whose effect depends on the level of potassium in the blood plasma (such as cardiac glycosides and antiarrhythmic drugs), as well as with drugs that cause ventricular tachycardia ( torsades de pointes), including some antiarrhythmic drugs, since hypokalemia contributes to the formation of ventricular tachycardia:

Class Ia antiarrhythmics (eg, quinidine, hydroquinidine, disopyramide)
class III antiarrhythmic drugs (eg amiodarone, sotalol, dofetilide, ibutilide)
certain antipsychotics (eg, thioridazine, chlorpromazine, levomepromazine, trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol)
other drugs (eg bepridil, cisapride, difemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, terfenadine, intravenous vincamine).

calcium salts

Thiazide diuretics may increase serum calcium due to decreased excretion. If it is necessary to use drugs that increase the content of calcium, you should regularly monitor the level of calcium in the blood serum and, accordingly, determine the dose of these drugs according to the result.

Interactions during laboratory tests

Through their effect on calcium metabolism, thiazides may alter the results of parathyroid function tests.

Carbamazepine.

Risk of symptomatic hyponatremia. Clinical observation of the patient and laboratory blood control are necessary.

Contrast media containing iodine

In the case of dehydration caused by diuretics, there is an increased risk of acute renal failure, especially with the introduction of high doses of drugs containing iodine. Before them, patients should restore the water balance.

Amphotericin B (parenteral), corticosteroids, ACTH, laxatives, and glycyrrhizin (found in licorice). Hydrochlorothiazide may exacerbate electrolyte imbalances, especially hypokalemia.

Application features

Losartan

Angioedema

Patients with a history of angioedema (swelling of the face, lips, throat and/or tongue) should be closely monitored.

Arterial hypotension and deficiency of fluid volume circulating

In patients with a deficit in the volume of fluid circulating and / or sodium in the body due to the intensive use of diuretics, restriction of salt intake, diarrhea or vomiting, symptomatic arterial hypotension may occur, especially after taking the first dose and after increasing the dose. Such conditions require their correction to the use of the drug or a decrease in the initial dose.

Violation of water and electrolyte balance

In patients with renal insufficiency, both diabetic and non-diabetic, electrolyte disturbances often occur that require correction. Therefore, it is necessary to regularly monitor the concentration of potassium in the blood plasma and creatinine clearance. Particularly careful monitoring requires patients with heart failure and creatinine clearance of 30 to 50 ml / min. Potassium-sparing diuretics, potassium supplements, and potassium salt substitutes are not recommended concomitantly with losartan.

Impaired liver function

Based on pharmacokinetic data indicating a significant increase in plasma concentrations of losartan in patients with liver cirrhosis, patients with a history of mild or moderate hepatic impairment should reduce the dose of the drug. Experience with the therapeutic use of losartan in patients with severe hepatic impairment, therefore, the drug is contraindicated in such patients.

Impaired kidney function

Due to inhibition of renin-angiotensin, changes in renal function, including renal failure, have been reported (in particular in patients whose renal function is dependent on renin-angiotensin-, for example, in severe heart failure or pre-existing impaired renal function).

As with other drugs that affect the renin-angiotensin-aldosterone system, an increase in blood urea and serum creatinine has also been reported in patients with bilateral renal artery stenosis or stenosis of the artery to a solitary kidney, these changes in renal function may be reversible after discontinuation of therapy . Losartan should be used with caution in patients with bilateral renal artery stenosis or arterial stenosis of a single kidney.

kidney transplant

There is no experience of using the drug in patients who have recently undergone kidney transplantation.

Primary hyperaldosteronism

Patients with primary aldosteronism usually do not respond to treatment with antihypertensive drugs, the mechanism of action of which is to inhibit the renin-angiotensin system. Therefore, they are not recommended to use losartan tablets.

Ischemic heart disease and cerebrovascular disease

As with any antihypertensive drug, a rapid decrease in blood pressure in patients with coronary heart disease and cerebrovascular disease may cause myocardial infarction or stroke.

Heart failure

In patients with heart failure, with or without impaired renal function, when using losartan, and when using any other drugs that act on the renin-angiotensin system, there is a risk of severe arterial hypotension and (very often acute) renal failure.

Stenosis of the aorta and mitral valve, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special caution should be exercised in patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Ethnic features

Like ACE inhibitors, losartan and other angiotensin antagonists are less effective in lowering blood pressure in black patients than in other races, most likely due to the higher incidence of low renin levels in the black patient population with arterial hypertension.

Pregnancy

Angiotensin II receptor antagonists should not be started during pregnancy. If continued angiotensin II receptor antagonist therapy cannot be considered essential, patients planning pregnancy should be switched to an alternative antihypertensive treatment that has an approved safety profile for use during pregnancy. If pregnancy is detected, treatment with losartan should be stopped immediately and, if possible, alternative therapy should be initiated.

Double blockade of renin-angiotensin-(RAAS)

With the simultaneous use of aliskiren and angiotensin II receptor antagonists or ACE inhibitors, the risk of arterial hypotension, hyperkalemia and impaired renal function, including acute renal failure, increases. In connection with the double blockade of renin-angiotensin-(RAAS), the simultaneous use of aliskiren and angiotensin II receptor antagonists or ACE inhibitors is not recommended (see Section "Interaction with other medicinal products and other forms of interaction"). If a double blockade of the RAAS is necessary, renal function, blood electrolyte levels and blood pressure should be carefully monitored. Angiotensin II receptor antagonists and ACE inhibitors should not be used concomitantly in diabetic patients.

Hydrochlorothiazide

Arterial hypotension and disturbance of water and electrolyte balance

As with other antihypertensive agents, symptomatic hypotension may occur in some patients while taking the drug. Patients should be observed for clinical signs of fluid electrolyte imbalance (eg, decreased fluid volume, hyponatremia, hypochloremic alkalosis, hypomagnesemia, or hypokalemia) that may result from concomitant diarrhea or vomiting. In such patients, at certain intervals, the level of electrolytes in the blood serum should be periodically determined. Dissolution hyponatremia may occur in patients prone to edema in hot weather.

Metabolic and endocrine effects

Thiazides are able to change glucose tolerance. Doses of antidiabetic drugs, including insulin, may need to be adjusted. During therapy with thiazides, latent diabetes mellitus may occur.

Thiazides can reduce the excretion of calcium in the urine, and also cause a slight and transient increase in the level of calcium in the blood serum. Severe hypercalcemia may be a sign of latent hyperparathyroidism. Thiazides should be discontinued prior to testing parathyroid function.

An increase in cholesterol and triglyceride levels may also be associated with thiazide diuretic therapy.

Thiazide therapy may lead to hyperuricemia and/or gout in some patients. Since losartan reduces urinary uric acid, losartan in combination with hydrochlorothiazide reduces diuretic-induced hyperuricemia.

Impaired liver function

Thiazides should be used with caution in patients with hepatic impairment or progressive liver disease, as they can cause intrahepatic cholestasis, and minor changes in fluid and electrolyte balance can cause hepatic coma. The drug is contraindicated in patients with severe hepatic impairment.

Other states

In patients receiving thiazides, allergic reactions may occur regardless of a history of allergic conditions or bronchial asthma. Relapses or worsening of systemic lupus erythematosus have been reported in patients treated with thiazides.

Special information about some ingredients

Lorista ® H 100 contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Use during pregnancy or lactation.

Pregnancy

Losartan

The drug is contraindicated for pregnant women or women planning pregnancy. If pregnancy is confirmed during treatment, its use must be immediately discontinued and replaced with another drug approved for use by pregnant women. Epidemiological conclusions about the risk of teratogenicity due to the influence of ACE inhibitors during the first trimester of pregnancy are not unambiguous, but a slight increase in risk cannot be ruled out. So far, there are no controlled epidemiological data on the risk associated with the use of angiotensin II inhibitors, a similar risk is possible for this class of drugs. If continued angiotensin II inhibitor therapy cannot be considered essential, patients planning pregnancy should be switched to an alternative antihypertensive treatment that has an approved safety profile for use during pregnancy. If pregnancy is detected, treatment with an angiotensin II inhibitor should be stopped immediately and, if possible, alternative therapy should be initiated.

It is known that the use of angiotensin II inhibitors during the II and III trimester of pregnancy can cause fetotoxicity (decreased renal function, oligohydramnios, retardation of the ossification of the skull) and neonatal toxicity (renal failure, arterial hypotension, hyperkalemia).

If the use of angiotensin II inhibitors occurred in the second trimester of pregnancy, it is recommended to conduct an ultrasound examination of the function of the kidneys and skull.

Infants whose mothers have taken angiotensin II inhibitors should be closely monitored for hypotension.

Hydrochlorothiazide

There is limited experience with the use of hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are limited.

Hydrochlorothiazide crosses the placental barrier. Given the pharmacological mechanism of action of hydrochlorothiazide, its use during the II and III trimester can damage the blood supply between the placenta and the fetus and cause jaundice, electrolyte imbalance and thrombocytopenia in the fetus and newborn.

Hydrochlorothiazide should not be used to treat gestational edema, as well as gestational hypertension or preeclampsia due to the risk of a decrease in blood plasma volume and the occurrence of uteroplacental hypoperfusion without a beneficial effect on the course of the disease.

Hydrochlorothiazide should not be used to treat hypertension in pregnant women unless alternative treatment cannot be used.

Lactation

It is not recommended to use the drug due to the lack of sufficient data on the use during lactation. The patient should be switched to an alternative antihypertensive treatment that has an approved safety profile for use during lactation, especially in neonates or premature infants.

The ability to influence the reaction rate when driving vehicles or operating other mechanisms.

No studies have been conducted on the effect of the drug on the ability to drive a car and work with mechanisms.

However, while driving or using other mechanisms, dizziness or fatigue may occur when using antihypertensive drugs, especially at the beginning of treatment or when the dose is increased.

Method of application and dose.

Lorista ® H 100 can be used together with other antihypertensive agents.

The tablet should be swallowed with a glass of water.

Lorista ® H 100 can be taken with or without food.

Arterial hypertension

Losartan and hydrochlorothiazide are not used as initial therapy, but are used in patients whose blood pressure is appropriately not controlled by losartan or hydrochlorothiazide alone.

For patients whose blood pressure will be adequately controlled by monotherapy, a decision may be made to switch to combination therapy.

The usual maintenance dose is 1 tablet Lorist ® H (50 mg / 12.5 mg) once a day. For patients in whom the use of 1 tablet of Lorista® N does not give a sufficient effect, the dose can be increased to 1 tablet of Lorista® HD (100 mg / 25 mg) 1 time per day.

The maximum dose is 1 tablet Lorist ® HD 100 mg / 25 mg 1 time per day. The antihypertensive effect is achieved within 3-4 weeks after the start of therapy.

Lorista ® H 100 is intended for patients receiving a titrated dose of losartan 100 mg and requiring additional blood pressure monitoring.

Reducing the risk of cardiovascular disease and death in hypertensive patients with left ventricular hypertrophy

The initial dose is 50 mg of losartan 1 time per day. Patients who fail to achieve the target blood pressure level with losartan 50 mg per day should be treated with a combination of losartan with low doses of hydrochlorothiazide (12.5 mg) and, if necessary, increase the dose to 100 mg losartan / 125 mg hydrochlorothiazide 1 time per day. If necessary, the dose should be increased to 100 mg of losartan and 25 mg of hydrochlorothiazide 1 time per day.

Lorista ® H, Lorista ® H 100 and Lorista ® HD are alternative medicines for patients who control hypertension by concomitant administration of losartan and hydrochlorothiazide at appropriate doses.

Use in patients with impaired renal function and patients undergoing hemodialysis sessions

No initial dose adjustment is needed for patients with moderate renal impairment (creatinine clearance 30-50 ml/min). Losartan/hydrochlorothiazide combination tablets are not recommended for patients undergoing hemodialysis sessions. The drug should not be used in patients with severe renal impairment (creatinine clearance<30 мл / мин).

Use in patients with a decrease in intravascular volume of circulating fluid

Correction of fluid and / or sodium deficits should be carried out before starting the use of losartan / hydrochlorothiazide tablets.

Use in patients with impaired liver function

The drug is contraindicated in patients with severe hepatic impairment.

Use in elderly patients

Usually there is no need for dose adjustment for elderly patients.

Children.

There is no experience of using the drug in children, so the combination of losartan / hydrochlorothiazide should not be used in this category of patients.

Overdose

There are no specific data on the treatment of overdose with the drug. Overdose therapy is symptomatic and supportive. It is necessary to interrupt the course of therapy with the drug and carefully monitor the patient's condition. If the drug has been taken recently, it is necessary to induce vomiting and take measures aimed at eliminating dehydration, electrolyte disturbances, hepatic coma and arterial hypotension.

Losartan

Data on drug overdose in humans are limited. The most likely manifestations of an overdose are arterial hypotension, tachycardia, bradycardia may be the result of parasympathetic (vagal) stimulation. In the case of symptomatic arterial hypotension, maintenance therapy is indicated.

Losartan and its active metabolite are not removed by hemodialysis.

Hydrochlorothiazide

Often overdose symptoms are due to electrolyte deficiency (hypokalemia, hypochloremia, hyponatremia) and dehydration due to excessive urination. With the simultaneous administration of cardiac glycosides, hypokalemia can cause an increase in arrhythmias.

Hydrochlorothiazide is removed by hemodialysis, but the extent of removal has not been established.

Adverse reactions

Adverse reactions that may occur during treatment, classified into groups according to the frequency of occurrence: very often ³1 / 10; often: ³1 / 100 -<1/10; нечасто ³1 / 1000 - <1/100; редко ³1 / 10000 - <1/1000; очень редко <1/10000; неизвестно (нельзя подсчитать по имеющимся данным).

In studies of losartan potassium and hydrochlorothiazide, no adverse reactions were observed that are unusual for this combination of substances. Adverse reactions were limited to those previously observed for losartan potassium and/or hydrochlorothiazide.

During the hypertension studies, dizziness was the only side effect associated with the active substance and occurred in more than 1% of patients (significantly more than in the placebo group).

In addition to these reactions, there are such side reactions:

From the side of the liver and biliary tract: rarely - hepatitis.

laboratory indicators: rarely - hyperkalemia, increased levels of alanine aminotransferase (ALT). Additional adverse reactions that have been observed with the use of one of the individual components of the drug and may be potential side effects of the drug when using the combination of losartan potassium / hydrochlorothiazide are as follows:

Losartan:

on the part of the blood and lymphatic system: infrequently - anemia, Henoch-Genoch purpura, ecchymosis, hemolysis;

unknown - thrombocytopenia

from the immune system: rarely - hypersensitivity reactions: anaphylactic reactions, angioedema, including edema of the larynx and glottis, leading to airway obstruction and / or swelling of the face, lips, pharynx and / or tongue; history of angioedema with the use of drugs, including ACE inhibitors urticaria

on the part of metabolism and nutrition: infrequently - anorexia, gout;

mental disorders: often - insomnia;

infrequently - a feeling of fear, anxiety disorder, panic disorder, confusion, depression, abnormal dreams, sleep disorders, drowsiness, memory impairment;

from the nervous system: often - headache, dizziness

infrequently - nervousness, paresthesia, peripheral neuropathy, tremor, migraine, loss of consciousness; unknown - taste perversion;

on the part of the organs of vision: infrequently - blurred vision, burning / tingling in the eyes, conjunctivitis, decreased visual activity;

on the part of the hearing organs and the vestibular apparatus: infrequently - vertigo, ringing in the ears

From the side of the heart: infrequently - arterial hypotension, orthostatic hypotension, sternalgia, angina pectoris, block II degree, cerebrovascular disorders, myocardial infarction, palpitations, arrhythmias (atrial fibrillation, sinus bradycardia, tachycardia, ventricular tachycardia, ventricular fibrillation)

from the side of the vessels: infrequently - vasculitis

unknown - dose-dependent orthostatic effects

on the part of the respiratory system, chest organs and mediastinum: often - cough, upper respiratory tract infections, nasal congestion, sinusitis, changes in the sinuses;

infrequently - pharyngeal discomfort, pharyngitis, laryngitis, shortness of breath, bronchitis, epistaxis, rhinitis, airway congestion

from the gastrointestinal tract: often - abdominal pain, nausea, diarrhea, dyspepsia

infrequently - constipation, toothache, dry mouth, flatulence, gastritis, vomiting, intestinal obstruction;

unknown - pancreatitis

From the side of the liver and biliary tract: unknown - changes in liver function parameters

From the skin and subcutaneous tissues: infrequently - alopecia, dermatitis, dry skin, erythema, redness, photosensitivity, itching, rash, urticaria, increased sweating;

from the musculoskeletal and connective tissue: often - muscle cramps, back pain, pain in the legs, myalgia

infrequently - pain in the hands, swelling of the joints, pain in the knees, bone and muscle pain, pain in the shoulders, feeling of stiffness in the joints, arthralgia, arthritis, coxalgia, fibromyalgia, muscle weakness,

unknown - rhabdomyolysis;

From the side of the kidneys and urinary tract: often - impaired renal function, renal failure

infrequently - nocturia, frequent urination, urinary tract infections;

from the genital organs and mammary glands: infrequently - decreased libido, erectile dysfunction / impotence

general disorders: often - asthenia, fatigue, chest pain; infrequently - swelling of the face, fever;

unknown - flu-like symptoms, malaise;

laboratory parameters: often - hyperkalemia, a slight decrease in hematocrit and hemoglobin; infrequently - a slight decrease in the level of urea and creatinine in the blood serum; very rarely - increased liver enzymes and bilirubin.

Hydrochlorothiazide:

from the blood and lymphatic system: infrequently - agranulocytosis, aplastic anemia, hemolytic anemia, leukopenia, purpura, thrombocytopenia

from the immune system: rarely - anaphylactic reactions;

on the part of metabolism and nutrition: infrequently - anorexia, hyperglycemia, hyperuricemia, hypokalemia, hyponatremia

mental disorders: infrequently - insomnia, mood changes;

from the nervous system: often - headache;

on the part of the organs of vision: infrequently - reversible blurred vision, xanthopsia;

from the side of the vessels: infrequently - necrotizing angiitis (vasculitis, cutaneous vasculitis)

from the respiratory system, chest organs and mediastinum: infrequently - respiratory distress, including pneumonitis and pulmonary edema;

from the gastrointestinal tract: rarely - inflammation of the salivary glands, spasms, stomach irritation, nausea, vomiting, diarrhea, constipation

from the liver and biliary tract: infrequently - jaundice (intrahepatic cholestasis), pancreatitis

from the skin and subcutaneous tissues: infrequently - photosensitivity, urticaria, toxic epidermal necrolysis

Storage conditions

Store at a temperature not exceeding 30 ° C in the original packaging to protect against moisture. Keep out of the reach of children.

Package

10 tablets in a blister, 3 or 6 blisters in a cardboard box.

14 tablets in a blister, 2 or 4 blisters in a cardboard box.

15 tablets in a blister, 2 or 4 or 6 blisters in a cardboard box.

The page contains instructions for use Lorists. It is available in various dosage forms of the drug (tablets 12.5 mg, 25 mg, 50 mg and 100 mg, N and ND plus with diuretic hydrochlorothiazide), and also has a number of analogues. This annotation has been verified by experts. Leave your feedback about the use of Lorista, which will help other site visitors. The drug is used for various diseases (to reduce pressure in arterial hypertension). The tool has a number of side effects and features of interaction with other substances. Doses of the drug differ for adults and children. There are restrictions on the use of the drug during pregnancy and during breastfeeding. Treatment with Lorista can only be prescribed by a qualified doctor. The duration of therapy may vary and depends on the specific disease.

Instructions for use and dosage

The drug is taken orally, regardless of food intake, the frequency of administration is 1 time per day.

With arterial hypertension, the average daily dose is 50 mg. The maximum antihypertensive effect is achieved within 3-6 weeks of therapy. It is possible to achieve a more pronounced effect by increasing the dose of the drug to 100 mg per day in two doses or in one dose.

Against the background of taking diuretics in high doses, it is recommended to start therapy with Lorista with 25 mg per day in one dose.

Elderly patients, patients with impaired renal function (including patients on hemodialysis) do not require adjustment of the initial dose of the drug.

In patients with impaired liver function, the drug should be prescribed at a lower dose.

In chronic heart failure, the initial dose of the drug is 12.5 mg per day in one dose. In order to reach the usual maintenance dose of 50 mg per day, the dose must be increased gradually at intervals of 1 week (eg, 12.5 mg, 25 mg, 50 mg per day). Lorista is usually given in combination with diuretics and cardiac glycosides.

To reduce the risk of stroke in patients with arterial hypertension and left ventricular hypertrophy, the standard initial dose is 50 mg per day. In the future, low-dose hydrochlorothiazide may be added and / or the dose of Lorista may be increased to 100 mg per day.

For kidney protection in type 2 diabetic patients with proteinuria, the standard starting dose of Lorista is 50 mg daily. The dose of the drug can be increased to 100 mg per day, taking into account the decrease in blood pressure.

Release forms

Tablets 12.5 mg, 25 mg, 50 mg and 100 mg.

Lorista N (additionally contains 12.5 mg of hydrochlorothiazide).

Lorista ND (additionally contains 25 mg of hydrochlorothiazide).

Compound

Losartan potassium + excipients.

Losartan potassium + Hydrochlorothiazide + excipients (Lorista H and ND).

Lorista- selective angiotensin 2 type AT1 receptor antagonist of non-protein nature.

Losartan (the active ingredient of Lorista) and its biologically active carboxyl metabolite (EXP-3174) block all physiologically significant effects of angiotensin 2 on AT1 receptors, regardless of the route of its synthesis: it leads to an increase in plasma renin activity, reduces the concentration of aldosterone in blood plasma.

Losartan indirectly causes the activation of AT2 receptors by increasing the level of angiotensin 2. Losartan does not inhibit the activity of kininase 2, an enzyme that is involved in the metabolism of bradykinin.

Reduces OPSS, pressure in the pulmonary circulation; reduces afterload, has a diuretic effect.

Prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure.

Taking Lorista once a day leads to a statistically significant decrease in systolic and diastolic blood pressure. During the day, losartan evenly controls blood pressure, while the antihypertensive effect corresponds to the natural circadian rhythm. The decrease in blood pressure at the end of the dose of the drug was approximately 70-80% of the effect at the peak of the drug, 5-6 hours after administration. There is no withdrawal syndrome; also, losartan does not have a clinically significant effect on heart rate.

Losartan is effective in men and women, as well as in older (≥ 65 years) and younger patients (≤ 65 years).

Hydrochlorothiazide is a thiazide diuretic, the diuretic effect of which is associated with impaired reabsorption of sodium, chlorine, potassium, magnesium, and water ions in the distal nephron; delays the excretion of calcium ions, uric acid. Has antihypertensive properties; hypotensive effect develops due to the expansion of arterioles. Virtually no effect on normal blood pressure. The diuretic effect occurs after 1-2 hours, reaches a maximum after 4 hours and lasts 6-12 hours.

The antihypertensive effect occurs after 3-4 days, but it may take 3-4 weeks to achieve the optimal therapeutic effect.

Pharmacokinetics

The pharmacokinetics of losartan and hydrochlorothiazide with simultaneous use does not differ from that with their separate use.

Losartan

Well absorbed from the gastrointestinal tract. Taking the drug with food does not have a clinically significant effect on its serum concentrations. Practically does not penetrate through the blood-brain (BBB). About 58% of the drug is excreted in the bile, 35% in the urine.

Hydrochlorothiazide

After oral administration, the absorption of hydrochlorothiazide is 60-80%. Hydrochlorothiazide is not metabolized and is rapidly excreted by the kidneys.

Indications

arterial hypertension;
reduced risk of stroke in patients with arterial hypertension and left ventricular hypertrophy;
chronic heart failure (as part of combination therapy, with intolerance or ineffectiveness of therapy with ACE inhibitors);
protection of kidney function in patients with type 2 diabetes mellitus with proteinuria to reduce proteinuria, reduce the progression of kidney damage, reduce the risk of end-stage development (preventing the need for dialysis, the likelihood of an increase in serum creatinine), or death.

Contraindications

arterial hypotension;
hyperkalemia;
dehydration;
lactose intolerance;
galactosemia or glucose/galactose malabsorption syndrome;
pregnancy;
lactation period;
age up to 18 years (efficacy and safety in children have not been established);
hypersensitivity to losartan and / or other components of the drug.

special instructions

Patients with a reduced volume of circulating blood (for example, during therapy with large doses of diuretics) may develop symptomatic arterial hypotension. Before taking losartan, it is necessary to eliminate existing disorders, or start therapy with small doses.

In patients with mild to moderate liver cirrhosis, the concentration of losartan and its active metabolite in the blood plasma after oral administration is higher than in healthy people. Therefore, in patients with a history of liver disease, therapy at lower doses is recommended.

Patients with impaired renal function, both with and without diabetes mellitus, often develop hyperkalemia, which should be borne in mind, but only in rare cases do they stop treatment as a result. During the period of treatment, the concentration of potassium in the blood should be regularly monitored, especially in elderly patients, with impaired renal function.

Drugs that act on the renin-angiotensin system may increase serum urea and creatinine in patients with bilateral renal artery stenosis or unilateral stenosis of the artery to a solitary kidney. Changes in renal function may be reversible after discontinuation of therapy. During treatment, it is necessary to regularly monitor the concentration of creatinine in the blood serum at regular intervals.

Influence on the ability to drive vehicles and control mechanisms

There are no data on the effect of Lorist on the ability to drive vehicles or other technical means.

Side effect

dizziness;
asthenia;
headache;
fatigue;
insomnia;
anxiety;
sleep disturbance;
drowsiness;
memory disorders;
peripheral neuropathy;
paresthesia;
hypoesthesia;
migraine;
tremor;
depression;
orthostatic hypotension (dose-dependent);
heartbeat;
tachycardia;
bradycardia;
arrhythmias;
angina;
nasal congestion;
cough;
bronchitis;
swelling of the nasal mucosa;
nausea, vomiting;
diarrhea;
abdominal pain;
anorexia;
dry mouth;
toothache;
flatulence;
constipation;
imperative urge to urinate;
impaired renal function;
decreased libido;
impotence;
convulsions;
pain in the back, chest, legs;
tinnitus;
taste disorder;
visual impairment;
conjunctivitis;
anemia;
purpura of Shenlein-Henoch;
dry skin;
increased sweating;
alopecia;
gout;
hives;
skin rash;
angioedema (including swelling of the larynx and tongue, causing airway obstruction and / or swelling of the face, lips, pharynx).

drug interaction

There were no clinically significant drug interactions with hydrochlorothiazide, digoxin, indirect anticoagulants, cimetidine, phenobarbital, ketoconazole and erythromycin.

During simultaneous administration with rifampicin and fluconazole, a decrease in the level of the active metabolite of losartan potassium was noted. The clinical consequences of this phenomenon are unknown.

Simultaneous use with potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride) and potassium preparations increases the risk of hyperkalemia.

The simultaneous use of non-steroidal anti-inflammatory drugs, including selective COX-2 inhibitors, may reduce the effect of diuretics and other antihypertensive drugs.

When Lorista is administered concomitantly with thiazide diuretics, the reduction in blood pressure is approximately additive. Enhances (mutually) the effect of other antihypertensive drugs (diuretics, beta-blockers, sympatholytics).

Analogues of the drug Lorista

Structural analogues for the active substance:

Blocktran;
Brozaar;
Vasotens;
Vero Losartan;
Zisacar;
Cardomine Sanovel;
Carsartan;
Cozaar;
Lakea;
Lozap;
Losarel;
Losartan;
Losartan potassium;
Losacor;
Lotor;
Presartan;
Renicard.

Use during pregnancy and lactation

There are no data on the use of Lorist during pregnancy. Renal perfusion of the fetus, which depends on the development of the renin-angiotensin system, begins to function in the 3rd trimester of pregnancy. The risk to the fetus increases when taking losartan in the 2nd and 3rd trimesters. When pregnancy is established, losartan therapy should be discontinued immediately.

There are no data on the allocation of losartan with breast milk. Therefore, the issue of stopping breastfeeding or discontinuing losartan therapy should be considered, taking into account its importance to the mother.

Arterial hypertension (for patients who are indicated for combination therapy). Reducing the risk of cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy.

Contraindications Lorista H 100 tablets 12.5mg + 100mg

Hypersensitivity to losartan, to drugs that are derivatives of sulfonamides and other components of the drug, anuria, severe renal dysfunction (creatinine clearance (CC) less than 30 ml / min.), Hyperkalemia, dehydration (including against the background of taking high doses of diuretics) , severe liver dysfunction, refractory hypokalemia, pregnancy, lactation, arterial hypotension, age under 18 years (efficacy and safety have not been established), lactase deficiency, galactosemia or glucose / galactose malabsorption syndrome. With caution: violations of the water and electrolyte balance of the blood (hyponatremia, hypochloremic alkalosis, hypomagnesemia, hypokalemia), bilateral stenosis of the renal arteries or stenosis of the artery of a single kidney, diabetes mellitus, hypercalcemia, hyperuricemia and / or gout, aggravated allergic history (in some patients, angioedema developed earlier when taking other drugs, including ACE inhibitors) and bronchial asthma, systemic blood diseases (including systemic lupus erythematosus), simultaneous prescription of non-steroidal anti-inflammatory drugs (NSAIDs), including cyclooxygenase-II inhibitors (COX- 2 inhibitors). Use during pregnancy and lactation. There are no data on the use of losartan during pregnancy. Fetal renal perfusion, which depends on the development of the renin-angiotensin system, begins to function in the third trimester of pregnancy. The risk to the fetus increases when taking losartan in the second and third trimesters. When pregnancy is established, therapy should be discontinued immediately. If necessary, the appointment of the drug during lactation, it is necessary to stop breastfeeding.

Method of application and dosage Lorista H 100 tablets 12.5mg + 100mg

Inside, regardless of the meal. The drug can be combined with other antihypertensive agents. Arterial hypertension. The initial and maintenance dose is 1 tablet of the drug (50/12.5 mg) 1 time per day. The maximum antihypertensive effect is achieved within three weeks of therapy. To achieve a more pronounced effect, it is possible to increase the dose of the drug up to 2 tablets (50/12.5 mg) 1 time per day. The maximum daily dose is 2 tablets of the drug. In patients with a reduced volume of circulating blood (for example, while taking high doses of diuretics), the recommended initial dose of losartan in patients with hypovolemia is 25 mg once a day. In this regard, therapy should be started after the abolition of diuretics and correction of hypovolemia. In elderly patients and patients with moderate renal insufficiency, including those on dialysis, no initial dose adjustment is required. Reducing the risk of cardiovascular morbidity and mortality in patients with arterial hypertension and left ventricular hypertrophy. The standard starting dose of losartan is 50 mg once daily. Patients who fail to achieve target blood pressure levels while taking losartan 50 mg / day require selection of therapy by combining losartan with low doses of hydrochlorothiazide (12.5 mg), and, if necessary, increase the dose of losartan to 100 mg per day. in combination with hydrochlorothiazide at a dose of 12.5 mg / day, in the future - increase to 2 tablets of the drug 50 / 12.5 mg in total (100 mg of losartan and 25 mg of hydrochlorothiazide once a day).

Lorista (the active ingredient is losartan) is an antihypertensive drug, an angiotensin II receptor blocker of selective action (shows antagonism exclusively to AT1 type receptors). Means for the treatment of cardiovascular diseases are today, perhaps, the most demanded part of the pharmacy assortment, occupying the largest area in the windows. This is not surprising: cardiovascular pathology is now firmly entrenched in the sole leading position in the structure of total mortality, exceeding similar indicators from all other possible causes combined. The antihypertensive effect of lorista is based on the ability of the drug to erect an insurmountable barrier between AT1 receptors and angiotensin II, thereby blocking all the physiologically significant effects of the latter, regardless of the way it is formed in the body. Thus, angiotensin II cannot realize its remarkable vasopressor potential, despite the fact that its amount does not decrease, as happens with treatment with angiotensin-converting enzyme inhibitors. It is important that, unlike the latter, lorista does not inhibit the enzyme kininase II, which is involved in the metabolism of bradykinin. As a result, there is no accumulation of excess bradykinin, which avoids the associated side effects in the form of cough and angioedema. Lorista reduces the total peripheral vascular resistance, pressure in the pulmonary (pulmonary) circulation, reduces afterload on the myocardium, and has a moderate diuretic effect. The drug prevents the development and progression of left ventricular hypertrophy (a predictor of cardiovascular events), increases resistance to physical activity in patients suffering from chronic heart failure. In order to achieve a clinically significant decrease in systolic (upper) and diastolic (lower) blood pressure, it is enough to take lorista once a day. The drug maintains blood pressure at a given level throughout the day, without sudden changes and in accordance with the natural circadian rhythm.

The decrease in blood pressure at the end of the action of a single dose of lorista is about 70-80% of the antihypertensive effect 5-6 hours after administration, when the peak of the drug is noted. The drug does not cause a reflex increase in heart rate and rebound increase in blood pressure after discontinuation of pharmacotherapy. Lorista is effective in patients regardless of their gender and age. One of the main studies demonstrating the effectiveness of the drug in arterial hypertension was the LIFE multicenter randomized trial. More than 9,000 patients took part in it, who, in addition to stably elevated blood pressure, also had left ventricular hypertrophy. The study participants were divided into two groups, taking losartan (lorista) and atenolol, respectively. When analyzing the results of the study, it was found that mortality in the losartan group was almost two times lower than in the atenolol group. Patients in the lozaratan group were less likely to develop cardiovascular events such as ischemic stroke and acute myocardial infarction. The dynamics of blood pressure reduction was comparable in both groups, while in the lozaratan group, patients showed a much more pronounced regression of left ventricular hypertrophy. Thus, Lorista proved to be a more promising drug in the treatment of arterial hypertension than atenolol. In general, Lorista, as well as all sartans (as the group of angiotensin II receptor blockers is more compactly called), are better tolerated than other groups of antihypertensive drugs. If we talk exclusively about losartan (lorist), then this drug has the most solid evidence base among all sartans, being the most studied representative of this group of drugs and having the largest number of indications for use.

Pharmacology

Selective antagonist of angiotensin II type AT 1 receptors of non-protein nature.

In vivo and in vitro, losartan and its biologically active carboxyl metabolite (EXP-3174) block all physiologically significant effects of angiotensin II on AT 1 receptors, regardless of the route of its synthesis: it leads to an increase in plasma renin activity, reduces the concentration of aldosterone in blood plasma.

Losartan indirectly causes the activation of AT 2 receptors by increasing the level of angiotensin II. Losartan does not inhibit the activity of kininase II, an enzyme that is involved in the metabolism of bradykinin.

Reduces OPSS, pressure in the pulmonary circulation; reduces afterload, has a diuretic effect.

Prevents the development of myocardial hypertrophy, increases exercise tolerance in patients with chronic heart failure.

Taking losartan 1 time / day leads to a statistically significant decrease in systolic and diastolic blood pressure. During the day, losartan evenly controls blood pressure, while the antihypertensive effect corresponds to the natural circadian rhythm. The decrease in blood pressure at the end of the dose of the drug was approximately 70-80% of the effect at the peak of the drug, 5-6 hours after administration. There is no withdrawal syndrome; also, losartan does not have a clinically significant effect on heart rate.

Losartan is effective in men and women, as well as in older (≥65 years) and younger patients (≤65 years).

Pharmacokinetics

Suction

Losartan is well absorbed from the gastrointestinal tract. Taking the drug with food does not have a clinically significant effect on its serum concentrations.

Bioavailability is about 33%. Cmax of losartan in blood plasma is achieved 1 hour after ingestion. C max EXP-3174 in blood plasma is reached after 3-4 hours.

Distribution

More than 99% percent of losartan and EXP-3174 binds to plasma proteins, mainly albumin.

V d of losartan is 34 liters. It penetrates very poorly through the BBB.

Metabolism

It undergoes significant first pass metabolism in the liver, forming the active metabolite EXP-3174 (14%) and a number of inactive metabolites, including 2 main metabolites formed by hydroxylation of the butyl group of the chain and a less significant metabolite, N-2-tetrazol glucuronide.

breeding

The plasma clearance of losartan and EXP-3174 is approximately 10 ml/sec (600 ml/min) and 0.83 ml/sec (50 ml/min), respectively. The renal clearance of losartan and EXP-3174 is about 1.23 ml/sec (74 ml/min) and 0.43 ml/sec (26 ml/min), respectively. T 1/2 of losartan is 2 hours. T 1/2 of the active metabolite is 6-9 hours. About 58% of the drug is excreted in the bile, 35% - by the kidneys.

Release form

Yellow film-coated tablets, oval, slightly biconvex, scored on one side and chamfered.

Excipients: cellactose (a mixture of lactose monohydrate and cellulose), pregelatinized starch, corn starch, microcrystalline cellulose, anhydrous colloidal silicon dioxide, magnesium stearate.

Shell composition: hypromellose, talc, propylene glycol, quinoline yellow dye (E104), titanium dioxide (E171).

10 pieces. - cellular contour packings (3) - packs of cardboard.
10 pieces. - cellular contour packings (6) - packs of cardboard.
10 pieces. - cellular contour packings (9) - packs of cardboard.

Dosage

The drug is taken orally, regardless of food intake, the frequency of administration is 1 time / day.

Against the background of taking diuretics in high doses, it is recommended to start therapy with Lorista with 25 mg / day in one dose.

Elderly patients, patients with impaired renal function (including patients on hemodialysis) do not require adjustment of the initial dose of the drug.

In patients with impaired liver function, the drug should be prescribed at a lower dose.

In chronic heart failure, the initial dose of the drug is 12.5 mg / day in one dose. In order to reach the usual maintenance dose of 50 mg/day, the dose must be increased gradually at 1-week intervals (eg, 12.5 mg, 25 mg, 50 mg/day). Lorista is usually given in combination with diuretics and cardiac glycosides.

The scheme for increasing the dose of the drug is presented in the table.

To reduce the risk of stroke in patients with hypertension and left ventricular hypertrophy, the standard starting dose is 50 mg/day. In the future, low-dose hydrochlorothiazide can be added and / or the dose of Loristy can be increased to 100 mg / day.

For kidney protection in type 2 diabetic patients with proteinuria, the standard starting dose of Lorista is 50 mg/day. The dose of the drug can be increased to 100 mg / day, taking into account the decrease in blood pressure.

Overdose

Symptoms: pronounced decrease in blood pressure, tachycardia; bradycardia may develop as a result of parasympathetic (vagal) stimulation.

Treatment: forced diuresis, symptomatic therapy. Hemodialysis is ineffective.

Interaction

There were no clinically significant drug interactions with hydrochlorothiazide, digoxin, indirect anticoagulants, cimetidine, phenobarbital, ketoconazole and erythromycin.

Simultaneous use with potassium-sparing diuretics (eg, spironolactone, triamterene, amiloride) and potassium preparations increases the risk of hyperkalemia.

The simultaneous use of NSAIDs, including selective COX-2 inhibitors, may reduce the effect of diuretics and other antihypertensive drugs.

When losartan is given concomitantly with thiazide diuretics, the reduction in blood pressure is approximately additive. Enhances (mutually) the effect of other antihypertensive drugs (diuretics, beta-blockers, sympatholytics).

Side effects

From the side of the central nervous system and peripheral nervous system: ≥1% - dizziness, asthenia, headache, fatigue, insomnia;<1% - беспокойство, нарушение сна, сонливость, расстройства памяти, периферическая невропатия, парестезии, гипостезии, мигрень, тремор, атаксия, депрессия, синкопе.

From the side of the cardiovascular system: orthostatic hypotension (dose-dependent), palpitations, tachycardia, bradycardia, arrhythmias, angina pectoris, vasculitis.

From the respiratory system: ≥1% - nasal congestion, cough *, infections of the upper respiratory tract, pharyngitis, dyspnea, bronchitis, swelling of the nasal mucosa.

From the digestive system: ≥1% - nausea, diarrhea *, dyspepsia *, abdominal pain;<1% - анорексия, сухость во рту, зубная боль, рвота, метеоризм, гастрит, запор, гепатит, нарушение функции печени; очень редко - повышение активности ферментов печени, гипербилирубинемия.

From the urinary system:<1% - императивные позывы на мочеиспускание, инфекции мочевыводящих путей, нарушение функции почек; иногда - умеренное повышение уровня мочевины и креатинина в сыворотке крови.

From the reproductive system:<1% - снижение либидо, импотенция.

From the musculoskeletal system: ≥1% - convulsions, myalgia *, pain in the back, chest, legs;<1% - артралгия, артрит, боль в плече, колене, фибромиалгия.

From the sense organs:<1% - звон в ушах, нарушение вкуса, нарушения зрения, конъюнктивит.

On the part of the hematopoietic system: infrequently - anemia, Shenlein-Genoch purpura.

Dermatological reactions:<1% - сухость кожи, эритема, фотосенсибилизация, повышенное потоотделение, алопеция.

From the side of metabolism: hyperkalemia, gout.

Allergic reactions:<1% - крапивница, кожная сыпь, зуд, ангионевротический отек (включая отек гортани и языка, вызывающий обструкцию дыхательных путей и/или отек лица, губ, глотки). Иногда ангионевротический отек развивался ранее при приеме других лекарственных средств, в т.ч. ингибиторов АПФ.

* - side effects, the incidence of which is comparable to placebo.

In most cases, Lorista ® is well tolerated, side effects are mild and transient and do not require discontinuation of the drug.

Indications

arterial hypertension;
reduced risk of stroke in patients with arterial hypertension and left ventricular hypertrophy;
chronic heart failure (as part of combination therapy, with intolerance or ineffectiveness of therapy with ACE inhibitors);
protection of kidney function in patients with type 2 diabetes mellitus with proteinuria to reduce proteinuria, reduce the progression of kidney damage, reduce the risk of end-stage development (preventing the need for dialysis, the likelihood of an increase in serum creatinine), or death.

Contraindications

arterial hypotension;
hyperkalemia;
dehydration;
lactose intolerance;
galactosemia or glucose/galactose malabsorption syndrome;
pregnancy;
lactation period;
age up to 18 years (efficacy and safety have not been established);
hypersensitivity to losartan and / or other components of the drug.

The drug should be used with caution in case of hepatic and / or renal insufficiency, reduced BCC, impaired water and electrolyte balance, bilateral renal artery stenosis or stenosis of the artery of a single kidney.

Application features

Use during pregnancy and lactation

There are no data on the use of losartan during pregnancy. Renal perfusion of the fetus, which depends on the development of the renin-angiotensin system, begins to function in the third trimester of pregnancy. The risk to the fetus increases with the use of losartan in the II and III trimesters. When pregnancy is established, losartan therapy should be discontinued immediately.

Application for violations of liver function

Patients with a history of liver disease are advised to use lower doses.

Application for violations of kidney function

With caution, losartan is prescribed to patients with impaired renal function, bilateral stenosis of the renal arteries or unilateral stenosis of the artery of a single kidney. The concentration of potassium, urea and creatinine in the blood serum should be regularly monitored.

Use in children

special instructions

Patients with reduced BCC (for example, during therapy with large doses of diuretics) may develop symptomatic arterial hypotension. Before taking losartan, it is necessary to eliminate existing disorders, or start therapy with small doses.

Pediatric use

The drug is contraindicated for the treatment of children and adolescents under the age of 18 years, since there is no experience of using the drug in pediatrics.

Influence on the ability to drive vehicles and control mechanisms

There are no data on the effect of losartan on the ability to drive vehicles or other technical means.

Compound

I tablet contains:

Active substance: losartan potassium 12.5 mg, 25 mg, 50 mg, 100 mg.

Excipients: cellactose (cellulose, lactose monohydrate), corn starch, pregelatinized starch, microcrystalline cellulose, anhydrous colloidal silicon dioxide, magnesium stearate;

Sheath: hypromellose, talc, propylene glycol, titanium dioxide (E171), quinoline yellow dye* (E104).

* quinoline yellow is used in the manufacture of 12.5 mg and 25 mg tablets and is not used in the manufacture of 50 and 100 mg tablets.

Description

Tablets 12.5 mg. Oval, slightly biconvex tablets, film-coated from light yellow to yellow.

Tablets 25 mg. Oval, slightly biconvex, yellow film-coated tablets, scored on one side.

Tablets 50 mg. Round, slightly biconvex, white film-coated tablets with a score on one side, with a chamfer.

Tablets 100 mg. Oval, slightly biconvex, white film-coated tablets.

pharmachologic effect

Losartan is a synthetic oral angiotensin receptor antagonist.

I (type ATi). Angiotensin II, a potent vasoconstrictor, is the primary active hormone of the renin-angiotensin system and an important determinant of the pathophysiology of hypertension. Angiotensin II binds to ATi receptors found in many body tissues (eg, vascular smooth muscle, adrenal glands, kidneys, and heart) and causes several important biological actions, including vasoconstriction and aldosterone release. Angiotensin II also stimulates the proliferation of smooth muscle cells.

Losartan selectively blocks ATj receptors. In vitro and in vivo, losartan and its pharmacologically active carboxy-acid metabolite E-3174 block all physiologically significant actions of angiotensin II, regardless of the source or route of synthesis.

Losartan is not an agonist and does not block other hormone receptors or ion channels important in cardiovascular regulation. In addition, losartan does not inhibit ACE (kininase II), an enzyme that degrades bradykinin. As a consequence, there is no potentiation of undesirable effects mediated by bradykinin.

When taking losartan, the removal of the negative feedback of angiotensin II on renin secretion leads to an increase in plasma renin activity (ARP). An increase in ARP leads to an increase in plasma angiotensin II. Despite these increases, antihypertensive activity and suppression of plasma aldosterone concentration persist, indicating effective blockade of the angiotensin I receptor. After discontinuation of losartan, ARP and angiotensin II values fell within three days to baseline values.

Both losartan and its major active metabolite have much greater affinity for the ATi receptor than for the AT2 receptor. The active metabolite is 10-40 times more active than losartan on a weight basis.

Hypertension research

In controlled clinical trials, once-daily administration of losartan to patients with mild to moderate essential hypertension provided a statistically significant reduction in systolic and diastolic blood pressure. Blood pressure measurements 24 hours post-dose relative to 5-6 hours post-dose showed a decrease in blood pressure within 24 hours; the natural circadian rhythm was preserved. The decrease in blood pressure at the end of the interval between doses of the drug was 70 - 80% of the effect observed 5-6 hours after taking the dose of the drug. Withdrawal of losartan in patients with hypertension did not lead to a sharp increase in blood pressure (rebound phenomenon). Despite a pronounced decrease in blood pressure, losartan did not have clinically significant effects on heart rate.

Losartan is equally effective in men and women, as well as in younger (under 65 years) and elderly hypertensive patients.

StudyLIFE

The LIFE study (Losartan Intervention For Endpoint Reduction in Hypertension) was a randomized, triple-blind, active-controlled study in 9193 hypertensive patients aged 55 to 80 years with ECG-documented left ventricular hypertrophy. Patients were randomized to receive losartan 50 mg once daily or atenolol 50 mg once daily. If the target blood pressure (

The median follow-up was 4.8 years.

The primary endpoint was the composite endpoint of cardiovascular disease and death due to cardiovascular disease, as measured by the reduction in the combined incidence of cardiovascular death, stroke, and infarction.

Porous, tablets, film-coated myocardium. Blood pressure was significantly reduced to similar levels in the two groups. Losartan therapy resulted in a 13.0% risk reduction (p = 0.021, 95% confidence interval 0.77-0.98) compared with atenolol for patients who achieved the primary composite endpoint. This was mainly due to a reduction in the frequency of stroke. Therapy with losartan resulted in a 25% reduction in the risk of stroke compared with atenolol (p = 0.001, 95% confidence interval 0.63-0.89). There were no significant differences in the incidence of cardiovascular death and myocardial infarction between treatment groups. Race

In the LIFE study, black patients treated with losartan were at greater risk of experiencing the primary composite endpoint, ie. cardiovascular event (eg, myocardial infarction, cardiovascular death) and especially stroke than black patients treated with atenolol. Therefore, the results observed with losartan versus atenolol in the LIFE study regarding cardiovascular morbidity and mortality do not apply to black patients with hypertension and left ventricular hypertrophy.

StudyRENAAL

The RENAAL study (Reduction of Endpoints in NIDDM with the Angiotensin II Receptor Antagonist Losartan) was a controlled clinical study conducted worldwide in 1513 patients with type 2 diabetes mellitus with proteinuria. with or without hypertension. 751 patients received losartan.

The aim of the study was to demonstrate the renal protective effect of losartan potassium in addition to the blood pressure lowering benefit. Patients with proteinuria and serum creatinine 1.3-3.0 mg/dL were randomized to receive losartan 50 mg once daily, titrated as needed, until blood pressure response was achieved, or placebo, on conventional antihypertensive therapy, except ACE inhibitors and angiotensin II antagonists.

Investigators were instructed to titrate study drug up to 100 mg per day, as needed; 72% of patients took a dose of 100 mg per day most of the time. Other antihypertensive agents (diuretics, calcium antagonists, alpha and beta receptor blockers, and centrally acting antihypertensives) were allowed as adjuvant therapy as needed in both groups. Patients were followed up to 4.6 years (mean 3.4 years).

The primary endpoint of the study was a composite endpoint of 2-fold increase in serum creatinine, end-stage renal disease (need for dialysis or transplant), or death.

The results showed that treatment with losartan (327 events) compared with placebo (359 events) resulted in a 16.1% risk reduction (p = 0.022) in the number of patients reaching the primary composite endpoint. For the following individual and composite components of the primary endpoint, the results showed a significant risk reduction in the losartan group: 25.3% risk reduction for doubling serum creatinine (p = 0.006); risk reduction by 28.6% for end-stage renal disease (p = 0.002); 19.9% risk reduction for end-stage renal disease or death (p = 0.009); a 21.0% risk reduction for a doubling of serum creatinine or for end-stage renal disease (p = 0.01).

There were no significant differences in the incidence of death from any cause between the two treatment groups.

In this study, losartan was generally well tolerated, as demonstrated by the discontinuation rate due to adverse events that was comparable to that in the placebo group.

StudyHEAAL

The HEAAL study (Heart Failure Endpoint Evaluation of Angiotensin II Antagonist Losartan) was a controlled clinical trial conducted worldwide in 3834 patients aged 18 to 98 years with heart failure ( NYHA class II-IV) who did not tolerate ACE inhibitor therapy. Patients were randomized to receive losartan 50 mg once daily or losartan 150 mg, on conventional therapy, excluding inhibitors.

Patients were followed up for 4 years (median 4.7 years). The primary endpoint of the study was a composite endpoint of death from any cause or hospitalization for heart failure. The results showed that treatment with losartan 150 mg (828 events), compared with losartan 50 mg (889 events), resulted in a 10.1% risk reduction (p=0.027, 95% CI 0.82-0.99) in terms of number patients who reach the primary composite endpoint. This was mainly due to a reduction in the frequency of hospitalization for heart failure. Therapy with losartan 150 mg reduced the risk of hospitalization for heart failure by 13.5% compared with losartan 50 mg (p = 0.025, 95% confidence interval 0.76-0.98). There were no significant differences in the incidence of death from any cause between treatment groups. Impaired renal function, hypotension, and hyperkalemia were more common in the 150 mg group than in the 50 mg group, but these adverse events did not result in significantly more discontinuations in the 150 mg group.

StudyELITE I andELITE II

In the ELITE study, conducted over 48 weeks in 722 patients with heart failure (NYHA class II-IV), no difference was observed between patients treated with losartan and patients treated with captopril in relation to the primary endpoint of long-term change in kidney function. The observation of the ELITE study that, compared with captopril, losartan reduced the risk of death was not confirmed in the subsequent ELITE II study, which is described below.

In the ELITE II study, losartan 50 mg once daily (initial dose 12.5 mg, increased to 25 mg, then 50 mg once daily) was compared with captopril 50 mg three times daily (initial dose 12.5 mg, increased to 25 mg, then 50 mg three times a day). The primary end point of this prospective study was death from any cause.

In this study, 3152 patients with heart failure (NYHA class II-IV) were followed for almost two years (median: 1.5 years) to determine whether losartan was superior to captopril in reducing all-cause mortality. The primary endpoint showed no statistically significant difference between losartan and captopril in terms of reduction in all-cause mortality.

In both comparator-controlled (rather than placebo-controlled) clinical trials in patients with heart failure, losartan was shown to be better tolerated than captopril, as measured by a significantly lower discontinuation rate due to adverse events and a significantly lower incidence of cough.

Increased mortality was observed in ELITE II in a small subgroup (22% of all patients with heart failure) taking beta-blockers at baseline.

Pharmacokinetics

Suction

After oral administration, losartan is rapidly absorbed and metabolized during the "first pass", forming an active carboxyl metabolite and other inactive metabolites. The systemic bioavailability of losartan tablets is approximately 33%. Average peak concentrations of losartan and its active metabolite are reached after 1 hour and 3-4 hours, respectively.

Distribution

Losartan and its active metabolite are >99% bound to plasma proteins, predominantly albumin. The volume of distribution of losartan is 34 liters.

Biotransformation

About 14% of an intravenous or oral dose of losartan is converted to its active metabolite. Following oral and intravenous administration of 14C-labeled potassium losartan, the circulating plasma radioactivity is predominantly attributed to losartan and its active metabolite. Minimal conversion of losartan to its active metabolite was observed in approximately one percent of the subjects studied.

In addition to the active metabolite, inactive metabolites are formed.

breeding

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 about 74 ml/min and 26 ml/min, respectively. When losartan is taken orally, approximately 4% of the dose is excreted in the urine unchanged and about 6% of the dose is excreted in the urine as an active metabolite. The pharmacokinetics of losartan and its active metabolite are linear with oral doses of losartan potassium up to 200 mg.

After oral administration, plasma concentrations of losartan and its active metabolite decrease polyexponentially with a terminal elimination half-life of about 2 hours and 6-9 hours, respectively. When taking 100 mg once a day, neither losartan nor its active metabolite accumulates in plasma to a significant extent.

Excretion of losartan and its metabolites is carried out with bile and urine. Following an oral dose/following intravenous administration of 14C-labelled losartan in humans, approximately 35%/43% of the dose of radioactivity is recovered in the urine and 58%/50% in the feces.

Characteristics in Patients

In elderly hypertensive patients, plasma concentrations of losartan and its active metabolite do not differ significantly from those found in plasma of younger hypertensive patients.

In hypertensive female patients, plasma levels of losartan were twice as high as in hypertensive male patients, while plasma levels of the active metabolite did not differ between men and women.

In patients with mild to moderate alcoholic cirrhosis, plasma levels of losartan and its active metabolite after oral administration were 5 and 1.7 times higher than in young male volunteers.

Plasma concentrations of losartan are not changed in patients with creatinine clearance greater than 10 ml/min. Compared with patients with normal renal function, the AUC for losartan is approximately 2-fold higher in patients on hemodialysis.

Plasma concentrations of the active metabolite are not altered in patients with renal insufficiency or in patients on hemodialysis.

Indications for use

Treatment of essential hypertension.

Reducing the risk of stroke in adult patients with arterial hypertension and left ventricular hypertrophy documented by ECG (see Pharmacodynamics section, LIFE study, Race)

Treatment of chronic heart failure in adult patients who are not indicated for therapy with angiotensin-converting enzyme (ACE) inhibitors due to incompatibilities, especially with cough, or in the presence of contraindications. Patients with heart failure who have been stabilized with an ACE inhibitor should not be switched to losartan. In patients, the left ventricular ejection fraction should be

Treatment of renal insufficiency in adult patients with hypertension and type 2 diabetes mellitus with proteinuria > 0.5 g/day as part of antihypertensive therapy.

Contraindications

Hypersensitivity to the active substance or excipients. Second and third trimesters of pregnancy.

Severe liver failure.

Pregnancy and lactation

The use of losartan is contraindicated in the second and third trimesters of pregnancy. Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy is inconclusive; however, a slight increase in risk cannot be ruled out. While there are no controlled data on risk with angiotensin II receptor inhibitors (AIIRA), similar risks may exist for this class of drugs. Unless continued AIIRA therapy is considered vital, patients planning a pregnancy should switch to alternative antihypertensive therapies with an established safety profile for use during pregnancy. If pregnancy is detected, treatment with losartan should be stopped immediately and, if appropriate, alternative therapy should be initiated.

Exposure to AIIRA therapy during the second and third trimesters of pregnancy is known to cause fetal toxicity in humans (decreased renal function, oligohydramnios, delayed ossification of the skull bones) and neonatal toxicity (renal failure, hypotension, hyperkalemia). If losartan is used from the second trimester of pregnancy, an ultrasound examination of the skull and kidney function is recommended.

Infants whose mothers have taken losartan should be closely monitored for hypotension.

Lactation

Since there is no information regarding the use of losartan in breastfeeding, losartan is not recommended for use, and alternative therapies with established safety profiles in breastfeeding are preferred, especially when feeding a newborn or premature infant.

Dosage and administration

Dosing regimen

Losartan tablets should be swallowed with a glass of water.

Losartan may be taken with or without food.

hypertension

The usual initial and maintenance dose is 50 mg once daily for most patients. The maximum antihypertensive effect is achieved 3-6 weeks after the start of therapy. Some patients may benefit from increasing the dose to 100 mg once daily (in the morning).

Losartan may be used with other antihypertensive agents, especially diuretics (eg, hydrochlorothiazide).

Reduced risk of stroke in hypertensive patients who have left ventricular hypertrophy ventricle documented by ECG

The usual starting dose is 50 mg losartan once daily. A low dose of hydrochlorothiazide should be added and/or the dose of losartan should be increased to 100 mg once daily based on blood pressure response.

Heart failure

The usual starting dose of losartan in patients with heart failure is 12.5 mg once daily. The dose of the drug should be titrated at weekly intervals (i.e. 12.5 mg daily, 25 mg daily, 50 mg daily, 100 mg daily, up to a maximum dose of 150 mg once daily), depending on patient tolerance .

Patients with arterial hypertension and type 2 diabetes mellitus and proteinuria > 0.5 g/day

The usual starting dose is 50 mg once daily. The dose may be increased to 100 mg once daily based on blood pressure response, one month after initiation of therapy and beyond. Losartan may be used with other antihypertensive agents (eg, diuretics, calcium channel blockers, alpha- or beta-blockers, and centrally acting drugs), as well as with insulin and other commonly used hypoglycemic drugs (such as sulfonylurea derivatives, glitazones, and glucosidase inhibitors). Special groups of patents

Use in patients with depleted intravascular volume For patients with intravascular volume depletion (i.e., those treated with high doses of diuretics), an initial dose of 25 mg once daily should be considered.

Applicationv patients with renal insufficiency and in patients on hemodialysis

No initial dose adjustment is required in patients with renal insufficiency and in patients on hemodialysis.

Application at patients With violation Functions liver

A lower dose should be considered in patients with a history of hepatic impairment. There is no therapeutic experience in patients with severe hepatic impairment. Accordingly, losartan is contraindicated in patients with severe hepatic impairment.

Use in elderly patients

Although consideration should be given to initiating therapy with a dose of 25 mg in patients over 75 years of age, dose adjustment is usually not required for elderly patients.

Side effect

Losartan has been evaluated in the following clinical studies:

in controlled clinical trials in more than 3000 adult patients aged 18 years and over with essential hypertension, in a controlled clinical trial in 177 hypertensive pediatric patients aged 6 to 16 years

in a controlled clinical trial in more than 9,000 hypertensive patients aged 55 to 80 years with left ventricular hypertrophy in a controlled clinical trial in more than 7,700 adult patients with chronic heart failure

in a controlled clinical trial in more than 1500 patients with type 2 diabetes mellitus 31 years of age and older with proteinuria In these clinical studies, the most common adverse reaction was dizziness.

The frequency of the side effects listed below is determined using the following criteria:

Very common (>1/10),

Frequent (>1/100 -

Uncommon (>1/1000 -

Rare (>1/10 000-

very rare (

Unknown (cannot be determined from available data).

hypertension

In controlled clinical trials involving more than 3300 adult patients aged 18 years or more with essential hypertension, the following adverse reactions were reported:

In a controlled clinical trial in patients with chronic heart failure (see the ELITE I, ELITE II and HEAAL studies), the following adverse reactions were reported:

In a clinical study involving patients with type 2 diabetes mellitus with nephropathy, 9.9% of patients treated with losartan tablets developed hyperkalemia > 5.5 mmol / l and 3.4% of patients treated with placebo.

Renal and urinary tract disorders:

As a consequence of the suppression of the renin-angiotensin-aldosterone system, changes in renal function, including renal failure, have been noted in patients at risk; these changes in renal function may be reversible after discontinuation of therapy.

Overdose

Symptoms: There are limited data on overdose in humans. The most likely manifestations of overdose may be hypotension and tachycardia. Bradycardia can develop due to parasympathetic (vagal) stimulation.

Treatment: If symptomatic hypotension occurs, supportive therapy should be given.

Measures depend on the time of administration of the drug and the type and severity of the symptoms. Priority should be given to stabilization of the cardiovascular system. After oral administration, a sufficient dose of activated charcoal is indicated. After that, careful monitoring of vital parameters should be carried out. Vital parameters should be adjusted if necessary.

Neither losartan nor the active metabolite can be removed by hemodialysis.

Interaction with other drugs

Other antihypertensive agents may increase the hypotensive effect of losartan. Concomitant use with other substances that may cause hypotension as an adverse reaction (for example, tricyclic antidepressants, antipsychotics, baclofen and amifostine) may increase the risk of hypotension.

Losartan is predominantly metabolized by cytochrome P450 (CYP) 2C9 to the active carboxy-acid metabolite. In a clinical study, fluconazole (a CYP2C9 inhibitor) was found to reduce exposure to the active metabolite by approximately 50%. It was found that concomitant therapy with losartan with rifampicin (an inducer of metabolic enzymes) resulted in a 40% reduction in the plasma concentration of the active metabolite. The clinical significance of these effects is not known. There were no differences in exposure with concomitant therapy with fluvastatin (a weak inhibitor of CYP2C9).

As with other drugs that block angiotensin II or its effects, concomitant use of other potassium-sparing drugs (eg, potassium-sparing diuretics: amiloride, triamterene, spironolactone) or may increase potassium levels (eg, heparin), potassium supplements, or potassium-containing substitutes salt can lead to an increase in the content of potassium in the blood serum. Concomitant use of these drugs is not recommended.

Reversible increases in serum lithium concentrations and toxicity have been reported with concomitant administration of lithium with ACE inhibitors. Very rare cases have also been reported with angiotensin II receptor antagonists. Lithium and losartan should be administered with caution at the same time. If this combination is vital, monitoring of serum lithium is recommended when used concomitantly.

With the simultaneous appointment of angiotensin II antagonists and NSAIDs (i.e., selective COX-2 inhibitors, acetylsalicylic acid in anti-inflammatory doses and non-selective NSAIDs), a weakening of the antihypertensive effect may occur. The concomitant use of angiotensin II antagonists or diuretics and NSAIDs may lead to an increased risk of worsening renal function, including possible acute renal failure, and an increase in serum potassium, especially in patients with existing decreased renal function. This combination should be administered with caution.

Dual blockade (eg, by adding an ACE inhibitor to an angiotensin II receptor antagonist) should be limited to individually defined cases, with close monitoring of renal function. Some studies have shown that in patients with established atherosclerotic disease, heart failure, or diabetes with end-stage organ damage, dual blockade of the renin-angiotensin-aldosterone system is associated with a higher incidence of hypotension, syncope, hyperkalemia, and renal function changes (including acute renal failure) , compared with the use of a single agent of the renin-angiotensin-aldosterone system.

Application features

Hypersensitivity

Angioedema. Patients with a history of angioedema (swelling of the face, lips, throat and/or tongue) should be closely monitored.

Hypotension and disturbance of water and electrolyte balance

Symptomatic hypotension, especially after the first dose and after dose increases, may occur in patients with volume and/or sodium depletion due to intensive diuretic therapy, a salt-restricted diet, diarrhea, or vomiting. These conditions should be corrected before the appointment of losartan or use a lower initial dose.

Electrolyte imbalances

Electrolyte disturbances are common in patients with renal insufficiency, with or without diabetes, and should be considered. In a clinical study conducted in patients with type 2 diabetes mellitus with nephropathy, the incidence of hyperkalemia was higher in the losartan group compared to the placebo group. Accordingly, plasma potassium concentrations as well as creatinine clearance values should be closely monitored, especially in patients with heart failure and creatinine clearance of 30–50 ml/min.

Liver dysfunction

Based on pharmacokinetic data that demonstrate a significant increase in plasma concentrations of losartan in patients with cirrhosis of the liver, a lower dose should be considered in patients with a history of liver failure. There is no experience with the therapeutic use of losartan in patients with severe hepatic impairment. Accordingly, losartan should not be administered to patients with severe hepatic impairment.

Kidney dysfunction

As a consequence of the suppression of the renin-angiotensin system, changes in renal function, including renal failure, have been noted (in particular, in patients whose kidney function depends on the renin-angiotensin-aldosterone system, for example, in patients with severe heart failure or existing renal dysfunction). As with the use of other drugs acting on the renin-angiotensin-aldosterone system, there has been an increase in blood urea and serum creatinine in patients with bilateral renal artery stenosis or unilateral stenosis of the artery of a single kidney; these changes in renal function may be reversible after discontinuation of therapy. Losartan should be used with caution in patients with bilateral renal artery stenosis or unilateral stenosis of the artery to a single kidney.

The concomitant use of losartan and ACE inhibitors has been shown to impair renal function. Accordingly, the simultaneous use of these drugs is not recommended.

kidney transplant

There is no experience of use in patients with a recent kidney transplant.

Primary aldosteronism

Patients with primary aldosteronism will generally not respond to antihypertensive drugs that act by inhibiting the renin-angiotensin system. Accordingly, the use of losartan is not recommended.

Coronary artery disease and cerebrovascular disease

As with any antihypertensive drug, excessive lowering of blood pressure in patients with ischemic cardiovascular and cerebrovascular disease can lead to myocardial infarction or stroke.

Heart failure

In patients with heart failure, with or without renal insufficiency, there is - as with other drugs that act on the renin-angiotensin system - the risk of severe arterial hypotension and (often acute) renal failure.

There is insufficient experience with the therapeutic use of losartan in patients with heart failure and concomitant severe renal failure, in patients with severe heart failure (NYHA class IV), as well as in patients with heart failure and symptomatic life-threatening cardiac arrhythmias. Accordingly, losartan should be used with caution in these patient populations. Losartan should be used with caution in combination with beta-blockers.

Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy

As with other vasodilators, special care should be taken when treating patients with aortic or mitral valve stenosis or obstructive hypertrophic cardiomyopathy.

Other instructions and precautions

As observed for angiotensin-converting enzyme inhibitors, losartan and other angiotensin antagonists appear to be less effective in lowering blood pressure in black people than in people of other races, possibly due to the greater prevalence of low-renin conditions in the black people with hypertension.

Special precautions regarding auxiliary components Lorista contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

Storage conditions

Tablets 12.5 mg, 25 mg, 100 mg: Does not require special storage conditions.

Tablets 50 mg: Store at a temperature not exceeding 30°C. Store in original packaging.

Keep out of the reach of children.

Best before date

Do not use later than the date indicated on the package.