Kozaar

General characteristics. Structure:

Active ingredient: 50 mg or 100 mg of a lozartan of potassium.

Excipients: cellulose microcrystallic, lactoses monohydrate, starch corn prezhelatinizirovanny, magnesium stearate.

Structure of a cover: a hypro rod (from 0.3% of silicon of dioxide), a gipromelloza, titanium dioxide, Brazilian wax palm wax.

Pharmacological properties:

Pharmacodynamics. The specific antagonist of receptors of angiotensin II (AT1 type) for intake. Angiotensin II selectively contacts the AT1-receptors which are in many fabrics (in smooth muscle fabrics of vessels, in adrenal glands, kidneys and heart) and performs several important biological functions, including vasoconstriction and release of Aldosteronum. Angiotensin II also stimulates growth of smooth muscle cells. Lozartan and him pharmacological an active metabolite (Е 3174) both in vitro, and in vivo block all physiological effects of angiotensin II, irrespective of a source or a way of synthesis. Unlike some peptide antagonists of angiotensin II лозартан has no effects of an agonist.

Lozartan selectively contacts AT1 receptors and does not communicate and does not block receptors of other hormones and ion channels playing an important role in regulation of function of cardiovascular system. Besides, лозартан does not inhibit APF which is responsible for destruction of bradikinin. Therefore the effects which directly are not connected with blockade of AT1 receptors, in particular, strengthening of the effects connected with influence of bradikinin or development of hypostases (лозартан - 1.7%, placebo - 1.9%), are not related to action of a lozartan.

At prolonged (6 weeks) treatment of patients with arterial hypertension lozartany in a dose of 100 mg/days 2-3-fold increase in level of angiotensin II at the time of achievement of Cmax of drug in a blood plasma was observed; at some patients a bigger increase in concentration of a lozartan was observed, especially with the small duration of treatment (2 weeks). In the course of treatment anti-hypertensive activity and decrease in concentration of Aldosteronum of plasma were shown in 2 and 6 weeks of therapy that indicates effective blockade of receptors of angiotensin II. However after cancellation of a lozartan activity of a renin of plasma and level of angiotensin II in 3 days decreased to the reference values observed prior to administration of drug.

As лозартан is a specific antagonist of AT1 - angiotensin II receptors, it does not inhibit APF, a kinase of II - enzyme which is inactivated by bradikinin. The research in which effects of 20 mg and 100 mg of a lozartan were compared to effects of APF inhibitor concerning reaction to angiotensin I, angiotensin II and bradykinin showed what лозартан blocks effects of angiotensin I and angiotensin II, without exerting impacts on effects of bradikinin that is caused by the specific mechanism of action of a lozartan. On the contrary, APF inhibitors block the answer of angiotensin I and increase expressiveness of the answer to bradykinin, without influencing expressiveness of the answer to angiotensin II that shows pharmakodinamichesky distinction between lozartany and APF inhibitors.

Concentration of a lozartan and its active metabolite in a blood plasma, and also anti-hypertensive effect of a lozartan increase with increase in a dose of drug. Since лозартан and its active metabolite are antagonists of receptors of angiotensin II, both of them cause anti-hypertensive effect.

In a research with a single dose of 100 mg of a lozartan healthy volunteers (men) drug use as the patients keeping to a diet with the limited content of table salt, and the patients consuming a lot of table salt did not influence a glomerular filtration rate, an effective renal plazmotok and filtrational fraction. Lozartan has natriuretic effect which was more expressed at a low-salt diet and, apparently, was not connected with suppression of an early reabsorption of sodium in proximal renal tubules. Lozartan also caused passing increase in release of uric acid kidneys.

At the patients with arterial hypertension, a proteinuria (more than 2 g / 24 h) who are not suffering from a diabetes mellitus and accepting лозартан within 8 weeks in a dose from 50 mg to 100 mg reliable decrease in a proteinuria by 42%, fractional excretion of albumine and IgG was noted. At these patients лозартан stabilized a glomerular filtration rate and reduced filtrational fraction.

At the women in the postmenopauzny period with arterial hypertension accepting лозартан potassium in a dose of 50 mg/days within 4 weeks influence of therapy on the renal and system level of prostaglandins was not revealed.

Lozartan does not influence vegetative reflexes and does not possess a long-term effect concerning noradrenaline level in a blood plasma.

With arterial hypertension лозартан in doses to 150 mg/days does not cause clinically significant changes of level of triglycerides in patients on an empty stomach, the general cholesterol (Хс) and Hs-LPVP. In the same doses лозартан does not exert impact on glucose level in blood on an empty stomach.

In general, лозартан caused the reduction of serumal level of uric acid (as a rule, less than 0.4 mg/dl) remaining during long therapy. In controlled clinical trials which joined patients with arterial hypertension drug withdrawal cases in connection with increase in levels of creatinine or potassium in blood serum are noted.

Pharmacokinetics. Absorption. At intake лозартан it is well absorbed from a GIT and is exposed to effect of "the first passing" through a liver therefore the active carboxylated metabolite and inactive metabolites are formed. System bioavailability of a lozartan makes about 33%. Average Cmax of a lozartan and its active metabolite are reached in 1 h and in 3-4 h respectively. At reception of a lozartan during standard practice of food of clinically significant influence on a profile of concentration of a lozartan in a blood plasma it was not revealed.

Distribution. Lozartan and his active metabolite contact proteins of a blood plasma (generally with albumine) more than for 99%. Vd of a lozartan makes 34 l. Researches on rats showed what лозартан practically does not get through GEB.

Metabolism. About 14% of a dose of a lozartan (at intake and in introduction) turn into its active metabolite. After intake or in/in introductions of a lozartan, marked 14C, the radioactivity of the circulating blood plasma first of all is connected with existence in it of a lozartan and its active metabolite. Also biologically inactive metabolites, including two the main, formed as a result of a hydroxylation of a butyl side chain, and one minor - a N-2-tetrazole-glucuronide are formed.

Removal. The plasma clearance of a lozartan and its active metabolite makes about 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. At reception of a lozartan inside about 4% of a dose are removed in not changed view with urine and about 6% of a dose are removed with urine in the form of an active metabolite. Lozartan and his active metabolite have linear pharmacokinetics at oral administration of a lozartan of potassium in doses to 200 mg.

After intake plasma concentration of a lozartan and its active metabolite decrease polieksponentsialno with final T1/2 about 2 and 6-9 h respectively. At administration of drug in a dose of 100 mg of 1 times/days there is no significant cumulation in a blood plasma neither a lozartana, nor its active a metabolite.

Removal of a lozartan and its metabolites happens to bile and urine. After intake of a lozartan, marked 14C, about 35% of a radioactive label it is found in urine also 58% - in Calais. Later in/in introductions of a lozartan, marked 14C, about 43% of a radioactive label also 50% in Calais come to light in urine.

Pharmacokinetics at special groups of patients. Concentration of a lozartan and its active metabolite in a blood plasma at elderly people with arterial hypertension significantly do not differ from these indicators at younger patients with arterial hypertension.

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

At reception of a lozartan inside at patients with cirrhosis of alcoholic genesis easy and moderate severity of concentration of a lozartan and its active metabolite in a blood plasma appeared in 5 and 1.7 times (respectively) more, than at young healthy 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 normal function of kidneys. When comparing the size AUC at the patients who are on a hemodialysis was approximately twice more, than at patients with normal function of kidneys. Plasma concentration of an active metabolite do not change at patients with a renal failure or at the patients who are on a hemodialysis. Lozartan and his active metabolite cannot be removed by means of a hemodialysis.

Indications to use:

— arterial hypertension;

— the decrease in risk of the associated cardiovascular incidence and mortality at patients with arterial hypertension and a hypertrophy of a left ventricle which is shown decrease in total in the frequency of cardiovascular mortality, frequency of a stroke and a myocardial infarction;

— protection of kidneys at patients with a diabetes mellitus of type 2 with a proteinuria - the delay of progressing of a renal failure which is shown decrease in frequency of a giperkreatininemiya, frequency of development of an end-stage of HPN demanding carrying out a hemodialysis or transplantation of kidneys
rates of mortality, and also decrease in a proteinuria;

— chronic heart failure at inefficiency of treatment by APF inhibitors.

Route of administration and doses:

Kozaar is accepted inside regardless of meal, use both in the form of monotherapy, and in in a combination with other anti-hypertensive means is possible.

At arterial hypertension the standard initial and maintenance dose for most of patients makes 50 mg of 1 times/days. The maximum hypotensive effect is reached in 3-6 weeks after the beginning of therapy. At some patients for achievement of bigger effect the dose can be increased to 100 mg of 1 times/days.

At patients with reduced OTsK (for example, at reception of diuretics in high doses) the initial dose of drug should be lowered to 25 mg of 1 times/days.

Elderly people have no need for selection of an initial dose and at patients with a renal failure, including patients on dialysis.

Patients with a liver disease in the anamnesis are recommended to appoint drug in lower doses.

For decrease in risk of the associated cardiovascular incidence and mortality at patients with arterial hypertension and a hypertrophy of a left ventricle the standard initial dose of drug makes 50 mg of 1 times/days. Further it is recommended to add a hydrochlorothiazide in low doses or to increase Kozaar's dose to 100 mg of 1 times/days taking into account extent of decrease in the ABP.

For protection of function of kidneys at patients with a diabetes mellitus of type 2 and a proteinuria the standard initial dose of drug makes 50 mg of 1 times/days. Further it is recommended to increase Kozaar's dose to 100 mg of 1 times/days taking into account extent of decrease in the ABP. Kozaar can be appointed together with other anti-hypertensive means (diuretics, blockers of calcium channels, alpha and beta adrenoblockers, drugs of the central action), insulin and other hypoglycemic means (derivatives of sulphonylurea, a glitazona and inhibitors of glucosidase).

At chronic heart failure the initial dose of Kozaar makes 12.5 mg of 1 times/days. As a rule, the dose is titrated with a week interval (i.e. 12.5 mg/days, 25 mg/days, 50 mg/days) to a usual maintenance dose of 50 mg of 1 times/days depending on individual portability.

Features of use:

Use at pregnancy and feeding by a breast. Kozaar's use at pregnancy is contraindicated. In II and III trimesters of pregnancy of the drugs operating on a renin-angiotenzivnuyu system serious damages or even death of the developing fruit therefore at pregnancy establishment Kozaar's reception has to be stopped at once can cause use. At a fruit the renal perfusion depending on development of system a renin angiotensin appears in the II trimester; the risk for a fruit increases if Kozaar appoint in II or the III trimester of pregnancy.

Kozaar in the period of a lactation is not recommended to accept. There is no experience of use of a lozartan during breastfeeding, and it is unknown whether it is allocated лозартан with breast milk. Since many medicines are allocated with breast milk and can make an adverse effect on babies, taking into account need of administration of drug for mother it is necessary to make the decision on the termination of breastfeeding or on drug withdrawal.

Use at abnormal liver functions. With care patients of a liver should appoint drug in the anamnesis.

Use at renal failures. With care patients should appoint drug with diseases of kidneys in the anamnesis.

Use for children. Safety and efficiency of drug at children up to 18 years are not established.

Special instructions. Manifestation of such symptom of hypersensitivity as a Quincke's disease is possible.

Patients with reduced OTsK (for example, the diuretics receiving treatment by high doses) can have a symptomatic arterial hypotension. Correction of such states needs to be carried out before Kozaar's appointment or to begin treatment with lower dose.

Disturbance of water and electrolytic balance is characteristic of patients with a renal failure with a diabetes mellitus or without diabetes mellitus therefore at purpose of drug of this category of patients it is necessary to observe extra care. In clinical trials in which patients with a diabetes mellitus 2 types with a proteinuria participated the number of cases of a hyperpotassemia was higher in the group receiving Kozaar than in the group receiving placebo. Several patients had to stop therapy in connection with the arisen hyperpotassemia.

During treatment by drug Kozaar patients should not accept drugs of potassium or substitutes of table salt containing potassium without preliminary approval of the doctor.

Data of pharmacokinetic researches indicate that concentration of a lozartan in a blood plasma of patients with cirrhosis considerably increases therefore patients with a liver disease in the anamnesis should appoint drug in lower dose.

Owing to inhibition a system renin-angiotenzinovoy at some susceptible patients changes of function of kidneys, including a renal failure were noted; these changes can disappear after the therapy termination.

Some drugs making impact on a renin-angiotenzinovuyu system can increase the level of urea of blood and serumal creatinine at patients with a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney. It was reported about emergence of similar effects at Kozaar's reception; changes of function of kidneys can disappear at the therapy termination.

At patients with dependent on activity system renin-angiotensin-aldosteronovoy function of kidneys (i.e. with heavy chronic heart failure) treatment by APF inhibitors in certain cases was followed by development of an oligouriya and/or the accruing azotemia, and an acute renal failure (seldom), and/or states with a lethal outcome. About similar outcomes it was reported also at treatment of this category of patients by Kozaar.

Clinical trials did not reveal any features concerning safety and efficiency of a lozartan at patients of advanced age.

Use in pediatrics. Safety and efficiency of drug at children up to 18 years are not established.

Side effects:

In controlled clinical trials of drug patients with essential arterial hypertension the only side effect connected with administration of drug had a dizziness which was observed more often than at purpose of placebo and arose at ≥1% of the patients receiving Kozaar. Besides, at ≤1% of patients the orthostatic reactions depending on a drug dose were noted. It was seldom reported about developing of rash, but the frequency of its emergence was less, than at placebo reception.

Controlled clinical trials showed that Kozaar is generally well had by patients with a hypertrophy of a left ventricle, patients with a diabetes mellitus of type 2 and a proteinuria. The rotatory and not rotatory vertigo, adynamy/weakness, decrease in the ABP and a hyperpotassemia were the most frequent side effects connected with administration of drug.

During these researches the following side effects against the background of Kozaar's (n=2085) reception and placebo (n=535) met at ≥ 1% of patients:

From an organism in general: pain in a stomach of 1.7% (placebo of 1.7%); weakness and fatigue of 3.8% (placebo of 3.9%), a stethalgia of 1.1% (placebo of 2.6%), swelled 1.7% (placebo of 1.9%)

From cardiovascular system: increase of heartbeat of 1% (placebo of 0.4%); tachycardia of 1% (placebo of 1.7%).

From the alimentary system: diarrhea of 1.9% (placebo of 1.9%); dyspepsia of 1.1% (placebo of 1.5%); nausea of 1.8% (placebo of 2.8%).

From bone muscular system: dorsodynia of 1.6% (placebo of 1.1%); muscular spasms of 1% (placebo of 1.1%).

From TsNS: dizziness of 4.1% (placebo of 2.4%); headache of 14.1% (placebo of 17.2%); sleeplessness of 1.1% (placebo of 0.7%).

From respiratory system: cough 3.1 (placebo of 2.6%); rhinedema of 1.3% (placebo of 1.1%); pharyngitises of 1.5% (placebo of 2.6%); sinusitis of 1% (placebo of 1.3%); infections of upper parts of respiratory tracts of 6.5% (placebo of 5.6%).

The following undesirable reactions were noted in broad clinical practice.

Allergic reactions: at the patients accepting лозартан the Quincke's disease, including hypostasis of a throat, glottis, the causing obstructions of respiratory tracts, and/or a face edema, lips, a throat and/or language was seldom observed. Some of these patients had instructions in the anamnesis on the postponed Quincke's disease at reception of APF inhibitors. It was seldom reported about emergence of a vasculitis, including Shenleyn-Genokh's purpura.

From the alimentary system: hepatitis (seldom), abnormal liver function.

From system of a hemopoiesis: anemia, thrombocytopenia.

From a musculoskeletal system: mialgiya; arthralgia; seldom - рабдомиолиз.

From TsNS: migraine, it is rare - a dysgeusia.

From respiratory system: cough.

Dermatological reactions: urticaria, itch, dermahemia.

From laboratory indicators: when performing controlled clinical trials at patients with essential arterial hypertension clinically significant changes of standard laboratory indicators were seldom connected with Kozaar's reception. At 1.5% of patients the hyperpotassemia (blood serum potassium> 5.5 ¼Ý¬ó/l was noted). In a research at patients with a diabetes mellitus of type 2 with a proteinuria the hyperpotassemia developed at 9.9% of patsent treated Kozaar and at 3.4% of patients, treated placebos. The increased ALT level was noted in rare instances and usually was returned to norm after therapy cancellation.

In general Kozaar is had well, side effects have easy and passing temper and do not demand drug withdrawal. Total frequency of side effects Kozaara is comparable with this indicator at placebo reception.

Interaction with other medicines:

Clinically significant interaction of drug with such medicines as a hydrochlorothiazide, digoxin, warfarin, Cimetidinum, phenobarbital, кетоконазол and erythromycin was not noted.

Rifampinum and флуконазол reduce the level of an active metabolite. Clinical value of these interactions is not studied.

As well as when using other means blocking formation of angiotensin II and its effects, the accompanying purpose of kaliysberegayushchy diuretics (Spironolactonum, Triamterenum, amiloride), the potassium additives and salts containing potassium can lead to increase in level of potassium in blood serum.

As well as when using other means influencing sodium removal, treatment lozartany can be followed by decrease in excretion and increase in serumal concentration of lithium therefore at simultaneous treatment with drugs of lithium it is necessary to control its serumal concentration.

NPVS, including the selection TsOG-2 inhibitors, can reduce effect of diuretics and other hypotensive drugs. Therefore the hypotensive effect of antagonists of receptors of angiotensin II can be weakened at simultaneous use of NPVS, including the selection TsOG-2 inhibitors.

With renal failures which received treatment of NPVS including the selection TsOG-2 inhibitors, co-administration of antagonists of receptors of angiotensin II can cause further deterioration in function of kidneys in some patients. Usually this effect is reversible.

Flukonazol, inhibitor of an isoenzyme 2C9 of P450 cytochrome, reduces plasma concentration of an active metabolite and increases concentration of a lozartan, however, the pharmakodinamichesky importance of this phenomenon is not established. It is shown that the persons which are not metabolizing лозартан in an active metabolite have very rare and specific defect of an isoenzyme 2C9 of P450 cytochrome.

Contraindications:

— pregnancy;

— hypersensitivity to drug components.

With care patients should appoint drug with the reduced OTsK, for example, receiving treatment by diuretics in high doses (there can be symptomatic hypotension), and also to patients with diseases of a liver and kidneys in the anamnesis.

Overdose:

Data on overdose are limited. The most probable symptoms of overdose: the expressed decrease in the ABP and tachycardia; bradycardia can arise owing to parasympathetic stimulation.

Treatment: symptomatic therapy. Lozartan and his active metabolite do not leave from a blood-groove at a hemodialysis.

Storage conditions:

Drug should be stored in densely closed packaging, in protected from light, the place, unavailable to children, at a temperature not above 30 °C. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

14 pieces - blisters (1) - packs cardboard.
14 pieces - blisters (2) - packs cardboard.