Tozaar 50

General characteristics. Structure:

Active ingredient: 50 mg of a lozartan of potassium.

Excipients: cellulose microcrystallic, lactose anhydrous, starch prezhelatinizirovanny, magnesium stearate, talc, silicon dioxide colloid anhydrous, gipromelloza, hydroxypropyl cellulose, titanium dioxide (Е 171).

Pharmacological properties:

Pharmacodynamics. Angiotensin II – a powerful vasoconstrictor, active hormone a renin-angiotenzinovoy of system and one of the most important factors of a pathophysiology of hypertensia. Angiotensin II contacts a receptor of AT1 which is found in many fabrics (for example in unstriated muscles of vessels, adrenal glands, kidneys and heart), defining a number of important biological effects, including vasoconstriction and release of Aldosteronum. Angiotensin II also stimulates proliferation of smooth muscle cells. Lozartan selectively contacts AT1 receptor. In the conditions of in vitro and in vivo лозартан and it pharmacological an active metabolite – carboxyl acid (E-3174) – all physiologically powerful influences of angiotensin II irrespective of a source or a way of synthesis block. Lozartan does not communicate and does not block other receptors of hormones or ion channels influencing cardiovascular regulation. Moreover, лозартан does not suppress APF (a kininaza of II) – enzyme which promotes disintegration of bradikinin. Thereof there is no strengthening of undesirable bradikininassotsiirovanny effects.

Use of a lozartan allows to reduce total quantity of lethal cases of the cardiovascular reasons, a stroke and myocardial infarction at patients with arterial hypertension with a hypertrophy of a left ventricle, provides protection of kidneys at patients with a diabetes mellitus ІІ type with a proteinuria.

Pharmacokinetics. Absorption: after oral administration лозартан well is soaked up and exposed to metabolism of the first passing with formation of an active metabolite of carboxyl acid and inactive metabolites. System bioavailability of tablets of a lozartan makes about 33%. Average maximum concentration of a lozartan and its active metabolite are reached respectively in 1 hour and 3-4 hours. When drug was used together with standard food, clinically significant influence on a concentration profile in a blood plasma of a lozartan was not observed.
Distribution: лозартан and its active metabolite for 3 99% contact plasma proteins, first of all albumine. The volume of distribution of a lozartan makes 34 liters. Researches indicate what лозартан badly gets through a blood-brain barrier.

Metabolism: about 14% of a dose of a lozartan turn into an active metabolite. Except it, inactive metabolites, are formed of them two main formed by a hydroxylation of a side chain butyl and one N-2-tetrazolovy glucuronide.

Elimination: the plasma clearance of a lozartan and its active metabolite makes 600 ml/min. and 50 ml/min. respectively. The renal clearance of a lozartan and its active metabolite makes about 74 ml/min. and 26 ml/min. respectively. When лозартан apply orally, about 4% of a dose are allocated in not changed view with urine, and about 6% of a dose are allocated with urine in the form of an active metabolite. Pharmacokinetic properties of a lozartan and its active metabolite linear at peroral doses of a lozartan of potassium to 200 mg.

After oral administration of concentration in a blood plasma of a lozartan and its active metabolite decrease polieksponentsialno with terminal time of semi-removal approximately

2 hours and 6-9 hours respectively. After oral administration of a 14C-mechenny lozartan approximately

35% of radioactivity find in urine, and 58% – in excrements.

Pharmacokinetics of special groups of patients. Patients of advanced age. Concentration of a lozartan and its active metabolite in a blood plasma of patients of advanced age with arterial hypertension significantly do not differ from these indicators at young patients with arterial hypertension.

Floor. Concentration of a lozartan in a blood plasma were twice higher at women with arterial hypertension, than at the men having arterial hypertension. Concentration of an active metabolite at men and women did not differ. This explicit to the pharmakok_netiyena distinction has no clinical value.

Abnormal liver function and kidneys. At intake at patients with slight and moderate alcoholic cirrhosis of concentration of a lozartan and its active metabolite in a blood plasma were respectively 1,7-5 times higher, than at young volunteers is a male.

Concentration of a lozartan in a blood plasma at patients with clearance of creatinine higher than 10 ml/min. did not differ from those at persons with not changed function of kidneys. When comparing the area under a pharmacokinetic curve "concentration time" (AUC) at the patients who are on a hemodialysis was approximately twice bigger, than patients with normal function of kidneys have AUC of a lozartan. Plasma concentration of an active metabolite do not change at patients with a renal failure or the patients who are on a hemodialysis. Lozartan and his active metabolite are not brought by means of a hemodialysis.

Children. The pharmacokinetics of a lozartan was studied at children with arterial hypertension. The age of investigated made from 1 month to 16 years. The daily dose of a lozartan made about 0,54-0,77 mg/kg of body weight (average doses).

Results of a research showed what лозартан turns into an active metabolite in all age groups. Pharmacokinetic parameters of a lozartan after oral administration similar at babies and children who learn to go, at children of preschool, school age.

Pharmacokinetic parameters of an active metabolite considerably differed in different age groups. These distinctions were statistically significant when comparing parameters at children of preschool age and teenagers. Exposure at babies and children who learn to go was rather big.

Indications to use:

- Treatment of essential hypertensia at adults, and also at children aged from 6 up to 18 years.
- Treatment of a disease of kidneys at adult patients with arterial hypertension and a diabetes mellitus ІІ type with a proteinuria ≥ 0,5 g/days – as a part of anti-hypertensive therapy.
- Treatment of chronic heart failure (at patients at the age of 60 years is also more senior) when use of inhibitors of an angiotensin-converting enzyme (APF) is considered impossible because of incompatibility, especially at cough, or is contraindicated. Patients with heart failure whose condition was stabilized at APF inhibitor use should not be transferred to treatment lozartany. At the patient the fraction of emission of a left ventricle has to make ≤ 40%, a fortune has to be clinically stable, the patient should adhere to the set treatment mode on chronic heart failure.
- Decrease in risk of development of a stroke in adult patients with arterial hypertension and a hypertrophy of a left ventricle that is confirmed to an ECG.

Route of administration and doses:

Drug can be used irrespective of meal, washing down with 1 glass of water.

Arterial hypertension. Usually initial and maintenance dose for most of patients makes 50 mg of drug of 1 times a day (1 tablet). The maximum anti-hypertensive effect is reached on 3-6 week from an initiation of treatment by drug. For some patients there can be more favorable an increase in a dose of drug to 100 mg of 1 times a day (morning).

Drug can be used in combination with other anti-hypertensive drugs, especially with diuretics (for example a hydrochlorothiazide).

Patients with arterial hypertension and a diabetes mellitus of the II type (a proteinuria ≥ 0,5 g/days). Usually initial dose makes 50 mg (1 tablet) of 1 times a day. It is possible to increase a dose to 100 mg of 1 times a day depending on what indicators of arterial pressure in 1 month after an initiation of treatment. Drug can be used with other anti-hypertensive drugs (for example diuretics, blockers of calcium channels, blockers α-or β-receptors, drugs of the central action), and also with insulin and other hypoglycemic drugs which widely use (for example derivatives of sulphonylurea, a glitazonama and inhibitors of α-glucosidase)))))))))).

Heart failure. Usually initial dose of a lozartan for 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 (i.e. 12,5 mg a day, 25 mg a day, 50 mg a day) to a usual maintenance dose of 50 mg (1 tablet) of 1 times a day depending on individual portability.

Reduction of risk of development of a stroke in patients with the arterial hypertension and a hypertrophy of a left ventricle confirmed on an ECG.

Usually initial dose makes 50 mg (1 tablet) of 1 times a day. Depending on changes of level of arterial pressure it is necessary to add a hydrochlorothiazide in a low dose to treatment and/or to increase a drug dose to 100 mg of 1 times a day.

Separate groups of patients. Use to patients with the lowered volume of the circulating blood.

Patients with the lowered volume of the circulating blood (for example, owing to treatment by high doses of diuretics) should begin therapy with a dose of 25 mg of 1 times a day.

Use to patients with a renal failure and to patients to whom carry out a hemodialysis.

At purpose of drug to patients with a renal failure, and also to patients to whom carry out a hemodialysis it is not necessary to carry out initial dose adjustment.

Use to patients with an abnormal liver function. For patients with an abnormal liver function in the anamnesis it is necessary to consider a question of purpose of drug in a smaller dose. There is no experience of treatment of patients with heavy abnormal liver functions therefore лозартан it is contraindicated to this group of patients.

Use to children. Data on efficiency and safety of use of a lozartan to children are more senior than 6 years for treatment of arterial hypertension are limited.

For children who can swallow of tablets and whose body weight more than 20 kg and less than 50 kg, the recommended dose makes 25 mg of 1 times a day. In exceptional cases the dose can be increased to maximum – 50 mg of 1 times a day. The dose should be adjusted depending on influence on the level of arterial pressure.

At patients with body weight more than 50 kg usually single dose makes 50 mg of 1 times a day. In exceptional cases the dose can be increased to maximum – 100 mg of 1 times a day. Use to children in the doses exceeding 1,4 mg/kg (or more than 100 mg) in days, was not studied.

Lozartan is not recommended for use to children under 6 years as data on use of drug in this group of patients are not enough.

Drug is not recommended to be used to children who have a glomerular filtration rate less than 30 ml/min. / 1,7Зм2 as there are no relevant data on use.

Lozartan is also not recommended for use to children with an abnormal liver function.

Use to patients of advanced age. As a rule, there is no need for correction of an initial dose for patients of advanced age though it is necessary to consider a possibility of purpose of drug in an initial dose of 25 mg for patients aged from 75 years.

Features of use:

Use during pregnancy or feeding by a breast. Pregnancy. Use of a lozartan during the I trimester of pregnancy is not recommended and it is contraindicated in II and III trimesters of pregnancy.

Epidemiological data on risk of teratogenic influence owing to use of APF inhibitors during the I trimester of pregnancy are not convincing, however small increase in risk is not excluded. As there are no controlled epidemiological data on risk at use of antagonists of receptors of angiotensin II (the MACAW ІІ), similar risks can exist also for this class of drugs. Except for cases when continuation of therapy of MACAW ІІ is considered necessary, the patients planning pregnancy should appoint alternative anti-hypertensive therapy with the established safety profile on use during pregnancy. If pregnancy is diagnosed, treatment of MACAW ІІ should be stopped immediately and if it is necessary, it is necessary to begin alternative treatment.

It is known that use of MACAW ІІ during II and III trimesters induces фетотоксичність (weakening of function of kidneys, олигогидрамнион, a delay of ossification of bones of a skull) and neonatal toxicity (a renal failure, arterial hypotension, a hyperpotassemia).

If during the II trimester of pregnancy MACAWS ІІ were applied, it is recommended to conduct ultrasonic examination for check of function of kidneys and a condition of bones of a skull.

The condition of newborns whose mothers applied the MACAW ІІ should be checked often concerning development of arterial hypotension.

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

Children. Safety and efficiency of use of drug are not established to children under 6 years.

Features of use. Hypersensitivity. Quincke's disease. It is necessary to control often a condition of patients with a Quincke's disease (a face edema, lips, a throat and/or language) in the anamnesis.

Arterial hypotension and water and electrolytic imbalance. Symptomatic arterial hypotension, especially after use of the first dose of drug or after increase in a dose, can arise at patients with the reduced intravascular volume or deficit of sodium caused by use of strong diuretics, dietary restriction of consumption of salt, diarrhea or vomiting. Such states demand correction before an initiation of treatment drug or decrease in an initial dose of drug (see. "Route of administration and doses"). The same recommendations concern children aged from 6 years.

Electrolytic imbalance. The electrolytic imbalance is often observed at patients with a renal failure (with or without diabetes mellitus) that it is necessary to take into account. During clinical trial with participation of patients with a diabetes mellitus of the II type and with a nephropathy the frequency of emergence of a hyperpotassemia was bigger at treatment lozartany, than at placebo reception. Therefore it is necessary to check often potassium concentration in a blood plasma and indicators of clearance of creatinine, especially at patients with heart failure and clearance of creatinine of 30-50 ml/min.

Simultaneous use of drug and the kaliysberegayushchy diuretics, additives of potassium and substitutes of salt containing potassium is not recommended.

Abnormal liver function. Considering the pharmacokinetic data indicating essential increase in concentration of a lozartan in a 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 drug to patients with heavy abnormal liver functions.

Drug is not recommended for use to children with abnormal liver functions.

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

The drugs influencing renin-angiotensin-aldosteronovu system can cause increase in levels of urea of blood and creatinine of blood serum in patients with a bilateral 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 use with care drug to patients with a bilateral stenosis of renal arteries or with a stenosis of an artery of the only kidney.

Use to children with renal failures. Drug is not recommended for use to children with a glomerular filtration rate less than 30 ml/min. / 1,73 in sq.m as there are no relevant data on use.

During the period of use of drug it is regularly necessary to check function of kidneys as its deterioration is possible. Especially it concerns situations when лозартан apply in the presence of other morbid conditions (fever, dehydration) which can influence renal function.

Simultaneous use of a lozartan 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 drug to patients to whom it is carried out only transplantation of a kidney.

Primary hyper aldosteronism. At patients with primary hyper aldosteronism the effect, as a rule, is not observed at use of drugs, the systems operating by inhibition a renin-angiotenzinovoy. Therefore drug is not recommended for this group of patients.

Diseases of coronary arteries and cerebrovascular diseases. As well as at use of other anti-hypertensive drugs, the excessive lowering of arterial pressure at patients with ischemic diseases of coronary arteries and cerebrovascular diseases can lead to development of a myocardial infarction or stroke.

Heart failure. As well as at use of other drugs influencing renin-angiotensin-aldosteronovuyu system patients with heart failure with/without renal failure have a risk of development of heavy arterial hypotension and (often acute) renal failure.

There is no sufficient therapeutic experience of use of a lozartan for patients with heart failure and the accompanying heavy renal failure, to patients with heavy heart failure (a class IV on NYHA), and also at patients with heart failure and symptomatic life-threatening cardiac arrhythmia. Therefore лозартан such group of patients should apply with care. It is necessary to apply at the same time with care лозартан and β-blockers..........

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

Excipients. Lactose is a part of drug. Patients with rare hereditary forms of intolerance of a galactose, deficit of lactase of Lapp and glyukozo-galaktozny malabsorption should not use this drug.

Other cautions. As it is established concerning APF inhibitors, лозартан and other antagonists of angiotensin are less effective at patients of negroid race, than for other patients, perhaps, because of low activity of a renin at patients with arterial hypertension who are representatives of negroid race.

Ability to influence speed of response at control of motor transport or work with other mechanisms. Did not conduct researches concerning influence of drug on ability to manage motor transport and mechanisms. However it is necessary to remember a possibility of development of side reactions from the central nervous system, such as dizziness and drowsiness, especially in an initiation of treatment and at increase in a dose of drug.

Side effects:

Dizziness was side reaction about which it was most often reported during clinical trials.

From a nervous system: often – dizziness, infrequently – drowsiness, a headache, sleeplessness, muscular spasms, is rare – paresthesia, migraine, a dysgeusia.

Mental disturbances: depression.

From heart: infrequently – palpitation, stenocardia, tachycardia, it is rare – a syncope, fibrillation of auricles, a stroke.

From vascular system: infrequently – symptomatic arterial hypotension (especially patients with intravascular dehydration have, for example, patients with heavy heart failure or at treatment by diuretics in high doses), dozozavisimy orthostatic effect, rash, arterial hypotension, including orthostatic hypotension.

From a digestive tract: infrequently – abdominal pain, dyspepsia, a lock, diarrhea, nausea, vomiting, pancreatitis.

From respiratory system: cough, cold, sinusitis, pharyngitis, upper respiratory tract infections, infrequently – диспноэ.

From acoustic organs: often – вертиго, a ring in ears.

From skin and hypodermic cellulose: infrequently – urticaria, an itch, rash, photosensitivity, an erythrosis.

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

From skeletal and muscular system: dorsodynia, mialgiya, arthralgia, рабдомиолиз.

From an urinary system: infections of urinary tract. As a result of inhibition renin-angiotensin-aldosteronovoy of system it was reported about changes of function of kidneys, including a renal failure at patients of risk group, such changes of renal function can be reversible at the therapy termination.

From immune system: seldom – hypersensitivity reactions (anaphylactic reactions, a Quincke's disease, including hypostasis of a throat and glottis that leads to obstruction of respiratory tracts and/or a face edema, lips, a throat and/or language), some patients in the anamnesis had a Quincke's disease connected using other drugs, including APF inhibitors, a vasculitis including Shenlyayna-Genokh's purpura.

From gepatobiliarny system: seldom – hepatitis, it is unknown – an abnormal liver function.

From reproductive system: erectile dysfunction / impotence.

General state: often – an adynamy, weakness, hypostasis, grippopodobny symptoms, an indisposition.

Laboratory indicators. In the course controlled clinical trials clinically significant changes of standard laboratory indicators were seldom connected using tablets of a lozartan. The ALT level increased seldom and was usually normalized after drug phase-out. The hyperpotassemia (potassium level in blood serum more than 5,5 mmol/l) was observed at 1,5% of patients with arterial hypertension, is frequent – a hypoglycemia, a hyperpotassemia, a hyponatremia, is rare – increase in level of urea of blood, creatinine in blood serum and potassium in blood serum.

Children. A profile of side reactions at children similar a profile at adult patients. Data concerning side reactions which were observed at children are limited.

Interaction with other medicines:

Other hypotensive drugs can strengthen hypotensive effect of a lozartan. Simultaneous use with other drugs which are capable to induce such side reaction as arterial hypotension (tricyclic antidepressants, antipsychotic means, Baclofenum and амифостин) can increase risk of developing of arterial hypotension.

Lozartan is metabolized preferential with participation of system of P450 (CYP) cytochrome 2C9 to active a carboxyacid metabolite. Clinical trials established what флуконазол (CYP2C9 inhibitor) reduces exposure of an active metabolite approximately by 50%. It is established that simultaneous treatment lozartany and rifampicin (the inductor of enzymes of metabolism) leads to decrease by 40% of concentration of an active metabolite in a blood plasma. Clinical value of this effect is unknown. There is no distinction in exposure at simultaneous use of a lozartan and to a fluvastatin (weak CYP2C9 inhibitor).

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

Reversible increase in concentration of lithium in blood serum, and also was reported about toxicity at simultaneous use of lithium with APF inhibitors. It was also very seldom reported about such MACAWS of II at use. Simultaneous treatment by lithium and lozartany should be carried out with care. If use of such combination is considered necessary, it is recommended to check lithium level in blood serum during the combined treatment.

At simultaneous use of MACAW of II and non-steroidal anti-inflammatory drugs (NPVS) (for example the selection inhibitors of cyclooxygenase-2 (TsOG-2), acetylsalicylic acid in the doses having antiinflammatory effect, non-selective NPVP) the anti-hypertensive effect can be weakened. Simultaneous use of MACAW of II or diuretics with NPVP can lead to increase in risk of deterioration in function of kidneys, including possible development of an acute renal failure, and also to increase in level of potassium in blood serum, especially at patients with the existing renal failure. It is necessary to appoint such combination with care, especially to patients of advanced age. Patients should carry out the corresponding hydration, it is also necessary to consider questions of monitoring of function of kidneys after the beginning of the accompanying therapy, further – periodically.

Contraindications:

Hypersensitivity to the active ingredient and any excipient which is a part of drug. Heavy abnormal liver functions. II and III trimesters of pregnancy.

Overdose:

Symptoms. It was not reported about drug overdose cases. Arterial hypotension, tachycardia can be the most probable symptoms, depending on the volume of overdose, bradycardia is possible.

Treatment. Treatment depends on time which passed after administration of drug and also on character and weight of symptoms.

Stabilization of function of cardiovascular system has to be a priority action. After oral administration of drug use of absorbent carbon in a suitable dose is shown. It is necessary to control often the main vital signs of an organism later and to adjust if necessary. Lozartan and active metabolites are not removed by means of a hemodialysis.

Storage conditions:

To store at a temperature not above 25 °C. To store in the place, unavailable to children. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in the blister, on 3 blisters in cardboard packaging.