Pharmacological properties

Pharmacodynamics. lozartan potassium — the antagonist of receptors of ii angiotensin (type at1). the ii angiotensin which is formed of angiotensin i at reaction with participation apf (ii kininaza), is a powerful vasoconstrictor, primary vasoactive hormone renin-angiotenzinovoy of a system and an important component of pathophysiological mechanisms ag. ii angiotensin also contacts a receptor at1 which is revealed in many fabrics (unstriated muscles of vessels, adrenal glands, kidneys and heart), defining a number of important biological effects, including vasoconstriction and release of Aldosteronum. ii angiotensin also stimulates proliferation of smooth muscle cells.

Lozartan and his active metabolite carboxyl acid are blocked by all physiologically significant influences of angiotensin II irrespective of a source or a way of synthesis.

Lozartan selectively contacts a receptor of AT ₁ , does not communicate and does not block other receptors of hormones or ion channels.

Moreover, losartan is not suppressed by APF (kininaza of II) — enzyme which promotes bradykinin disintegration. Thereof the effects which are directly not connected with blockade of a receptor of AT ₁ , such as strengthening of influence which mediator is bradykinin are not associated with use of a lozartan.

At use of a lozartan to increase in activity of renin in blood plasma. Such increase in activity leads to increase in level of angiotensin II in blood plasma. Though there is such growth, antihypertensive activity and suppression of concentration of Aldosteronum in blood plasma remain that demonstrates effective blockade of receptors of angiotensin II. After cancellation of a lozartan activity of renin in blood plasma and indicators of levels of angiotensin II within 3 days return to reference values.

As losartan, and its main metabolite have higher affinity to AT ₁ - to receptors, than AT ₂ . The active metabolite is 10-40 times more active, than losartan.

Pharmacokinetics. After oral administration losartan well is absorbed and exposed to metabolic transformations of the first passing. The system bioavailability is about 33%. Nearly 14% of an oral dose of a lozartan turn into an active carboxyl metabolite. The C _max a lozartan and its active metabolite is reached in 1 and 3–4 h respectively. Lozartan and an active metabolite intensively contact proteins of blood plasma, mainly albumine. T _½ lozartana makes 2 h, an active metabolite — 6–9 h. The pharmacokinetics of a lozartan and active metabolite is linear for oral doses of a lozartan up to 200 mg and does not change over time. Lozartan and an active metabolite accumulate in blood plasma in case of repeated reception of a dose of 1 times a day. About 4% of a dose are removed in not changed view with urine and about 6% — in the form of an active metabolite. Biliary excretion of medicament is a certain part of elimination of a lozartan and its active metabolite — about 35% of a dose get to urine and nearly 58% — in kcal.

Patients of advanced age. Reliable changes of pharmacokinetic characteristics at patients of advanced age with AG in comparison with young patients are not revealed.

Floor. Concentration of a lozartan in blood plasma at women with AG exceeded these indicators at men twice. The dependence of concentration of an active metabolite on a floor is not revealed.

Abnormal liver function and kidneys. Concentration of a lozartan and its active metabolite in blood plasma at patients with abnormal liver functions by 1.7-5 times exceed these indicators at patients from the liver which is not changed by function.

Concentration of a lozartan in blood plasma of patients with clearance of creatinine of 10 ml/min. from those at healthy patients. AUC at patients with heavy renal failures exceeded AUC of a lozartan of patients with normal function of kidneys twice. Plasma concentration of an active metabolite of a lozartan at the same time remained invariable. Lozartan and his active metabolite it is impossible to remove by means of a hemodialysis.

Pharmacokinetics at children. The active metabolite of a lozartan is formed at patients of all age groups. Indicators of pharmacokinetics of a lozartan after oral administration similar at newborns and children aged from 2 years, children of preschool, school age and teenagers. Pharmacokinetic indicators of a metabolite depend more on an age group, especially when comparing children of preschool age and teenagers. Exposure at newborns and children under 2 years is rather high.

Indication

Treatment of essential hypertensia at adults and also at children aged from 6 years. treatment of a disease of kidneys at adult patients with ag and type ii diabetes with a proteinuria of ≥0.5 g/days — as a part hell. treatment of chronic heart failure (at patients 60 years are aged more senior) in cases when use of inhibitors apf is considered impossible owing to intolerance (especially in cough) or in the presence of contraindications. to patients with heart failure whose condition at intake of inhibitors apf is stable the prescribing of medicament klosart is inexpedient. at the patient the fraction of emission of a left ventricle has to make ≤40%, a fortune has to be clinically stable, also the patient should adhere to the set treatment mode on chronic heart failure. reduction of risk of development of a stroke in adult patients with ag and a hypertrophy of a left ventricle which is confirmed to the ECG.

Use

to take the Pill irrespective of meal, washing down with 1 glass of water.

AG. For most of patients the initial and maintenance dose of the medicament Klosart makes 50 mg of 1 times a day. The maximum antihypertensive effect is reached on the 3-6th week after an initiation of treatment. For some patients there can be favorable an increase in a dose of medicament to 100 mg of 1 times a day (morning).

Klosart can be applied in combination with other antihypertensive drugs, especially with diuretics (for example a hydrochlorothiazide).

Patients with AG, diabetes of the II type and a proteinuria (≥0.5 g/days). Usually initial dose of the medicament Klosart makes 50 mg of 1 times a day. The dose can be raised to 100 mg of 1 times a day depending on what testimonies of the ABP in 1 month after an initiation of treatment. Klosart it is possible to apply together with other antihypertensive medicaments (diuretics, blockers of calcium channels, blockers α- or β-receptors, medicaments of the central action) and also with insulin and other hypoglycemic means (for example sulphonylurea, glitazona and inhibitors of glucosidase).

Heart failure. Usually initial dose of a lozartan at patients with chronic heart failure makes 12.5 mg of 1 times a day. As a rule, the dose is titrated with a week interval (that is 12.5; 25; 50 mg/days) to a usual maintenance dose of 50 mg (1 tablet Klosart of 50 mg) of 1 times a day depending on individual shipping.

Reduction of risk of development of a stroke in patients with AG and a hypertrophy of a left ventricle, is documented by means of the ECG. Usually initial dose makes 50 mg of 1 times a day. Depending on changes of the ABP level there can be necessary a purpose of a hydrochlorothiazide in a low dose and/or the dose of a lozartan should be raised to 100 mg of 1 times a day.

Separate groups of patients

Use for patients with reduced OCK. At patients with reduced OCK (for example owing to use of high doses of diuretics) it is necessary to begin therapy with a dose of 25 mg of 1 times a day.

Use for patients with a renal failure and the patients who are on a hemodialysis. When prescribing the medicament Klosart to patients with a renal failure and also initial dose adjustment is not required to patients to whom carry out a hemodialysis.

Use for patients with an abnormal liver function in the anamnesis. For patients with an abnormal liver function in the anamnesis it is necessary to consider a question of prescribing of medicament in the lowest dose. There is no experience of treatment of patients with heavy abnormal liver functions therefore Klosart is contraindicated to this group of patients.

Use for children is aged more senior than 6 years. For children who can swallow of tablets and at whom the body weight of 20 kg and 50 kg, the recommended dose makes 25 mg of 1 times a day. In exceptional cases the dose can be raised to maximum — 50 mg of 1 times a day. The dose should be adjusted depending on changes of the ABP level.

At patients with the body weight of 50 kg the recommended dose makes 50 mg of 1 times a day. In exceptional cases the dose can be raised to maximum — 100 mg of 1 times a day. Use of the doses exceeding 1.4 mg/kg (or more than 100 mg) in day, at children was not studied.

at children with an abnormal liver function.

Klosart is also not recommended to apply to children with the glomerular filtration rate (GFR) 30 ml/min. / 1.73 m ² as there are no relevant data concerning use.

Use for patients is aged more senior than 75 years. Therapy it is necessary to begin with a dose 25 mg of 1 times a day. Dose adjustment usually is not required.

Contraindication

Hypersensitivity to the active ingredient and any excipient which is a part of drug. heavy abnormal liver functions. the pregnant women or women planning pregnancy (see use during pregnancy and feeding by a breast) .odnovremenny use of a lozartan and aliskiren for patients with diabetes or with renal failures (skf 60 ml/min. / 1.73 sq.m) is contraindicated (see use, special instructions, interactions).

Side effects

from nervous system: dizziness, drowsiness, headache, insomnia, muscular spasms, paresthesias, stroke, migraine, dysgeusia.

from an organ of hearing and a labyrinth: vertigo, a ring in ears.

from mentality: depression.

from heart: palpitation, syncope, stenocardia, tachycardia, fibrillation of auricles.

from the vascular system: symptomatic hypotension (especially patients with intravascular dehydration have, for example, patients with heavy heart failure or at treatment by diuretics in high doses), dose-dependent orthostatic effect.

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

from a gepatobiliarny system: hepatitis, abnormal liver function.

from a respiratory system: cough, short wind, rhinorrhea, sinusitis, pharyngitis, upper respiratory tract infection.

from kidneys and urinary tract: changes of function of kidneys, including a renal failure at patients of risk group (such changes of function of kidneys can be reversible at the therapy termination), infections of urinary tract.

from the system of blood and lymphatic system: anemia, thrombocytopenia.

General state and disturbances connected with a medicament route of administration: asthenia/weakness, indisposition, hypostases, grippopodobny symptoms.

from skin and hypodermic cellulose: urticaria, itching, rash, photosensitivity, erythrosis.

from a musculoskeletal system and connective tissue: dorsodynia, myalgia, arthralgia, rhabdomyolysis.

from a reproductive system and mammary glands: erectile dysfunction / impotence.

from the immune system: reactions of hypersensitivity (anaphylactic reactions, a Quincke's disease, including edema of laryngeal and glottis that leads to obstruction of airways and/or edema of face, lips, drinks and/or language); at some patients in the anamnesis noted the Quincke's disease connected with use of other drugs, including APF inhibitors; a vasculitis, including Shenleyn's purpura — Genokh.

Laboratory indicators: a hypoglycemia, a hyperpotassemia, a hyponatremia, increase in the AlAT level, increase in level of urea in blood, creatinine in blood plasma.

Special instructions

Pregnancy. during pregnancy the use of antagonists of receptors of ii angiotensin is contraindicated. patients, the receiving antagonists of receptors of ii angiotensin and planning pregnancy have to pass to antihypertensive medicines which have the established safety profile for use during pregnancy. at pregnancy establishment the treatment by antagonists of receptors of ii angiotensin needs to be stopped urgently and if necessary to begin alternative treatment (see contraindications and use during pregnancy and feeding with a breast).

Hypersensitivity. Quincke's disease. During administration of medicament at patients with a Quincke's disease in the anamnesis (edemas of face, lips, throats and/or language) it is necessary to control the general state constantly.

Arterial hypotension and water and electrolytic imbalance. Symptomatic arterial hypotension, especially after use of the first dose or its increase, can arise at patients with the reduced OCK or deficiency of sodium caused by use of strong diuretics, dietary restriction of the use of salt, diarrhea or vomiting. Such states demand correction before an initiation of treatment losartany or decrease in an initial dose of drug. The same recommendations concern children aged 6 years are more senior.

Electrolytic imbalance. The electrolytic imbalance is often noted at patients with a renal failure (with/without diabetes) that it is necessary to take into account. It is necessary to control also carefully potassium concentration (possibility of a hyperpotassemia) in blood plasma and also indicators of clearance of creatinine, especially at patients with heart failure and clearance of creatinine of 30-50 ml/min.

does not recommend simultaneous use of a lozartan and the kaliysberegayushchy diuretics, additives of potassium and substitutes of salt containing potassium.

Abnormal liver function. Considering the pharmacokinetic data indicating significant increase in concentration of a lozartan in blood plasma of patients with cirrhosis it is necessary to consider a question of a dose decline for patients with existence in the anamnesis of abnormal liver functions. There is no experience of use of medicament for patients with heavy abnormal liver functions.

for use for children with abnormal liver functions.

Renal failure. It was reported about emergence of changes of function of kidneys, including a renal failure which connected system renin-angiotenzinovoy with suppression (especially patients with dependence have functions of kidneys from the system renin-angiotensin-aldosteronovoy (SRAA), that is patients with heavy dysfunctions of heart or already existing renal failures).

Drugs influencing RAAS can cause increase in level of urea and creatinine in blood plasma in patients with a bilateral stenosis of renal arteries, with a stenosis of renal arteries or with a stenosis of an artery of the only kidney.

These changes in function of kidneys can be reversible after the therapy termination. It is necessary to apply with care Klosart at patients with a bilateral stenosis of renal arteries or with a stenosis of an artery of the only kidney.

Use for children with a renal failure. Drug is not recommended for use for children with SKF of 30 ml/min. / 1.73 to m ² as there are no relevant data on use.

during use of the medicament Klosart should check regularly function of kidneys as its deterioration is possible. Especially it concerns situations when Klosart apply in the presence of other morbid conditions (fever, dehydration) which can influence function of kidneys.

Simultaneous use of the medicament Klosart and APF inhibitors worsens function of kidneys therefore such combination is not recommended.

Transplantation of a kidney. There is no experience concerning safety of use of a lozartan for patients to whom it is only carried out transplantation of a kidney.

Primary hyper aldosteronism. At patients with primary hyper aldosteronism, as a rule, do not note effect at use of the medicaments operating by inhibition system renin-angiotenzinovoy. Therefore Klosart is not recommended for this group of patients.

Coronary artery disease and cerebrovascular diseases. As well as at use of other antihypertensive drugs, excessive decrease in the ABP at patients with ischemic coronary artery diseases and cerebrovascular diseases can lead to development of a myocardial infarction or stroke.

Heart failure. As well as at use of other medicaments influencing RAAS the patients with heart failure with/without renal failures have a risk of developing heavy arterial hypotension and (often acute) renal failure.

does not have sufficient therapeutic experience of use of a lozartan for patients with heart failure and the accompanying heavy renal failure, patients with heavy heart failure (class IV on NYHA) and also at patients with heart failure and symptomatic life-threatening cardiac arrhythmia. Therefore lozartan it is necessary to apply with care at such group of patients. It is necessary to apply at the same time with care lozartan and blockers of β-adrenoceptors.

Stenosis of aortal and mitral valves, subaortic hypertrophic stenosis. As well as at use of other vazodilatator, with extra care patients should appoint Klosart with a stenosis of aortal and mitral valves or a subaortic hypertrophic stenosis.

Caution. As it is established concerning APF inhibitors, lozartan and other antagonists of angiotensin are less effective at patients of negroid race, than at other patients, perhaps, because of low activity of renin at patients with AG which are representatives of negroid race.

Double blockade of RAAS. Hypertensia, a faint, a stroke, a hyperpotassemia and also changes of kidneys (including OPN) are registered at predisposed persons, especially at combination of the medicines influencing this system (see INTERACTIONS). Therefore double blockade of RAAS by combination of blockers of receptors of angiotensin II (SCONCE) with APF inhibitors or aliskireny is not recommended.

Combination with aliskireny is contraindicated to patients with diabetes or a renal failure (SKF of 60 ml/min. / 1.73 m ² ).

Use during pregnancy and feeding by a breast

Pregnancy. It is contraindicated to the pregnant women or women planning pregnancy to apply medicine (see CONTRAINDICATIONS and SPECIAL INSTRUCTIONS). If during treatment the pregnancy is confirmed, use of medicament should be stopped and replaced immediately with other medicine allowed for use for pregnant women.

Knows that use of antagonists of receptors of angiotensin II in II and III trimester induces a fetotoksichnost (weakening of function of kidneys, oligogidramnion, a delay of ossification of bones of a skull) and neonatal toxicity (renal failure, arterial hypotension, a hyperpotassemia).

If in the II trimester of pregnancy applied antagonists of receptors of angiotensin II, it is recommended to carry out ultrasonography for check of function of kidneys and a condition of bones of a skull.

Condition of newborns whose mothers antagonists of receptors of angiotensin II applied should be checked often concerning development of arterial hypotension.

Feeding by a breast. As there is no information on use of a lozartan during feeding by a breast, it is not recommended to appoint this drug. Alternative treatment by medicaments with better the studied safety profile during feeding by a breast, especially in the period of a neonatality is desirable or if the child premature.

Children. Safety and efficiency of use of the medicament Klosart are not established to children under 6 years.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Data on influence of a lozartan on ability to run vehicles or to work with other mechanisms are limited. It is necessary to consider a possibility of development of such side reactions as dizziness and drowsiness, especially in an initiation of treatment and at increase in a dose of drug.

Interaction

Other antihypertensive medicaments can enhance hypotensive effect of a lozartan. simultaneous use with other medicaments which can induce such side effect as arterial hypotension (tricyclic antidepressants, antipsychotic means, Baclofenum and amifostin) can increase risk of developing of arterial hypotension.

Lozartan is mainly metabolized by P450 cytochrome (CYP) 2C9 of an active metabolite — carboxyacids. It is established what flukonazol reduces exposure of an active metabolite approximately by 50%, and simultaneous treatment lozartany and rifampicin (inductor of enzymes of metabolism) leads to decrease by 40% of concentration of an active metabolite in blood plasma. The clinical value of this effect is unknown. There are differences in exposure at simultaneous use of a lozartan and fluvastatin (weak CYP inhibitor 2C9).

As well as at use of other medicaments blocking angiotensin II or its effects, simultaneous use of the medicaments detaining potassium in an organism (for example kaliysberegayushchy diuretics: Spironolactonum, Triamterenum, amiloride), or can increase potassium level (for example heparin), the additives containing potassium, or the substitutes of salt containing potassium can lead to increase in content of potassium in blood plasma. Simultaneous use of such means is not recommended.

About reversible increase in concentration of lithium in blood plasma and also about toxicity it was reported at simultaneous use of lithium with APF inhibitors. Simultaneous use of medicaments of lithium and a lozartan should be carried out with care. If use of such combination is considered necessary, recommended to control lithium level in blood plasma during the treatment period.

At simultaneous use of antagonists of angiotensin II and NPVP (for example selection TsOG-2 inhibitors, acetylsalicylic acid in the doses having anti-inflammatory effect, non-selective NPVP) the antihypertensive effect can be weakened. Simultaneous use of antagonists of angiotensin II or diuretics with NPVP can lead to increase in risk of deterioration in function of kidneys, including possible development of OPN and also to increase in level of potassium in blood plasma, especially at patients with the existing renal failure. It is necessary to appoint such combination with care, especially at patients of advanced age. Patients should carry out the corresponding dehydration, it is also necessary to consider a question of monitoring of function of kidneys after the beginning of the accompanying therapy, further — periodically.

Double blockade (for example by addition of APF inhibitor or an aliskiren to antagonists of receptors of angiotensin II) has to be limited to individually certain cases with careful control of the ABP, function of kidneys and electrolytes. In separate researches it is shown that at patients with the established atherosclerosis, heart failure or diabetes with defeat of bodies the double blockade of RAAS is connected with higher frequency of developing of hypotension, faints, hyperpotassemias and also changes of function of kidneys (including OPN), in comparison with use of one medicament operating on RAAS. The combined introduction of an aliskiren with lozartany at patients with diabetes or at persons with a renal failure (SKF of 60 ml/min.) is not recommended (see CONTRAINDICATIONS).

Overdose

overdose Symptoms. data on overdose of a lozartan are limited. the most probable manifestations of overdose are hypotension and tachycardia; bradycardia can be a consequence of parasympathetic (vagal) stimulation.

Treatment. Treatment depends on duration of time, a past after administration of medicament and also on character and weight of symptoms. Stabilization of function of a cardiovascular system has to be a priority action. After oral administration of a lozartan the use of activated carbon in the corresponding dose is shown. It is necessary to control often key indicators of activity of an organism later and to adjust if necessary. Lozartan and his active metabolites are not removed at a hemodialysis.

Storage conditions

At a temperature not above 25 °C in original packing.