Lozartan

General characteristics. Structure:

Active ingredient: 12,5 mg, 25 mg, 50 mg or 100 mg of a lozartan of potassium.

Excipients: lactoses monohydrate − 115,000 mg, cellulose microcrystallic − 40,000 mg, croscarmellose sodium − 11,200 mg, povidone (polyvinylpirrolidone low-molecular) − 9,000 mg, silicon dioxide colloid − 2,000 mg, mg magnesium стеарат− 2,800.

Film cover: [гипромеллоза− 4,800 mg, talc − 1,600 mg, titanium dioxide −
0,826 mg, a macrogoal 4000 (polyethyleneglycol 4000) − 0,720 mg, ferrous oxide yellow (ferrous oxide) – 0,054 mg] or [the dry mix for a film covering containing a gipromelloza (60%), talc (20%), titanium dioxide (10,33%), a macrogoal 4000 (polyethyleneglycols 4000) (9%), ferrous oxide yellow (ferrous oxide) (0,67%)] − 8,000 mg.

Cardiological antihypertensive drug.

Pharmacological properties:

Pharmacodynamics. Lozartan is a 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 invitro, and invivo block all physiological effects of angiotensin II irrespective of a source or a way of synthesis. Lozartan selectively contacts AT1 receptors; 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 an angiotensin-converting enzyme (APF) which promotes degradation of bradikinin therefore the side effects indirectly connected with bradikinin (for example, a Quincke's disease) arise rather seldom.

At use of a lozartan lack of influence of negative feedback on secretion of a renin leads to increase in activity of a renin of a blood plasma. Increase in activity of a renin leads to increase in concentration angiotenzinaii in a blood plasma.

However anti-hypertensive activity and decrease in concentration of Aldosteronum of a blood plasma remain that indicates effective blockade of receptors of angiotensin II. After cancellation of a lozartan activity of a renin of a blood plasma and concentration of angiotensin II within 3 days decreased to the reference values observed prior to administration of drug.

Lozartan and his active metabolite have big affinity to a retseptoramangiotenzin of II (AT1 type).

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. The maximum anti-hypertensive effect develops in 3-6 weeks after the beginning of administration of drug.

At patients with arterial hypertension, a proteinuria (more than 2 g a day), without diabetes mellitus, drug use authentically reduces a proteinuria, excretion of albumine and immunoglobulin G (IgG).

At the women in the post-menopausal period with arterial hypertension accepting лозартан in a dose of 50 mg/days for 4 weeks influence of therapy on the renal and system level of prostaglandins was not revealed.
Lozartan does not exert impact on 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 a day does not cause clinically significant changes of concentration of triglycerides, the general cholesterol and cholesterol of lipoproteins of high density in patients. In the same doses лозартан does not exert impact on concentration of glucose in blood on an empty stomach. Lozartan caused the reduction of serumal concentration of uric acid (as a rule, less than 0,4 mg/dl) remaining during long therapy. In controlled clinical trials with participation of patients with arterial hypertension of cases of drug withdrawal in connection with increase in content of creatinine or potassium in blood serum it is noted.

Pharmacokinetics. Absorption. At intake лозартан it is well absorbed from digestive tract. System bioavailability of a lozartan makes about 33%, meal does not influence bioavailability of a lozartan. Average maximum concentration of a lozartan and its active metabolite are reached in 1 h and in 3-4 h respectively.

Distribution. Lozartan and his active metabolite contact proteins of a blood plasma (generally with albumine) more than for 99%. The volume of distribution of a lozartan makes 34 l. Lozartan practically does not get through a blood-brain barrier.

Metabolism. Lozartan is exposed to effect of "primary passing" through a liver, is metabolized with the participation of CYP2C9 isoenzyme tsitokhromar450. About 14% of a dose of the lozartan entered intravenously or inside turn into its active metabolite (EXP3174) with carboxyl group. Also biologically inactive metabolites are formed: two main (as a result of a hydroxylation of a side butyl chain) and less significant − a N-2-tetrazole-glucuronide.

Removal. 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.

At reception of a lozartan inside about 4% of a dose are removed in not changed look by kidneys and within 6% of a dose is removed by kidneys in the form of an active metabolite. Lozartan and his active metabolite have linear pharmacokinetics at intake of a lozartan in doses to 200 mg. After intake plasma concentration of a lozartan and its active metabolite decrease polieksponentsialno with final elimination half-lives of T1/2 about 2 and 6-9 h respectively.

Removal of a lozartan and its metabolites happens to bile and kidneys. After intake of a lozartan, marked 14C, about 35% of a radioactive label it is found in urine also 58% − in Calais.

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

Concentration of a lozartan in a blood plasma were twice higher at women with arterial hypertension in comparison with мужчинамис 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 of 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 patients with normal function of kidneys. At the patients needing a hemodialysis area size under a curve "concentration time" (AUC) is 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 do not leave from a blood-groove by means of a hemodialysis.

Indications to use:

- arterial hypertension;
- the decrease in risk to the associated cardiovascular incidence and a smertnosti of patients with arterial hypertension and a hypertrophy of a left ventricle which is shown decrease in cumulative frequency of cardiovascular mortality, frequency of a stroke and myocardial infarction;
- protection of kidneys at patients with a diabetes mellitus 2 types with a proteinuria – delay of progressing of a renal failure, the shown decrease in frequency of a giperkreatininemiya, frequency of development of an end-stage of the chronic renal failure (CRF) demanding carrying out a hemodialysis or transplantation of a kidney, rates of mortality, and also decrease in a proteinuria; 
- chronic heart failure at inefficiency of treatment by APF inhibitors.

Route of administration and doses:

Inside, regardless of meal. Drug can be accepted both in the form of monotherapy, and in a combination with other hypotensive drugs.

Arterial hypertension. The standard initial and maintenance dose for most of patients makes 50 mg of 1 times a day. The maximum anti-hypertensive effect is reached in 3-6 weeks from the beginning of therapy.

At some patients for achievement of bigger effect the dose can be increased to the maximum daily dose of 100 mg of 1 times a day.

At patients with a reduced volume of the circulating blood (for example, at reception of diuretics in high doses) the initial dose of drug should be lowered to 25 mg of 1 times a day (see the section "Special Instructions").

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

To patients with a liver failure (less than 9 points on a scale of Chayld-Pyyu) when holding a procedure of a hemodialysis, and also to patients 75 years are more senior it is recommended to appoint drug in lower initial dose of 25 mg of 1 times a day.

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 a day. Further it is recommended to add a hydrochlorothiazide or to increase Lozartan's dose to 100 mg (taking into account degree of a lowering of arterial pressure (ABP)) in one or in two steps.

Protection of kidneys at patients with a diabetes mellitus 2 types and a proteinuria. The standard initial dose of drug makes 50 mg of 1 times a day. Further it is recommended to increase Lozartan's dose to 100 mg of 1 times a day taking into account extent of decrease in the ABP. Lozartan can be appointed together with other hypotensive drugs (diuretics, blockers of "slow" calcium channels, alpha and beta adrenoblockers, hypotensive drugs of the central action), insulin and other hypoglycemic drugs (derivatives of sulphonylurea, a glitazonama and inhibitors of glucosidase).

Chronic heart failure. The initial dose of drug 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 of 1 times a day, 25 mg of 1 times a day, 50 mg of 1 times a day) to a usual maintenance dose of 50 mg of 1 times a day depending on individual portability.

Features of use:

Use at pregnancy and during breastfeeding. Lozartan's use at pregnancy is contraindicated.

The drugs influencing directly the renin-angiotensin-aldosteronovuyu system (RAAS) at use them in II and III trimesters of pregnancy can cause defect of development or even death of the developing fruit. Therefore when diagnosing pregnancy Lozartan's reception should be stopped immediately.

In pilot studies it is shown that drug causes defects of development and leads to death of a fruit or the newborn. It is considered that the mechanism of such influence consists in pharmacological the mediated influence on RAAS.

The renal perfusion of a fruit of the person depending on development of RAAS begins in the II trimester. The risk for a fruit increases if Lozartan accept in II or the III trimester of pregnancy. Use of antagonists of receptors angiotenzinaii in II or III trimesters of pregnancy has toxic effect on a fruit (depression of function of kidneys, development of an oligogidramnion, delay of ossification of a skull) and the newborn (a renal failure, arterial hypotension, a hyperpotassemia). If drug Lozartan was used in the II trimester of pregnancy later, performing ultrasonography of bones of a skull is recommended and to estimate function of kidneys.

It is unknown whether it is allocated лозартан with breast milk. At Lozartan's use during breastfeeding it is necessary to make the decision or on the breastfeeding termination, or on the treatment termination by drug, in view of importance it for mother.

Allergic reactions. At the patients accepting лозартан the anaphylactic reactions, a Quincke's disease with involvement of a throat and throat causing obstruction of respiratory tracts and/or a face edema, lips, a throat and/or language were seldom observed. Some of these patients in the anamnesis had instructions on the postponed Quincke's disease at reception of other medicines, including APF inhibitors. Therefore at purpose of drug patients with a Quincke's disease in the anamnesis should observe extra care.

Arterial hypotension and disturbance of water and electrolytic balance or decrease in OTsK. Patients with reduced OTsK (for example, receiving treatment by diuretics in high doses) can have a symptomatic arterial hypotension. Correction of such states needs to be carried out before purpose of a lozartan or to begin treatment with use of drug in lower dose (see the section "Route of Administration and Doses").

Disturbance of water and electrolytic balance is characteristic of patients with a renal failure with a diabetes mellitus 2 types or without diabetes mellitus therefore at purpose of drug of this category of patients it is necessary to observe extra care in connection with risk of development of a hyperpotassemia (see the section "Side effect", the subsection "From Laboratory Indicators").

During treatment it is regularly necessary to control the content of potassium in blood, especially at patients of advanced age, at renal failures. During treatment lozartany patients should not accept the drugs of potassium or substitutes of salt containing potassium without preliminary approval of the doctor.

Aortal or mitral stenoses, subaortic hypertrophic stenosis. As well as all drugs possessing vazodilatiruyushchy action antagonists of receptors to angiotensin II have to be appointed with care to patients with aortal or mitral stenoses, or a subaortic hypertrophic stenosis.

Coronary heart disease and cerebrovascular diseases. As well as all drugs possessing vazodilatiruyushchy action antagonists of receptors to angiotensin II have to be appointed with care to patients with coronary heart disease or cerebrovascular diseases as the excessive lowering of arterial pressure at this group of patients can lead to development of a myocardial infarction or stroke.

Chronic Heart Failure (CHF). As well as at use of other drugs having effect on RAAS patients with HSN and with or without renal failure, have a risk of development of heavy arterial hypotension or acute renal failure.

There is no sufficient experience of use of a lozartan for patients with heart failure and the accompanying heavy renal failure, at patients with heavy heart failure (the IV functional class on NYHA classification), and also at patients with heart failure and symptomatic life-threatening arrhythmias. Therefore лозартан patients of these groups should appoint with care.

Primary hyper aldosteronism. At patients with primary hyper aldosteronism affirmative answer on therapy by antihypertensives which work by RAAS inhibition therefore use of a lozartan is not recommended at this group of patients, as a rule, is not observed.

Abnormal liver function. Data of pharmacokinetic researches indicate that concentration of a lozartan in a blood plasma at patients with cirrhosis considerably increases therefore patients with liver diseases in the anamnesis should use drug in lower dose (see the section "Route of Administration and Doses").

Renal failure. Owing to RAAS inhibition at some predisposed patients changes of function of kidneys, including development of a renal failure were observed. These changes can take place after the treatment termination.

Some drugs making impact on RAAS can increase concentration of urea in blood and a syvorotochnogokreatinin at patients with a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney. Changes of function of kidneys can be reversible after therapy. During treatment it is regularly necessary to control concentration of creatinine in blood serum at regular intervals.

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

Influence on ability of control of vehicles and mechanisms. During treatment it is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity demanding the increased concentration of attention and speed of psychomotor reactions (dizziness, especially at the patients who were accepting diuretic medicines and passed to therapy with drug is possible).

Side effects:

In most cases лозартан it is well transferred, side effects have weak and passing character and do not demand drug withdrawal. The side effects observed at administration of drug are classified on category depending on the frequency of their emergence: very often ≥ 1/10 (10%); often> 1/100 (1%) ≤ 1/10 (10%); sometimes ≥ 1/1000 (0,1%), ≤ 1/100 (1%); seldom ≥1/10000 (0,01%), ≤ 1/1000 (0,1%); very seldom ≤ 1/10000 (0,01%), including separate events.

The side effects meeting with frequency more than 1%.

General disturbances: an adynamy, weakness, increased fatigue, pain in a thorax, peripheral hypostases.

From cardiovascular system: heart consciousness, tachycardia. 

From the alimentary system: abdominal pain, diarrhea, dyspepsia, nausea.

From a musculoskeletal system: dorsodynia, legs, muscular spasms.

From the central nervous system (CNS): dizziness, headache, sleeplessness.

From respiratory system: cough, bronchitis, rhinedema, pharyngitis, sinusitis, infections of upper parts of respiratory tracts.

The side effects meeting with frequency less than 1%.

From cardiovascular a sistemy:stenokardiya, symptomatic arterial hypotension (especially patients with intravascular dehydration have, for example, patients with heavy heart failure or at reception of diuretics in high doses), dozozavisimy orthostatic hypotension, bradycardia, arrhythmias, a myocardial infarction, a vasculitis.

From the alimentary system: anorexia, dryness of a mucous membrane of an oral cavity, dentagra, meteorism, gastritis, lock, hepatitis, abnormal liver functions, vomiting.

From integuments: a xeroderma, ecchymomas, an erythema, a photosensitization, the increased sweating, an alopecia.

Allergic reactions: urticaria, an itch, skin rash, a Quincke's disease (including the hypostasis of a throat, a voice fold causing obstruction of respiratory tracts, and/or a face edema, lips, a throat and/or language).

From system of a hemopoiesis: anemia, thrombocytopenia, eosinophilia, Shenleyna-Genokh's purpura.

From a nervous system and sense bodys: concern, a sleep disorder, drowsiness, memory disturbance, peripheral neuropathy, paresthesias, giposteziya, a tremor, an ataxy, a depression, a faint, a ring in ears, taste disturbance, a vision disorder, conjunctivitis, migraine.

From a musculoskeletal system: arthralgia, arthritis, shoulder pain and in a knee, fibromyalgia.

From an urinary system: imperative desires on an urination, infections of urinary tract, a renal failure.

From reproductive system: decrease in a libido, impotence.

Others: aggravation of a course of gout, nasal bleeding.

From laboratory indicators: often – a hyperpotassemia (content of potassium more than 5,5 mmol/l); infrequently - increase in concentration of urea, residual nitrogen, creatinine in blood serum; very seldom - moderate increase in activity of transaminases (aspartate aminotransferase, alaninaminotranspherase), a hyperbilirubinemia.

Attention! If any of the side effects specified in the instruction are aggravated or you noticed any other side effects which are not specified in the instruction, report about it to the doctor.

Interaction with other medicines:

It can be appointed with other antihypertensives. Clinically significant interaction of a lozartan with it medicines as a hydrochlorothiazide, digoxin, warfarin, Cimetidinum and phenobarbital, кетоконазол and erythromycin it is noted.

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

As well as at use of other means blocking formation of angiotensin II and its effects, simultaneous use of kaliysberegayushchy diuretics (for example, Spironolactonum, Triamterenum, amiloride, an eplerenon) or the means increasing the content of potassium (for example, heparin), the potassium additives and salts containing potassium can lead to increase in content of potassium in blood serum.

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

Non-steroidal anti-inflammatory drugs (NPVP), including the selection inhibitors of cyclooxygenase-2 (TsOG-2), can reduce effect of diuretics and other antihypertensives. Therefore the anti-hypertensive effect of antagonists of receptors to angiotenzinuiiili APF inhibitors can be weakened at simultaneous use with NPVP, including with the selection TsOG-2 inhibitors.

With a renal failure who received treatment of NPVP co-administration of antagonists of angiotensin II can cause further deterioration in function of kidneys in some patients. Usually this effect is reversible.

Other antihypertensives can increase expressiveness of anti-hypertensive action of a lozartan. Simultaneous use of drugs (for example, tricyclic antidepressants, neuroleptics, Baclofenum, amifostin) which reduce arterial pressure as the main or side effect, can increase risk of development of arterial hypotension.

Double blockade of RAAS using antagonists of receptors to angiotensin II, APF inhibitors or an aliskiren is associated with the increased risk of development of arterial hypotension, a syncope, a hyperpotassemia and renal failures (including an acute renal failure) in comparison with monotherapy. It is necessary to control carefully the arterial pressure, function of kidneys and water and electrolytic balance at the patients accepting лозартан and other medicines influencing RAAS. Lozartan is not recommended to apply along with aliskireny at patients with a diabetes mellitus. It is necessary to avoid simultaneous use of drug Lozartan and an aliskirena at patients with a renal failure (a glomerular filtration rate less than 60 ml/min.).

At simultaneous use with fluvastatiny (weak inhibitor of an isoenzyme of CYP 2C9) distinction of influence was not revealed.

If to you it is appointed лозартан, and you accept other drugs, consult about it with the doctor.

Contraindications:

- hypersensitivity to any of drug components;
- pregnancy and period of breastfeeding; 
- age up to 18 years;
- refractory hyperpotassemia; 
- lactose intolerance, deficit of lactase and syndrome of glyukozo-galaktozny malabsorption;
- dehydration;
- a heavy liver failure (there is no experience of use);
- simultaneous use with aliskireny for patients with a diabetes mellitus and/or with a renal failure (a glomerular filtration rate less than 60 ml/min.).

With care. A liver failure (less than 9 points on Chayld-Pyyu), arterial hypotension, the reduced the volume of the circulating blood (VCB), disturbance of water and electrolytic balance, a hyperpotassemia, a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney, a renal failure, states after transplantation of a kidney, an aortal and mitral stenosis, a subaortic hypertrophic stenosis, a Quincke's disease in the anamnesis, heavy heart failure (the IV functional class on NYHA classification), coronary heart disease, heart failure with life-threatening arrhythmias, cerebrovascular diseases, primary aldosteronism, heart failure with the accompanying heavy renal failure.

Overdose:

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

Treatment: artificial diuresis, symptomatic therapy. лозартан, its active metabolite are not brought out of an organism by means of a hemodialysis.

Storage conditions:

To store in the place protected from light at a temperature not over 25 ºС. To store in the place, unavailable to children. Period of validity 3 years. Not to use after a period of validity.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 12,5 mg, 25 mg, 50 mg or 100 mg. 10, 15, 20 or 30 tablets in a blister strip packaging from a film of polyvinyl chloride and aluminum foil. 30 or 60 tablets in bank from polyethylene of high density. 1, 2, 3 or 6 blister strip packagings on 10 tablets, 2, 4 or 6 blister strip packagings on 15 tablets, 1 or 3 blister strip packagings on 20 tablets, 1, 2 or 3 blister strip packagings on 30 tablets or one bank together with the instruction on a medical use in a pack from a cardboard.