Pharmacological properties

Lozap plus is a combination of a lozartan and a hydrochlorothiazide. at patients with ag and a hypertrophy of a left ventricle lozartan, especially in a combination with a hydrochlorothiazide, reduces risk of developing cardiovascular diseases and mortality that is proved by means of assessment of the combined frequency of development of cardiovascular mortality, a stroke and a myocardial infarction.

Components of medicament render to

additive antihypertensive effect, reducing the ABP level more than each of components separately. Owing to diuretic effect the hydrochlorothiazide increases activity of renin in blood plasma, stimulates secretion of Aldosteronum, increases the level of angiotensin II and reduces potassium level in blood plasma. Reception of a lozartan blocks all physiological effects of angiotensin II and owing to oppression of effects of Aldosteronum can promote reduction of the loss of potassium connected with diuretic use.

Lozartan has the moderated and taking place uricosuric effect.

Hydrochlorothiazide in insignificant degree increases the level of uric acid in blood; the combination of a lozartan and a hydrochlorothiazide reduces expressiveness of the hyperuricemia caused by diuretic.

Pharmacodynamics. Lozartan. During reception of a lozartan the elimination of negative feedback which consists in oppression by renin secretion angiotensin II, causes increase in activity of renin in blood plasma. Increase in renin in blood plasma is followed by increase in level of angiotensin II in blood plasma. At long (6 weeks) treatment of patients with AG lozartany in a dose of 100 mg/days at the time of achievement of the C _max in blood plasma the level of angiotensin II increased by 3 times. At some patients noted higher concentration of angiotensin II, especially at short treatment (2 weeks). However antihypertensive activity and decrease in concentration of Aldosteronum in blood plasma were shown in 2 and 6 weeks of therapy that indicates effective blockade of receptors of angiotensin II. Activity of renin in blood plasma and the level of angiotensin II decreased to reference values which noted prior to administration of drug, in 3 days after cancellation of a lozartan. Influence of medicament on activity of renin and level of angiotensin II are comparable with those at reception of 50 mg of a lozartan.

As lozartan is a specific antagonist of AT ₁ - angiotensin II receptors, it does not inhibit APF-kininaza II — the enzyme inactivating bradykinin. The research in which compared effects of 20 and 100 mg of a lozartan of potassium to effects of APF inhibitor concerning reaction to angiotensin I, II and bradykinin showed what lozartan blocks effects of angiotensin I and II, without affecting effects of bradykinin. These results answer specific mechanisms of action of a lozartan. On the contrary, APF inhibitor blocks reaction to angiotensin I and increases expressiveness of the answer to bradykinin, without affecting expressiveness of the answer to angiotensin II that shows a pharmakodinamichesky divergence between lozartany and APF inhibitors.

Concentration of a lozartan and its active metabolite in blood plasma and also antihypertensive effect of a lozartan increase with increase in a dose of drug. Lozartan and his active metabolite are antagonists of receptors of angiotensin II owing to what provide antihypertensive effect.

Pharmacokinetics. Absorption. Lozartan. At oral administration lozartan well is soaked up and exposed to metabolism at the first passing through a liver owing to what the active carboxylated metabolite and inactive metabolites are formed. The system bioavailability of a lozartan in the tableted form is about 33%. Average C _max lozartan and its active metabolite is reached in 1 and 3–4 h respectively. At use of a lozartan during standard practice of food of clinically significant influence on a profile of concentration of a lozartan in blood plasma it is not revealed.

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

Hydrochlorothiazide. The hydrochlorothiazide gets through a placental barrier (but not GEB) and comes to breast milk.

Metabolism. Lozartan. About 14% of a dose of a lozartan turn into its active metabolite. After oral introduction of a lozartan, marked ¹⁴ With, the radioactivity of the circulating blood plasma first of all is connected with existence in it of a lozartan and its active metabolite.

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Krom of an active metabolite, form biologically inactive, including two main metabolites, owing to hydroxylation of a butyl side chain, and one minor — a N-2-tetrazole-glucuronide.

Removal. Lozartan. The plasma clearance of a lozartan and its active metabolite is about 600 and 50 ml/min. respectively. The renal clearance of a lozartan and its active metabolite is about 74 and 26 ml/min. respectively. At oral administration of a lozartan of nearly 4% of a dose also about 6% of a dose are removed in not changed view with urine — with urine in the form of an active metabolite. Lozartan and his active metabolite have linear pharmacokinetics at oral administration of a lozartan in a dose to 200 mg.

After reception the plasma concentration of a lozartan and its active metabolite decrease poliexponentsialno with final T _½ about 2; 6–9 h respectively. At reception of 100 mg of medicament of 1 times a day lozartan, its active metabolite is kumulirut essentially in blood plasma.

Lozartan and his metabolites are removed by

with bile and urine. After oral administration of a lozartan, marked ¹⁴ With, about 35% of radioactivity reveal in urine and 58% — in Calais.

Hydrochlorothiazide. The hydrochlorothiazide is not exposed to metabolism and is quickly allocated with kidneys. At control of level of medicament in blood plasma throughout at least 24 Parts T _½ varied in the range of 5.6-14.8 h. Not less than 61% of the accepted dose were removed in not changed look for 24 h

Indication

Ag (at patients to whom combination therapy is appointed).

Reduction of risk of development of cardiovascular complications and mortality at patients with AG and a hypertrophy of a left ventricle.

Use

Ag. a usual initial and maintenance dose — 1 tablet of 1 times a day. at patients without adequate therapeutic response to reception of 1 tablet for 2–4 weeks the dose of medicament can be raised to 2 tablets of 1 times a day.

Maximum dose — 2 tablets of 1 times a day. As a rule, the stable antihypertensive effect is reached for 3 weeks after an initiation of treatment.

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

.

Reduction of risk of development of cardiovascular complications and mortality at patients with AG and a hypertrophy of a left ventricle. Patients at whom it is not possible to reach the AD target level at reception of a lozartan of 50 mg of 1 times a day need to pick up therapy with the combined use of a lozartan with low doses of a hydrochlorothiazide (12.5 mg). If necessary it is necessary to raise a dose of a lozartan to 100 mg in combination with a hydrochlorothiazide in a dose of 12.5 mg/days, further — to raise a dose to 2 tablets (only 100 mg of a lozartan and 25 mg of a hydrochlorothiazide a day at the same time).

can appoint

Lozap Plus along with other antihypertensive drugs.

Lozap Plus can be applied irrespective of meal. Whole needs to swallow of a tablet, washing down with water.

Contraindication

• Hypersensitivity to medicament components; anury; hypersensitivity to derivatives of streptocides; profound abnormal liver functions, kidneys; period of pregnancy and feeding by a breast; children's age up to 16 years.

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Side effects

as a result of clinical trials of use of a lozartan with a hydrochlorothiazide noted the undesirable phenomena specific to this combined drug. the undesirable phenomena were limited to about what it was reported earlier at use of a lozartan and/or hydrochlorothiazide separately. total frequency of the undesirable phenomena in which it was reported about reception of this combination was compared to that at placebo use. the percent of cases of the termination of therapy is also comparable with that at the patients accepting placebo. treatment lozartany potassium and a hydrochlorothiazide was transferred well. in most cases the undesirable phenomena were lungs, had passing character and did not demand the therapy termination.

In controlled clinical trials dizziness was noted in the isolated cases connected with administration of drug. It was considered the undesirable phenomenon which frequency exceeded that at intake of placebo more than for 1%.

Lozartan of potassium with a hydrochlorothiazide is well had by

to combinations at patients with AG and a hypertrophy of a left ventricle. Dizziness, the general weakness and fatigue were the most frequent side effects connected with administration of drug.

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in the course of post-marketing use of medicament it was reported about such additional undesirable reactions:

hypersensitivity: anaphylactic reactions, a Quincke's disease, including edema of laryngeal and glottis with development of obstruction of airways and/or edema of face, lips, throats and/or language; at some of these patients development of a Quincke's disease in the anamnesis at use of other drugs, including APF inhibitors is recorded. There are separate messages about development of vasculites, including Shenleyn's disease — Genokh at reception of a lozartan;

a GIT: there are separate messages about development of hepatitis and also diarrhea in patients which accepted lozartan;

respiratory system: it was reported about cough cases against the background of treatment lozartany;

integuments: small tortoiseshell.

Other side effects which noted at use of each of medicament components and which can be potential side effects of medicament are given by

below.

Lozartan: rash, dose-dependent orthostatic effects, abdominal pain, asthenia/fatigue, thorax pain, hypostases/puffiness, heart consciousness, tachycardia, dyspepsia, nausea, dorsodynia, muscular spasms, headache, insomnia, cough, congestion of a nose, pharyngitis, sinusitis, upper respiratory tract infections, migraine, abnormal liver function, anemia, myalgia, pruritus.

Hydrochlorothiazide: anorexia, irritation of a stomach, nausea, vomiting, spasms, diarrhea, a constipation, jaundice (intra hepatic cholestatic jaundice), pancreatitis, a sialadenitis, vertigo, paresthesias, a headache, a xanthopsia, a leukopenia, an agranulocytosis, thrombocytopenia, aplastic anemia, hemolytic anemia, a purpura, photosensitivity, fever, a necrotizing angiitis (a vasculitis, a skin vasculitis), a respiratory distress (including a pneumonitis and a fluid lungs), a toxic epidermal necrolysis, a hyperglycemia, a glucosuria, a hyperuricemia, an electrolytic imbalance, including a hyponatremia and a hypopotassemia, a renal failure, interstitial nephrite, a renal failure, muscular spasms, weakness, passing loss of visual acuity.

Special instructions needs to appoint

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with care to such categories of patients:

• with disturbance of water and electrolytic balance (dehydration, a hyponatremia, a gipokhloremichesky alkalosis, a hypomagnesiemia, a hypopotassemia) which can develop in intercurrent diarrhea or vomiting;
• with a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney; diabetes, hypercalcemia, hyperuricemia and/or gout; with the burdened allergological anamnesis and OH; in general diseases of connective tissue (including a system lupus erythematosus); hypovolemia (including owing to use of diuretics in high doses); at co-administration with NPVP, including TsOG-2 inhibitors.

Lozartan. Renal failure. There are messages that at some patients who took the medicament in connection with function oppression renin-angiotenzinovoy of a system noted change of function of kidneys, including a renal failure; these changes can be reversible and disappear after the therapy termination.

Other means which influence renin-angiotenzinovuyu a system can cause increase in content of urea and creatinine in blood of patients with a bilateral renal artery stenosis and a stenosis of an artery of the only kidney.

Similar effects noted

at reception of a lozartan; these changes of function of kidneys can be reversible and disappear after the therapy termination.

Hydrochlorothiazide. Arterial hypotension and disturbance of water and electrolytic balance. As well as at intake of any antihypertensive drugs, some patients can have a symptomatic arterial hypotension. Patients have to be under control for the purpose of early detection of clinical signs of disturbance of water and electrolytic balance, for example dehydration, a hyponatremia, a gipokhloremichesky alkalosis, a hypomagnesiemia or a hypopotassemia which can develop in intercurrent diarrhea or vomiting. At such patients it is necessary to exercise control of level of electrolytes in blood plasma.

Metabolic and endocrine effects. Therapy of a tiazidama can break tolerance to glucose. In some cases dose adjustment of hypoglycemic means, including insulin can be required.

Tiazida's

can reduce removal of calcium with urine and cause incidental and slight increase of level of calcium in blood plasma. The expressed hypercalcemia can testify to the latent hyperparathyreosis. It is necessary to stop intake of thiazide diuretic before a research of functions of epithelial bodies.

Increase in level XC and TG in blood can be also connected by

with therapy by thiazide diuretics.

use of thiazide diuretics can cause a hyperuricemia and/or gout In some patients. As lozartan reduces the level of uric acid, its combination with a hydrochlorothiazide reduces expressiveness of the hyperuricemia caused by diuretic.

Other effects. At the patients applying thiazide diuretics, reactions of hypersensitivity can note even in the absence of instructions on presence of an allergy or OH in the anamnesis. There are messages about development of aggravation or progressing of a system lupus erythematosus at use of thiazide diuretics.

Use of medicament can influence the speed of psychomotor reactions.

Interaction

Lozartan. in clinical trials of pharmacokinetics clinically significant interactions of medicament with a hydrochlorothiazide, digoxin, warfarin, Cimetidinum, phenobarbital, ketokonazoly and erythromycin are not revealed. it was reported that Rifampinum and flukonazol reduce the level of an active metabolite. clinical consequences of these interactions are not studied.

Combination of a lozartan, as well as other medicines 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 plasma.

NPVP, including selection TsOG-2 inhibitors, can reduce effect of diuretics and other hypotensive medicines. Therefore the hypotensive effect of antagonists of receptors of angiotensin II can decrease NPVP, including TsOG-2 inhibitors.

At some patients with impaired renal function which accepted NPVP (including TsOG-2 inhibitors) the therapy by antagonists of receptors of angiotensin II can serves as the reason of further deterioration in function of kidneys. These effects are usually reversible.

Hydrochlorothiazide. At simultaneous use of thiazide diuretics with:

ethanol, barbiturates and narcotic analgetics — risk of developing orthostatic hypotension can increase;

hypoglycemic means (peroral and insulin) — dose adjustment of hypoglycemic medicines can be required;

other antihypertensive medicaments — additive effect;

Colestyraminum and kolestipoly — in the presence of anion exchange pitches the absorption of a hydrochlorothiazide is broken by

. Single doses of Colestyraminum and a kolestipol connect a hydrochlorothiazide and reduce its absorption in a GIT by 85 and 43% respectively;

corticosteroids, AKTG — the significant decrease in level of electrolytes, in particular a hypopotassemia;

pressor amines (for example epinephrine) — reduction of expressiveness of the response to use of pressor amines is possible, but it is not enough to exclude their use;

muscle relaxants of not depolarizing action type (for example tubocurarine) — increase in expressiveness of effect of a muscle relaxant is possible;

lithium — diuretics reduce renal clearance of lithium and increase risk of emergence of its toxic action; their combined use is not recommended;

NPVP (including TsOG-2 inhibitors) — at some patients at reception of NPVP, including selection TsOG-2 inhibitors, diuretic, natriuretic and antihypertensive effects of diuretics can decrease.

Influence of medicament on results of laboratory researches. Due to influence of tiazid on calcium metabolism their reception can distort results of a research of function of epithelial bodies.

Overdose

Is not present data on specific treatment of overdose of drug. in case of overdose the therapy needs to be stopped, and the patient has to be under observation of the doctor. if the medicament is taken recently, it is necessary to cause vomiting and to take the measures directed to elimination of dehydration, electrolytic disturbances, a hepatic coma and hypotension. symptomatic treatment and supporting.

Lozartan. Data on overdose of medicament at people are limited. The most probable manifestations of overdose are hypotension, tachycardia; bradycardia can be a consequence of parasympathetic (vagal) stimulation. In case of symptomatic arterial hypotension the maintenance therapy is shown. Lozartan and his active metabolite are not brought by a hemodialysis.

Hydrochlorothiazide. The most often noted symptoms of overdose are a consequence of deficiency of electrolytes (hypopotassemia, a hypochloraemia, a hyponatremia) and dehydrations because of excessive urination. At a concomitant use of cardiac glycosides the hypopotassemia can cause increase in severity of arrhythmia. The hydrochlorothiazide is removed by a hemodialysis, however extent of removal is not established.

Storage conditions

At a temperature not above 30 °C.