Гизаар® Forte

General characteristics. Structure:

Active ingredients: 100 mg of a lozartan of potassium, 12,5 mg of a hydrochlorothiazide.

Excipients: cellulose microcrystallic (Avicel PH102), lactoses monohydrate, starch corn prezhelatinizirovanny 1500, magnesium stearate.

Structure of a film cover: hypro rod, gipromelloza, titanium dioxide (E171), wax of karnaubskiya.

Pharmacological properties:

Pharmacodynamics. Anti-hypertensive drug of the combined structure. Active agents of the drug Gizaar® render the additive anti-hypertensive effect, reducing the ABP level more than each of components separately. Owing to diuretic effect the hydrochlorothiazide increases activity of a renin of a blood plasma (ARP), stimulates secretion of Aldosteronum, increases the level of angiotensin II and reduces potassium level in blood serum. Reception of a lozartan blocks all physiological effects of angiotensin II and owing to suppression of effects of Aldosteronum promotes reduction of the loss of potassium caused by diuretic reception.

Lozartan has moderate and passing uricosuric effect. The hydrochlorothiazide causes small increase in level of uric acid in blood; the combination of a lozartan and a hydrochlorothiazide promotes reduction of expressiveness of the hyperuricemia caused by diuretic.

Lozartan. Lozartan is the antagonist of receptors of angiotensin II. Angiotensin II is a powerful vasoconstrictor, the main active hormone a system renin-angiotenzinovoy, and also a decisive pathophysiological link of development of arterial hypertension. Angiotensin II contacts the AT1 subtype receptors found in many fabrics (for example, in unstriated muscles of vessels, adrenal glands, kidneys and heart) and causes a number of important biological effects, including vasoconstriction and release of Aldosteronum. Angiotensin II also stimulates proliferation of smooth muscle cells. The role of the second type of receptors of angiotensin II - the AT2 subtype - in a cardiovascular homeostasis is unknown.

Angiotensin II selectively contacts AT1 receptors. Lozartan and him pharmacological the active metabolite (E-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 promotes degradation 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 of 1.9%), have no relation to action of a lozartan.

Lozartan eliminates the negative feedback which is in suppression by angiotensin II of secretion of a renin that leads to increase in ARP of blood. Increase in ARP is followed by increase in level of angiotensin II in plasma. At prolonged (6 weeks) treatment of patients with arterial hypertension lozartany in a dose of 100 mg/days, at the time of achievement in a blood plasma of the maximum concentration of drug, 2-3-fold increase in level of angiotensin II was observed. At some patients a bigger increase was observed, especially with the small duration of treatment (2 weeks). Anti-hypertensive activity and decrease in concentration of Aldosteronum of a blood plasma are shown in 2-6 weeks of therapy that indicates effective blockade of receptors of angiotensin II. ARP and level of angiotensin II decrease to reference values in 3 days after cancellation of a lozartan. Gizaar's impact on ARP and level of angiotensin II was comparable to that at reception of 50 mg of a lozartan.

As лозартан is a specific antagonist of AT1 receptors of angiotensin II, it does not inhibit APF (a kininaza of II) - enzyme which is inactivated by bradikinin. Results of a research in which action of 20 mg and 100 mg of a lozartan, and APF inhibitor on angiotensin I, angiotensin II and bradykinin was compared showed what лозартан blocks effects of angiotensin I and angiotensin II, without exerting impacts on effects of bradikinin. These data confirm the specific mechanism of action of a lozartan. In turn, APF inhibitor blocked reaction to angiotensin I and increased 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. As лозартан and its active metabolite are antagonists of receptors of angiotensin II, both of them make a contribution to anti-hypertensive effect.

In clinical trial with a single dose of 100 mg of a lozartan in which included healthy volunteers of men administration of drug in conditions it is high - and a low-salt diet did not influence the glomerular filtration rate (GFR), an effective renal plazmotok and filtrational fraction of kidneys. Lozartan showed 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 (> 2 g/days) who are not suffering from a diabetes mellitus and accepting within 8 weeks лозартан in a dose of 50 mg with gradual increase up to 100 mg reliable decrease in a proteinuria by 42% was noted. Fractional excretion of albumine also considerably decreased. At these patients лозартан stabilized SKF and reduced filtrational fraction.

At the women in the postmenopauzny period with arterial hypertension accepting лозартан in a dose of 50 mg/days within 4 weeks influence of therapy on renal and system levels 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 did not cause clinically significant changes of level of triglycerides in patients on an empty stomach, the general cholesterol and holesterina-LPVP. In the same doses лозартан did 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 because of increase in level of creatinine or potassium of blood serum are not registered.

In 12 weeks parallel placebo - a controlled research at patients with a left ventricular failure (the II-IV functional class on NYHA classification), the majority of which received diuretics and/or a digitalis, effects of a lozartan of potassium in doses of 2.5, 10, 25 and 50 mg/days were compared. In doses of 25 mg and 50 mg/days drug rendered positive hemodynamic and neurohormonal effects which were observed throughout all research. Hemodynamic effects included increase in cardiac index and reduction of pressure of jamming in pulmonary capillaries, and also reduction of OPSS, the average system ABP and ChSS. Neurohormonal effects were shown in the form of decrease in level of Aldosteronum and noradrenaline in blood.

At patients with arterial hypertension and a hypertrophy of a left ventricle лозартан, it is frequent in a combination with a hydrochlorothiazide, reduces risk of cardiovascular incidence and mortality that it was proved by means of assessment of the combined frequency of development of a stroke and a myocardial infarction, and also an indicator of cardiovascular mortality at this category of patients.

Hydrochlorothiazide. The mechanism of anti-hypertensive action of tiazid is unknown. Tiazida usually do not exert impact on the ABP normal level.

The hydrochlorothiazide is diuretic and anti-hypertensive means. It influences a reabsorption of electrolytes in distal tubules of kidneys. The hydrochlorothiazide approximately equally increases excretion of sodium and chlorine. The natriuresis can be followed by small loss of potassium ions and bicarbonate.

At intake the diuretic effect begins in 2 h, reaches a maximum on average in 4 h and proceeds from 6 to 12 h.

Pharmacokinetics. Absorption. Lozartan. At intake лозартан it is well absorbed from a GIT, is exposed to metabolism at "the first passing" through a liver, as a result of it the active carboxylated metabolite and inactive metabolites are formed. System bioavailability of a lozartan in the form of tablets makes about 33%. 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 meal of clinically significant influence on a profile of concentration of a lozartan in a blood plasma it was not revealed.

Lozartan and his active metabolite have linear pharmacokinetics at reception of a lozartan inside in doses to 200 mg.

Distribution. Lozartan. 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.

Hydrochlorothiazide. The hydrochlorothiazide gets through a placental barrier, is allocated with breast milk. Does not get through GEB.

Metabolism. Lozartan. About 14% of a dose of the lozartan entered in/in or inside turn into its active metabolite. After peroral and in/in introductions of a lozartan, marked 14C, the radioactivity of the circulating plasma first of all is connected with existence in it of a lozartan and its active metabolite.

In addition to an active metabolite as a result of a hydroxylation of a butyl side chain biologically inactive metabolites, including two main metabolites and one minor - a N-2-tetrazole-glucuronide are formed.

Removal. Lozartan. 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 with urine in not changed look, and about 6% of a dose - in the form of an active metabolite.

After intake plasma concentration of a lozartan and its active metabolite decrease polieksponentsialno with final T1/2 about 2 h and 6-9 h respectively. At a single dose of drug in a dose of 100 mg/days лозартан, its active metabolite significantly do not collect in a blood plasma.

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

Hydrochlorothiazide. The hydrochlorothiazide is not exposed to metabolism and is quickly removed by kidneys. T1/2 varies from 5.6 to 14.8 h. Not less than 61% of the dose accepted inside were removed in an invariable look during 24 h.

Pharmacokinetics in special clinical cases. Lozartan - a hydrochlorothiazide. Concentration of a lozartan and its active metabolite in a blood plasma and the speed of absorption of a hydrochlorothiazide at elderly patients with arterial hypertension significantly do not differ from these indicators at young patients with arterial hypertension.

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

At patients with slight and moderate alcoholic cirrhosis at intake of concentration of a lozartan and its active metabolite in a blood plasma were respectively 5-1.7 times higher, than at young volunteers is a male.

Concentration of a lozartan in a blood plasma at patients with KK more than 10 ml/min. did not differ from those at persons with not changed function of kidneys. AUC of a lozaratan at the patients who are on a hemodialysis was approximately twice more, than at patients with normal function of kidneys. Concentration in a blood plasma 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 cannot be removed by means of a hemodialysis.

Indications to use:

— arterial hypertension (at patients to whom the combination therapy is shown);

— decrease in risk of cardiovascular incidence and mortality at patients with arterial hypertension and a hypertrophy of a left ventricle.

Route of administration and doses:

Гизаар® it is possible to accept irrespective of meal.

At arterial hypertension appoint 1 таб. 1 times/days.

Гизаар® forte appoint to patients without adequate therapeutic response to reception 1 таб. the mg drug Гизаар® 50/12.5 within 2-4 weeks. As a rule, the anti-hypertensive effect is reached within 3 weeks after the beginning of therapy. In the absence of therapeutic effect the dose of the drug Гизаар® 50/12.5 of mg can be increased to 2 таб. 1 times/days. The maximum dose - 2 таб. drug Гизаар® 50/12.5 of mg of 1 times/days or 1 таб. drug Gizaar® forte (100/12.5 mg).

Selection of an initial dose of Gizaar for patients of advanced age is not required.

For the purpose of decrease in risk of cardiovascular incidence and mortality at patients with arterial hypertension and a hypertrophy of a left ventricle drug is appointed in a standard initial dose of a lozartan, a component of 50 mg of 1 times/days. Patients at whom it is not possible to reach target values of the ABP level against the background of reception of a lozartan of 50 mg/days need selection of therapy by a combination of a lozartan with low doses of a hydrochlorothiazide (12.5 mg), and, in case of need, it is necessary to increase a dose of a lozartan to 100 mg in combination with a hydrochlorothiazide in a dose of 12.5 mg/days, further - to increase a dose to 2 таб. Gizaara of 50 mg / 12.5 mg (only 100 mg of a lozartan and 25 mg of a hydrochlorothiazide a day once).

Гизаар® forte on 1 таб. 1 times/days are appointed to patients at whom it is not possible to reach target values of the ABP level against the background of reception 1 таб. drug Gizaar® (50/12.5 mg).

Features of use:

Use at pregnancy and feeding by a breast. Use of the drug Gizaar® is contraindicated at pregnancy. Use of the drugs exerting direct impact on a renin-angiotenzinovuyu system in II and III trimesters of pregnancy can do harm to the developing fruit and even to cause his death. Right after that as pregnancy is established Gizaar's reception should be stopped.

Adequate and strictly controlled clinical trials of safety of use of Gizaar at pregnancy were not conducted.

In pilot studies on animals it is shown that use of a lozartan can have teratogenic effect and cause death of a fruit and the newborn that is possibly connected with influence of this active agent on a renin-angiotenzinovuyu system.

At a fruit of the person perfusion of kidneys which depends on development a system renin-angiotenzinovoy begins in the II trimester; thus, the risk of disturbance of development and death of a fruit increases at Gizaar's use in II or III trimesters of pregnancy.

Tiazida get through a placental barrier and are defined in umbilical cord blood. Routine use of diuretics at pregnant healthy women is not recommended since it increases risk of development in a fruit of such adverse phenomena as embryonal jaundice and jaundice of newborns, and at mother - thrombocytopenia.

There are no data on what лозартан is allocated with breast milk. However it is known that tiazida are allocated with breast milk. Due to the risk of development of the adverse phenomena in babies in all cases the weighed decision on administration of drug during breastfeeding taking into account importance of therapy for mother has to be made.

If the decision is made that it is necessary to accept the drug Gizaar®, breastfeeding should be stopped.

Use at abnormal liver functions. Drug is contraindicated at the expressed abnormal liver functions.

Use at renal failures. Drug is contraindicated at the expressed renal failures (KK less than 30 ml/min.).

Use for children. Contraindication: age up to 18 years (efficiency and safety of use are not established).

Use for elderly patients. Selection of an initial dose of Gizaar for patients of advanced age is not required.

Special instructions. Гизаар® it is possible to appoint in combination with other anti-hypertensive means.

Lozartan. There are messages that at a number of the patients accepting drug in connection with function suppression a renin-angiotenzinovoy of system changes of function of kidneys, including a renal failure were observed; these changes had reversible character and disappeared after therapy cancellation.

Other means influencing a renin-angiotenzinovuyu system can lead to increase in content of urea and creatinine in blood at patients with a bilateral renal artery stenosis and a stenosis of an artery of the only kidney Similar effects were noted against the background of reception of a lozartan; these changes of function of kidneys were reversible and disappeared after therapy cancellation.

Hydrochlorothiazide. As well as in case of reception of any anti-hypertensive means, at a part of patients symptomatic arterial hypotension can be observed. Patients need observation for the purpose of early detection of clinical signs of disturbance of water and electrolytic balance, for example, of dehydration, to a hyponatremia, a gipokhloremichesky alkalosis, a hypomagnesiemia or a hypopotassemia which can develop against the background of intercurrent diarrhea or vomiting. At such patients control of level of electrolytes of blood serum is necessary.

Therapy of a tiazidama can lead to disturbance of tolerance to glucose. In some cases dose adjustment of hypoglycemic means can be required (including insulin).

Tiazida can reduce removal of calcium with urine and cause incidental and slight increase of level of calcium of blood serum. The expressed hypercalcemia can testify to the hidden hyperparathyreosis.

Due to the influence of tiazid on calcium metabolism, their reception can distort results of a research of function of epithelial bodies therefore before a research of functions of epithelial bodies thiazide diuretic should be cancelled.

Increase in level of cholesterol and triglycerides of blood can be also connected with therapy by thiazide diuretics.

At some patients reception of thiazide diuretics can lead to a hyperuricemia and/or development of gout. As лозартан reduces the level of uric acid, its combination with a hydrochlorothiazide reduces expressiveness of the hyperuricemia caused by diuretic.

At the patients receiving tiazida, hypersensitivity reactions can be observed even in case of lack of instructions on existence of an allergy or bronchial asthma in the anamnesis. There are messages on development of an aggravation or progressing of hard currency against the background of reception of thiazide diuretics.

In the analysis of all population of the patients included in the research LIFE (Losartan Intervention For Endpoint reduction in hypertension - Impact of a lozartan on reduction of frequency of final points at patients with arterial hypertension, n=9193), treatment lozartany was followed by reduction of risk of achievement of primary combined final point (cardiovascular death, a stroke and a myocardial infarction) by 13% (p=0.021) in comparison with atenololy. However the patients of negroid race receiving атенолол had smaller risk of succession of events of primary combined final point in comparison with the black patients accepting лозартан (p=0.03).

Use in pediatrics. Efficiency and safety of use of drug for children aged up to 18 years is not established.

Side effects:

In clinical trials with лозартаном / the hydrochlorothiazide did not observe the undesirable phenomena specific to this combined drug.

Side reactions were limited to about what it was already reported at use of a lozartan and/or hydrochlorothiazide separately. Total frequency of side reactions about which it was reported at purpose of this combination was comparable to that when using placebo. Frequency of cancellation of therapy was also comparable to that at the patients receiving placebo. In most cases side reactions were lungs, had passing character and did not demand therapy cancellation.

In controlled clinical trials dizziness was only, connected with administration of drug, undesirable reaction which frequency exceeded that at placebo reception more, than on 1 or more percent.

Lozartan with a hydrochlorothiazide, in general, is well had to combinations at patients with arterial hypertension and a hypertrophy of a left ventricle. Dizziness, weakness and fatigue were the most frequent side reactions.

In the course of post-marketing experience of use of drug it was reported about the following additional side reactions.

Allergic reactions and immunopathological reactions: anaphylactic reactions, a Quincke's disease, including hypostasis of a throat and a glottis with development of obstruction of respiratory tracts and/or a face edema, lips, a throat and/or language, at the patients accepting лозартан; some of these patients had instructions on development of a Quincke's disease in the anamnesis when using other drugs, including APF inhibitors. There are rare messages on development of vasculites (including Shenleyn-Genokh's purpuras) against the background of reception of a lozartan.

From the alimentary system: seldom - hepatitis, diarrhea (at the patients accepting лозартан).

From respiratory system: cough is possible (at the patients accepting лозартан).

Dermatological reactions: the small tortoiseshell raised sacred and photosensitivity.

From laboratory indicators: in controlled clinical trials against the background of administration of drug of Gizaar® clinically significant changes of standard laboratory indicators were noted seldom. The hyperpotassemia (potassium blood serum more than 5.5 ¼Ý¬ó/l) was observed at 0.7% of patients that did not demand drug withdrawal. Increase in activity of ALT was noted seldom and usually disappeared after therapy cancellation.

Interaction with other medicines:

Lozartan. In clinical trials of pharmacokinetics clinically significant interaction of a lozartan with a hydrochlorothiazide, digoxin, warfarin, Cimetidinum, phenobarbital, ketokonazoly and erythromycin was not revealed.

The combination of a lozartan, as well as other means blocking angiotensin II or its effects to kaliysberegayushchy diuretics (for example, Spironolactonum, Triamterenum, amiloride), kaliysoderzhashchy additives or salts of potassium can lead to increase in level of potassium in blood serum.

NPVP (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 with NPVP (including TsOG-2 inhibitors).

At some patients with renal failures receiving therapy of NPVP (including TsOG-2 inhibitors), treatment by antagonists of receptors of angiotensin II can cause further deterioration in function of kidneys. These effects are usually reversible.

Hydrochlorothiazide. At simultaneous use of thiazide diuretics with barbiturates, opioid analgetics, ethanol increase in risk of development of orthostatic arterial hypotension is possible.

At simultaneous use dose adjustment of hypoglycemic means can be required (for intake and insulin).

At use of a hydrochlorothiazide with other anti-hypertensive means the additive effect is observed.

In the presence of anion exchange pitches absorption of a hydrochlorothiazide is broken. Colestyraminum or колестипол in single doses connect a hydrochlorothiazide and reduce its absorption from a GIT by 85% and 43%, respectively.

Use of corticosteroids, AKTG leads to the expressed decrease in level of electrolytes, in particular can cause a hypopotassemia.

Decrease in expressiveness of the response to administration of pressor amines is possible (for example, Epinephrinum).

Strengthening of action of muscle relaxants of not depolarizing action type is possible (for example, tubocurarine).

Diuretics reduce renal clearance of lithium and increase risk of emergence of its toxic action; the combined use of diuretics and drugs of lithium is not recommended.

In certain cases reception of NPVS (including the selection TsOG-2 inhibitors), can reduce diuretic, natriuretic and anti-hypertensive effects of diuretics.

Contraindications:

— anury;

— the expressed renal failures (KK less than 30 ml/min.);

— the expressed abnormal liver functions;

— age up to 18 years (efficiency and safety of use are not established);

— hypersensitivity to any of drug components;

— hypersensitivity to derivatives of sulfonamides.

Tablets contain lactose therefore patients with a rare hereditary lactose intolerance, deficit of lactase or the broken absorption of a glyukozo-galactose should not accept this drug.

With care it is necessary to use drug at disturbance of water and electrolytic balance of blood, for example against the background of diarrhea or vomiting (a hyponatremia, a gipokhloremichesky alkalosis, a hypomagnesiemia, a hypopotassemia); at patients with a renal failure (KK of 30-50 ml/min.), with a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney; at a diabetes mellitus; at patients with a hypercalcemia, a hyperuricemia and/or gout; at patients with the burdened allergological anamnesis and bronchial asthma; at general diseases of connecting fabric (including hard currency); at a hypovolemia (including against the background of reception of diuretics in high doses); and also at co-administration with NPVP (including with TsOG-2 inhibitors).

Overdose:

Data on overdose of a lozartan at people are limited. The most probable symptoms of overdose are the expressed decrease in the ABP and tachycardia; bradycardia can be a consequence of parasympathetic (vagal) stimulation.

Treatment: in case of symptomatic arterial hypotension the maintenance therapy is shown. Lozartan and his active metabolite are not brought by means of a hemodialysis

The most frequent symptoms of overdose of a hydrochlorothiazide are a consequence of deficit of electrolytes (a hypopotassemia, a hypochloraemia, a hyponatremia) and dehydrations owing to an excessive diuresis. At a concomitant use of cardiac glycosides the hypopotassemia can aggravate the course of arrhythmias. It is not established in what degree the hydrochlorothiazide can be removed from an organism by means of a hemodialysis.

There are no data on specific treatment of overdose of the drug Gizaar®. Treatment is symptomatic and supporting. Administration of drug has to be stopped, and for the patient it is necessary to establish observation. If drug is accepted recently, provocation of vomiting, and also elimination of dehydration, electrolytic disturbances, a hepatic coma and decrease in the ABP is recommended by standard methods.

Storage conditions:

Drug should be stored at a temperature of 15-30 °C in the place, unavailable to children. A period of validity - 3 years.

Issue conditions:

According to the recipe

Packaging:

10 pieces - blisters (5) - packs cardboard.
14 pieces - blisters (2) - packs cardboard.