Pharmacological properties

Pharmacodynamics. lozartan — the synthetic antagonist of receptors of ii angiotensin (type at1) for oral administration. ii angiotensin — a powerful vasoconstrictor — is active hormone renin-angiotenzinovoy of a system and one of the most important factors of a pathophysiology ag. ii angiotensin contacts a receptor at1 which is found in many fabrics (for example in unstriated muscles of vessels, adrenal glands, kidneys and heart), defining a number of important biological effects, including vasoconstriction and release of Aldosteronum. ii angiotensin also stimulates proliferation of smooth muscle cells.

Lozartan selectively contacts a receptor of AT ₁ . In conditions _p vitro and _p vivo lozartan and it pharmacological an active metabolite carboxyl acid (E3174) block all physiologically significant influences of angiotensin II, irrespective of a source or a way of synthesis.

Lozartan does not communicate and does not block other receptors of hormones or ion channels. Moreover, lozartan APF (kininaza of II) — the enzyme promoting bradykinin disintegration does not oppress. As a result the effects which are directly not connected with blockade of a receptor of AT ₁ , such as strengthening of influences which mediator is bradykinin are not associated with use of a lozartan.

elimination of negative reverse reaction of angiotensin II to secretion of renin leads

At use of a lozartan to increase in activity of renin in blood plasma. Such increase in activity leads to growth of angiotensin II in blood plasma. Though there is such growth, antihypertensive activity and oppression of concentration of Aldosteronum in blood plasma remain that demonstrates effective blockade of receptors of angiotensin II. After cancellation of a lozartan activity of renin in blood plasma and angiotensin II level indicators within 3 days return to reference values.

As lozartan, and its main metabolite, have higher affinity to AT ₁ to receptors, than AT ₂ . The active metabolite is 10-40 times more active, than lozartan.

Use of a lozartan allows to reduce total number of lethal cases from the cardiovascular reasons, a stroke and myocardial infarction at sick AG with a hypertrophy of a left ventricle, provides protection of kidneys at patients with diabetes of the II type with a proteinuria.

Pharmacokinetics. Absorption. After oral administration lozartan it is well soaked up. At metabolism of the first passing through a liver the active metabolite of carboxyl acid and other inactive metabolites are formed. The system bioavailability at use of tablets of a lozartan is about 33%. Average C _max a lozartan is reached during 1 h, and his active metabolite — for 3–4 h

Distribution. More than 99% of a lozartan and its active metabolite contact proteins of blood plasma, mainly albumine. The volume of distribution of a lozartan is 34 l.

Biotransformation. Nearly 14% of a lozartan turn into its active metabolite. After oral administration ¹⁴ S-mechennogo a lozartana of potassium the main radioactive materials circulating in blood plasma are lozartan and its active metabolite. The minimum transformation of a lozartan to its active metabolite was noted approximately at 1% of the studied persons.

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Krom of an active metabolite, it is formed as well an inactive metabolite.

Removal. 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. After oral administration of a lozartan of nearly 4% of a dose also about 6% of a dose are removed with urine in not changed look — with urine in the form of an active metabolite. At oral administration of a lozartan of potassium in doses up to 200 mg pharmacokinetics of a lozartan and its active metabolite linear.

After oral administration the plasma concentration of a lozartan and its active metabolite decrease poliexponentsialno, with final T _½ 2 and 6–9 h respectively. At use of a dose of 100 mg of 1 times a day lozartan, its active metabolite do not collect in blood plasma in a significant amount.

Lozartan and his metabolites are removed by

both with bile, and with urine. After oral administration ¹⁴ S-mechennogo a lozartana about 35/43% are radioactive marked medicament also 58/50% are revealed in urine — in Calais.

Pharmacokinetics at separate groups of patients

Patients of advanced age. At patients of advanced age with AG of concentration of a lozartan and its active metabolite in blood plasma significantly do not differ from those at patients of young age with AG.

Floor. Concentration of a lozartan in blood plasma were twice higher at women with AG in comparison with men. Concentration of an active metabolite at men and women did not differ.

Abnormal liver function and kidneys

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

did not differ in

Concentration of a lozartan in blood plasma at patients with clearance of creatinine of 10 ml/min. from such at persons with not changed function of kidneys. When comparing AUC at patients with normal function of kidneys of AUC of a lozartan at the patients who are on a hemodialysis was approximately twice more. Concentration of an active metabolite in blood plasma 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.

Pharmacokinetics at children. The pharmacokinetics of a lozartan was studied with participation of 50 children with AG aged from 1 month up to 16 years, after oral administration of 1 times a day in doses from 0.54 to 0.77 mg/kg of body weight (average doses). Results showed that the active metabolite of a lozartan is formed at patients of all age groups. Results indicate approximately similar indicators of pharmacokinetics of a lozartan after oral administration at newborns and children under 2 years, children of preschool, school age and at teenagers. Pharmacokinetic indicators of a metabolite differed more depending on an age group. When comparing children of preschool age and teenagers such distinctions were significant. Newborns and children under 2 years had rather high exposure.

Indication

Treatment in essential hypertensia at adults and also at children and teenagers aged from 6 years.

Treatment of a disease of kidneys at adult patients with AG and diabetes of the II type with a proteinuria of ≥0.5 g/days — as a part of antihypertensive therapy.

Treatment in chronic heart failure (at patients aged from 60 years) when use of APF inhibitors is considered impossible because of incompatibility, especially in cough or is contraindicated. Patients with heart failure whose condition was stabilized at APF inhibitor use should not be transferred to treatment lozartany. At the patient the fraction of emission of a left ventricle has to make ≤40%, a fortune has to be clinically stable, also the patient should observe the set treatment mode on chronic heart failure.

Reduction of risk of development of a stroke in adult patients with AG and a hypertrophy of a left ventricle that is confirmed to the ECG.

Use

can take the Pill irrespective of meal, washing down with 1 glass of water.

AG. The usual initial and maintenance dose makes 50 mg of 1 times a day (1 tablet of 50 mg). The maximum antihypertensive effect is reached in 3–6 weeks after an initiation of treatment. For some patients there can be useful an increase in a dose to 100 mg of 1 times a day (morning). Lozartan it is possible to accept along with other antihypertensive drugs, especially diuretics (for example a hydrochlorothiazide).

Patients with AG and diabetes of the II type with a proteinuria of ≥0.5 g/days. The usual initial dose makes 50 mg of 1 times a day. The dose can be raised to 100 mg of 1 times a day depending on the ABP indicators in 1 month after an initiation of treatment. Lozartan it is possible to apply along with other antihypertensive medicaments (for example diuretics, blockers of calcium channels, blockers α- or β-adrenoceptors and medicaments of the central action) and also with insulin and other hypoglycemic medicaments which are used widely (for example medicaments of sulphonylurea, a glitazon and glucosidase inhibitors).

Heart failure. Usually initial dose of a lozartan for patients with chronic heart failure makes 12.5 mg of 1 times a day. As a rule, the dose is titrated with a week interval (that is 12.5; 25; 50 mg/days) to a usual maintenance dose of 50 mg (1 tablet of 50 mg) of 1 times a day depending on individual shipping.

Reduction of risk of developing of a stroke at patients with AG and the hypertrophy of a left ventricle confirmed on the ECG. The usual initial dose makes 50 mg of a lozartan of 1 times a day. Depending on reaction of the patient to treatment it is necessary to add to the therapeutic scheme in a low dose and/or to raise a dose to 100 mg of 1 times a day.

Separate groups of patients

Use for patients with reduction of OCK. To patients with reduction of OCK (for example accepting diuretics in high doses) appoint an initial dose of 25 mg of 1 times a day (see. Special INSTRUCTIONS).

Use for patients with a renal failure or at the persons which are on a hemodialysis. For patients with a renal failure and the persons which are on a hemodialysis there is no need for correction of an initial dose.

Use for patients with a liver failure. For patients with an abnormal liver function in the anamnesis it is necessary to consider a question of prescribing of medicament in lower dose. There is no experience of treatment of patients with heavy abnormal liver functions therefore lozartan it is contraindicated to this group of patients.

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

Children. Data on efficiency and safety of use of a lozartan for children and teenagers aged from 6 years for treatment of AG are limited. Also there are not enough data on pharmacokinetics at children with AG aged from 1 month

For children who can swallow of tablets and who have a body weight more than 20 kg and less than 50 kg, the recommended dose makes 25 mg of 1 times a day. In exceptional cases the dose can be raised to maximum — 50 mg of 1 times a day. The dose should be korrigirovat depending on influence on the ABP level.

At patients with body weight more than 50 kg usually single dose makes 50 mg of 1 times a day. In exceptional cases the dose can be raised to maximum — 100 mg of 1 times a day. Use of medicament in the doses exceeding 1.4 mg/kg (or 100 mg) in day, at children was not studied.

Lozartan is not recommended to

for use for children under 6 years as this group of patients have not enough data on medicament use.

Drug is not recommended to be used to children from SKF of 30 ml/min. / 1.73 m ² as there are no relevant data on use.

Lozartan is also not recommended to

for use for children with an abnormal liver function.

Contraindication

Hypersensitivity to active ingredient and to any of the excipients which are a part of drug, heavy abnormal liver functions. medicament is contraindicated to the pregnant women or women planning pregnancy. contraindicated simultaneous use of medicament with the medicines containing aliskiren, to patients with diabetes and a renal failure (skf 60 ml/min. / 1.73 sq.m).

Side reaction about which it was most often reported dizziness was p>

.

Frequency of emergence of the side effects provided below is classified by

as follows: very often (≥1/10); often (≥1/100, 1/10); infrequently (≥1/1000, 1/100); seldom (≥1/10,000, 1/1000); very seldom (1/10,000), frequency is unknown (it cannot be determined by the available data).

AG

from nervous system: often — dizziness, vertigo; infrequently — drowsiness, a headache, sleep disorders.

from heart: infrequently — heart consciousness, stenocardia, tachycardia.

from vessels: infrequently — symptomatic arterial hypotension (especially patients with deficit of intravascular volume have liquids, for example patients with heavy heart failure or applying diuretics in high doses), dose-dependent orthostatic effect, rash.

from a digestive tract: infrequently — abdominal pain, dyspepsia, a constipation.

from a respiratory system: cough, cold, sinusitis, pharyngitis, upper respiratory tract infection.

Disturbance of the general state and reaction in the injection site of drug: infrequently — an asthenia, weakness, hypostases.

Laboratory indicators. Clinically significant changes of standard laboratory indicators were seldom connected with use of tablets of a lozartan. The AlAT level increased seldom and was usually normalized after medicament withdrawal. The hyperpotassemia (potassium level in blood plasma of 5.5 mmol/l) was observed at 1.5% of patients with AG.

Patients with a hypertrophy of a left ventricle of heart

from nervous system: often — dizziness.

from an organ of hearing and a labyrinth: often — vertigo.

General state and disturbances connected with a medicament route of administration: often — asthenia/weakness.

Chronic heart failure

from nervous system: infrequently — dizziness, a headache; seldom — paresthesias.

from heart: seldom — faints, fibrillation of auricles, a stroke.

from the vascular system: infrequently — arterial hypotension, including orthostatic hypotension.

from a respiratory path, bodies of a thorax and mediastinum: infrequently — an asthma.

from a digestive tract: seldom — diarrhea, nausea, vomiting.

from skin and hypodermic cellulose: infrequently — urticaria, an itching, rash.

General state and disturbances connected with a medicament route of administration: often — asthenia/weakness.

Laboratory indicators: infrequently — increase in level of urea, creatinine in blood plasma and potassium in blood plasma.

AG and diabetes of the II type, followed by a disease of kidneys

from nervous system: often — dizziness.

from the vascular system: often — arterial hypotension.

General state and disturbances connected with a medicament route of administration: often — asthenia/weakness.

Laboratory indicators: often — a hypoglycemia, a hyperpotassemia.

Following side reactions arose more often at the patients receiving lozartan than patients have groups of placebo.

from the system of blood and lymphatic system: anemia.

from heart: faints, palpitation.

from the vascular system: orthostatic hypotension.

from a digestive tract: diarrhea.

from a musculoskeletal system and connective tissue: dorsodynia.

from kidneys and urinary tract: infections of urinary tract.

General state and disturbances connected with a medicament route of administration: grippopodobny symptoms.

Laboratory indicators. In clinical trial with participation of patients with diabetes of the II type and a nephropathy 9.9% of the patients receiving tablets of a lozartan had a hyperpotassemia 5.5 mekv/l and at 3.4% of patients of group of placebo.

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Post-marketing observations

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During post-marketing observation it was reported about the following side reactions.

from blood and lymphatic system: anemia, thrombocytopenia.

from an organ of hearing and a labyrinth: a ring in ears.

from the immune system: seldom — reactions of hypersensitivity (anaphylactic reactions, a Quincke's disease, including edema of laryngeal and glottis that leads to obstruction of airways and/or a face edema, lips, drinks and/or language); some patients in the anamnesis had a Quincke's disease connected with use of other drugs, including APF inhibitors a vasculitis, including Genokh's purpura — Genokh.

from nervous system: migraine, dysgeusia.

from a respiratory path, bodies of a thorax and mediastinum: cough.

from a digestive tract: diarrhea, pancreatitis, vomiting.

General state and disturbances connected with a medicament route of administration: indisposition.

from digestive system: seldom — hepatitis, it is unknown — an abnormal liver function.

from skin and hypodermic cellulose: urticaria, itching, rash, photosensitivity, erythrosis.

from a musculoskeletal system and connective tissue: myalgia, arthralgia, rhabdomyolysis.

from a reproductive system and mammary glands: erectile dysfunction / impotence.

from kidneys and urinary tract: as a result of inhibition the system renin-angiotensin-aldosteronovoy (SRAA), it was reported about changes of function of kidneys, including a renal failure at patients of risk group; such changes of kidneys can be reversible at the therapy termination.

Mental disturbances: depression.

Laboratory indicators: hyponatremia.

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Children

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Profile of side reactions at children is similar to a profile at adult patients. Data on side reactions at children are limited.

Special instructions

Hypersensitivity

Quincke's disease. It is necessary to control often the state of health of patients with a Quincke's disease (edema of face, lips, throats and/or language) in the anamnesis.

Arterial hypotension and water and electrolytic imbalance. Symptomatic arterial hypotension, especially after use of the first dose of medicament or after increase in a dose, can arise at patients with the lowered OCK or the deficiency of sodium caused by use of powerful diuretics, dietary restriction of consumption of table salt, diarrhea or vomiting. Such states demand correction before an initiation of treatment lozartany or decrease in an initial dose of medicament (see USE). The same recommendations concern children aged from 6 years.

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

it is not recommended to p the simultaneous use of a lozartan and kaliysberegayushchy diuretics, additives of potassium and its salt containing potassium.

Double blockade of RAAS. There are evidential data that simultaneous use of APF inhibitors, blockers of receptors of angiotensin II or an aliskiren increases risk of developing of hypotension, a hyperpotassemia and suppresses function of kidneys (including development of OPN). In this regard double blockade of RAAS with the combined use of APF inhibitors, blockers of receptors of angiotensin II or aliskireny is not recommended.

In urgent cases double blockade of RAAS the patient has to be under observation of the expert and with careful monitoring of function of kidneys, electrolytic balance and the ABP.

APF Inhibitors and blockers of receptors of angiotensin II should not be applied at the same time at patients with a diabetic nephropathy.

Combination with aliskireny is contraindicated to

at patients with diabetes or a renal failure (SKF of 60 ml/min. / 1.73 m ² ).

Abnormal liver function. In view of the pharmacokinetic data indicating significant increase in concentration of a lozartan in blood plasma of patients with cirrhosis it is necessary to consider a question of a dose decline for patients with existence in the anamnesis of an abnormal liver function. There is no experience of use of medicament for patients with heavy abnormal liver functions.

Lozartan is not recommended to

for use for children with abnormal liver functions.

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

Drugs influencing RAAS can cause increase in level of urea and creatinine of blood plasma in patients with a bilateral stenosis of renal arteries or with a stenosis of an artery of the only kidney. These changes in function of kidneys can be reversible after the therapy termination. It is necessary to apply with care lozartan to patients with a bilateral stenosis of renal arteries or with a stenosis of an artery of the only kidney.

Use for children with renal failures. Drug is recommended for use for children from SKF of 30 ml/min. / 1.73 to m ² as there are no relevant data on use.

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

Simultaneous use of a lozartan and APF inhibitors worsens function of kidneys therefore such combination is not recommended.

Transplantation of a kidney. There is no experience concerning safety of use of medicament for patients by which it is only carried out transplantation of a kidney.

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

Coronary artery disease and cerebrovascular diseases. As well as at use of other antihypertensive drugs, excessive decrease in the ABP at patients with ischemic coronary artery diseases and cerebrovascular diseases can lead to development of a myocardial infarction or stroke.

Heart failure. As well as at use of other medicaments influencing RAAS the patients with heart failure with/without renal failure have a risk of developing heavy arterial hypotension and (often acute) renal failure.

does not have sufficient therapeutic experience of use of a lozartan for patients with heart failure and the accompanying heavy renal failure, patients with heavy heart failure (class IV on NYHA) and also patients with heart failure and symptomatic life-threatening cardiac arrhythmia.

Therefore lozartan should be applied with care in such group of patients. It is necessary to apply with care at the same time lozartan and blockers of β-adrenoceptors.

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

Other preventions. As it is established on APF inhibitors, lozartan and other antagonists of angiotensin are less effective at patients of negroid race, than at other patients, perhaps, because of low activity of renin at patients with AG which are representatives of negroid race.

Use during pregnancy and feeding by a breast

Pregnancy. It is known that use of antagonists of receptors of angiotensin II in II and III trimester induces a fetotoksichnost (weakening of function of kidneys, oligogidramnion, a delay of ossification of bones of a skull) and neonatal toxicity (renal failure, arterial hypotension, a hyperpotassemia).

If in the II trimester of pregnancy were applied by antagonists of receptors of angiotensin II, it is recommended to carry out ultrasonography for check of function of kidneys and a condition of bones of a skull.

Condition of newborns whose mothers antagonists of receptors of angiotensin II applied to a thicket should be controlled concerning development of arterial hypotension.

Lozartan should not be applied to the pregnant women or women planning pregnancy. If during treatment the pregnancy is confirmed by medicine, its use should be stopped and replaced immediately with other medicine allowed for use for pregnant women.

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

Children. Data on safety and efficiency of use of medicament for children aged from 6 months up to 6 years are not established. The data which are available now are provided in the section PHARMACOLOGICAL PROPERTIES, however any recommendations concerning medicament dosing to children under 6 years cannot be provided.

Ability to influence speed of response at control of vehicles or work with other mechanisms. Did not conduct researches of influence of medicament on ability to run vehicles or work with mechanisms. However it is necessary to remember a possibility of development of such side reactions as dizziness and drowsiness, especially in an initiation of treatment and at increase in a dose of drug.

Interaction

Other hypotensive medicaments can strengthen hypotensive action of a lozartan. simultaneous use with other medicaments which can induce such side reaction as arterial hypotension (tricyclic antidepressants, antipsychotic means, Baclofenum and amifostin) can increase risk of developing of arterial hypotension.

Lozartan is metabolized by

with participation of a system of P450 cytochrome (CYP) 2C9 to an active carboxyacid metabolite. Flukonazol (CYP inhibitor 2C9) reduces exposure of an active metabolite approximately by 50%. It is established that simultaneous treatment lozartany and rifampicin (inductor of enzymes of metabolism) leads to decrease by 40% of concentration of an active metabolite in blood plasma. The clinical value of this effect is unknown. There are differences in exposure at the combined use of a lozartan and fluvastatin (weak CYP inhibitor 2C9).

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

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About reversible increase in concentration of lithium in blood plasma and also about toxicity it was reported at the combined use of lithium with APF inhibitors. It was also very seldom reported about cases at use of antagonists of receptors of angiotensin II. Simultaneous use of lithium and a lozartan should be carried out with care. If use of such combination is considered necessary, recommended to control lithium level in blood plasma during the combined treatment.

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At simultaneous use of antagonists of angiotensin II and NPVP (for example selection TsOG-2 inhibitors, acetylsalicylic acid in the doses having anti-inflammatory effect, non-selective NPVP) the antihypertensive effect can be weakened. Simultaneous use of antagonists of angiotensin II or diuretics with NPVP can lead to increase in risk of a renal failure, including possible development of OPN and also to increase in level of potassium in blood plasma, especially at patients with the existing renal failure. It is necessary to appoint such combination with care, especially to patients of advanced age. Patients should carry out the corresponding dehydration, it is also necessary to consider a question of monitoring of function of kidneys after the beginning of the accompanying therapy, further — periodically.

data that double blockade of RAAS the combined use of APF inhibitors, blockers of receptors of angiotensin II or an aliskiren is associated with the bigger frequency of emergence of such undesirable phenomena as arterial hypotension, the hyperpotassemia and depression of function of kidneys (including OPN), in comparison with use of one means and also influences RAAS Exist. Double blockade has to be limited only to the cases defined individually and be followed by careful monitoring of the ABP, function of kidneys and electrolytic balance. It is not necessary to apply at the same time aliskiren with lozartany at patients with diabetes or with a renal failure (SKF of 60 ml/min.) (see CONTRAINDICATIONS).

Overdose

intoxication Symptoms. it was not reported about medicament overdose cases. arterial hypotension, tachycardia, bradycardia can be the most probable symptoms, depending on overdose volume. treatment in intoxication. treatment depends on duration of time, a past after administration of medicament and also on character and weight of symptoms.

Priority measure. After administration of medicament the use of activated carbon in the corresponding dose is shown. It is necessary to control often key indicators of activity of an organism later and to korrigirovat if necessary. Lozartan and active metabolites are not removed when carrying out a hemodialysis.

Storage conditions

At a temperature not above 30 °C.

Information for experts of health care. Instruction for medical use of the medicament LOZAP ^® , tablets of p/o of 12.5 mg. Order MZ of Ukraine of 27.07.2015 No. 468. River of page of MZ of Ukraine No. UA/3906/01/01. Instruction for medical use of the medicament LOZAP ^® , tablets of p/o of 50 mg. Order MZ of Ukraine of 27.07.2015 No. 468. River of page of MZ of Ukraine No. UA/3906/01/03. Instruction for medical use of the medicament LOZAP ^® , tablets of p/o of 100 mg. Order MZ of Ukraine of 27.07.2015 No. 468. River of page of MZ of Ukraine No. UA/3906/01/04.