Инхибейс

General characteristics. Structure:

Active agent: tsilazaprit (anhydrous) 1 mg, 2.5 mg and 5 mg;

Excipients: lactoses monohydrate, starch corn, a gipromelloza 3 сПз, talc, the sodium stearylfumarating; tablet cover: gipromelloza 6 сПз, talc, titanium dioxide (Е 171), dye ferrous oxide yellow (Е 172) (tablets of 5 mg), dye ferrous oxide red (Е 172) (tablets of 1 mg).

Pharmacological properties:

Pharmacodynamics. Инхибейс® - specific it is long the operating angiotensin-converting enzyme inhibitor. Blocking APF, reduces formation of II angiotensin of angiotensin I and by that system renin-angiotensin-aldosteronovoy suppresses function that leads to decrease in secretion of Aldosteronum, decrease in the general peripheric vascular resistance (GPVR), arterial pressure (AP) and preloading. In the recommended doses the effect of the drug Inkhibeys® at patients with the arterial hypertension (AH) and at patients with chronic heart failure remains on an extent till 24 o'clock.
At patients with normal function of kidneys during treatment with the drug Inkhibeys® concentration of potassium ions in blood serum usually remains within norm. At the patients who are at the same time accepting kaliysberegayushchy diuretics increase in level of potassium is possible.
Tsilazapril reduces systolic and diastolic the ABP both in a standing position, and in a prone position, usually without orthostatic reactions. Drug is effective at any degree of AG, and also at renovascular hypertensia. The anti-hypertensive effect of the drug Inkhibeys® is usually shown within the first hour after intake and reaches a maximum in 3-7 hours. Reflex tachycardia does not arise though the little changes of heart rate which do not have clinical value can be observed. At some patients decrease in the ABP can decrease by the time of the following administration of drug.

At prolonged treatment anti-hypertensive effect of the drug Inkhibeys® remains. The syndrome of "cancellation" is absent.
At patients with AG and with a moderate or heavy renal failure, the glomerular filtration rate and a renal blood stream at treatment by the drug Inkhibeys®, as a rule, do not change, despite clinically significant decrease in the ABP.

As well as in case of other APF inhibitors, anti-hypertensive effect of the drug Inkhibeys® at patients of negroid race can be less expressed, than at sick other races. If Inkhibeys® is applied in a combination with a hydrochlorothiazide, distinctions in operation drug at sick different racial accessories is not observed.
Patients with chronic heart failure have an activity system renin-angiotensin-aldosteronovoy, and also a sympathetic nervous system is usually increased that leads to increase in system vasoconstriction and to strengthening of a delay of sodium and liquid in an organism. At the patients receiving diuretics and/or drugs of a foxglove, Inkhibeys®, suppressing function system renin-angiotensin-aldosteronovoy, reduces load of heart, reducing OPSS (afterload) and pressure in pulmonary capillaries (preloading). Besides, at these patients portability of exercise stresses considerably improves that increases quality of their life. Hemodynamic and clinical effects are reached quickly and remain long.

Pharmacokinetics. Tsilazapril is well soaked up from digestive tract. Meal just before administration of drug detains a little and reduces absorption that, however, has no therapeutic value. It is metabolized with formation of an active metabolite - a tsilazaprilata. After reception of a tsilazapril inside bioavailability of a tsilazaprilat makes about 60%. The maximum concentration of a tsilazapril and its active metabolite of a tsilazaprilat in a blood plasma are reached within 2 hours after reception and are directly proportional to a dose.

Tsilazaprilat is brought in not changed look through kidneys; the period of its semi-removal at intake of 1 times a day makes 9 hours. At patients with a renal failure concentration of a tsilazaprilat in a blood plasma is higher, than at patients with normal function of kidneys. At patients with an end-stage of a renal failure elimination is absent, however by means of a hemodialysis it is possible to reduce concentration of both a tsilazapril, and a tsilazaprilat.
At patients of advanced age concentration of a tsilazaprilat in a blood plasma can be 40% higher, and the clearance - is 20% lower, than at young patients.
At patients with cirrhosis increase in plasma concentration and decrease in plasma and renal clearance is observed that is more expressed in relation to a tsilazapril, than to its active metabolite to a tsilazaprilat.
At patients with chronic heart failure the clearance of a tsilazaprilat correlates with the clearance of creatinine (CC). Thus, correction of the mode of dosing at patients with chronic heart failure is carried out depending on KK (see the section "Route of Administration and Doses").

Indications to use:

Arterial hypertension, including, renovascular.
Chronic heart failure (as a part of a combination therapy).

Route of administration and doses:

Инхибейс® it is necessary to accept inside, once a day at the same time days, irrespective of meal.

Arterial hypertension: the recommended initial dose of 1-1.25 mg (1/2 tablets on 2.5 mg) once a day. The dose should be selected individually depending on ABP loudspeakers. Maintenance doses of the drug Inkhibeys® - from 2.5 and to the maximum dose in 5 mg, once a day. If at reception of a dose of 5 mg once a day the ABP decreases insufficiently, for strengthening of hypotensive effect it is at the same time possible to appoint diuretics (except kaliysberegayushchy diuretics) in a low dose.

Renovascular hypertensia: treatment it is necessary to begin with the drug Inkhibeys® with a dose 0.5 mg (1/2 tablets on 1 mg) once a day as in patients with renovascular hypertensia APF inhibitors can cause more expressed decrease in the ABP, than in patients with arterial hypertension. The maintenance dose is selected individually.
The patients with arterial hypertension receiving diuretics: the recommended initial dose for these patients makes 0.5 mg (1/2 tablets on 1 mg) once a day to reduce probability of developing of symptomatic arterial hypotension, diuretic should be cancelled in 2-3 days prior to treatment by the drug Inkhibeys®. In need of its reception it is possible to renew then.

Patients of advanced age: at arterial hypertension the initial dose of the drug Inkhibeys® makes from 0.5 (1/2 tablets on 1 mg) till 1:25 (1/2 tablets of 2.5 mg) mg a day. The maintenance dose is selected individually depending on portability of drug, reaction of the patient to treatment and its clinical state.

Chronic heart failure: treatment it is necessary to begin with the drug Inkhibeys® with a dose 0.5 mg (1/2 tablets on 1 mg) under careful medical observation once a day. Depending on portability of drug and a clinical state the dose is raised to the smallest maintenance dose in 1 mg a day. Further selection of a dose within a usual maintenance dose of 1-2.5 mg a day is made on the basis of the therapeutic response of the patient to treatment, its clinical condition and portability of drug. The maximum daily dose makes 5 mg.
The patients of advanced age with chronic heart failure accepting high doses of diuretics should observe strictly recommended initial dose of 0.5 mg.

Renal failure: the dose decline depending on KK can be required by patients with a renal failure.
The following mode of dosing is recommended:

Clearance of creatinine	Initial dose	The highest dose
more than 40 ml/min.	1 mg once a day	5 mg once a day
10-40 ml/min.	0.5 mg once a day	2.5 mg once a day
less than 10 ml/min.	0.25-0.5 mg one or two times a week, depending on ABP loudspeakers

Cirrhosis: if patients with cirrhosis need treatment by the drug Inkhibeys®, it should be begun with care with a dose 0.5 mg (1/2 tablets on 1 mg) once a day as the expressed arterial hypotension can develop.

Children up to 18 years: efficiency and safety of use of the drug Inkhibeys® is not established.

Features of use:

Seldom reception of APF inhibitors was associated with the syndrome which is beginning with cholestatic jaundice and coming to an end with a fulminantny necrosis of a liver (sometimes with a lethal outcome). The mechanism of this phenomenon is unknown. At development of jaundice or substantial increase of activity of "hepatic" enzymes it is necessary to cancel reception of APF inhibitors and to make the corresponding medical observation.

At reception of APF inhibitors the neutropenia and an agranulocytosis were seldom observed. It is necessary to control periodically number of leukocytes at patients with general diseases of connecting fabric and damage of kidneys, such as a system lupus erythematosus and a scleroderma; and also at the patients receiving immunosuppressive therapy, especially at damage of kidneys.

Symptomatic arterial hypotension against the background of reception of APF inhibitors, especially at patients with the hyponatremia and a hypovolemia caused by vomiting, diarrhea, the previous treatment by diuretics, an electrolyte-deficient diet or dialysis was sometimes observed.

In case of acute arterial hypotension of the patient it is necessary to lay with the raised legs; introduction of 0.9% of solution of sodium of the chloride or drug increasing OTsK can be required by him. After compensation of OTsK treatment by the drug Inkhibeys® can be continued. However, if symptoms do not disappear, it is necessary to reduce a dose or to cancel drug.

Arterial pressure can decrease also at the patients with a chronic circulatory unefficiency receiving APF inhibitors. However, in clinical trials in which patients with a chronic circulatory unefficiency accepted Inkhibeys® in a dose of 0.5 mg symptoms of arterial hypotension did not arise.

Use of APF inhibitors can cause arterial hypotension during surgical interventions in a combination to the means for the general anesthesia which are also possessing hypotensive action. In such cases increase in OTsK by intravenous infusion can be shown to the patient or - if this measure does not help - angiotensin II infusions. Before surgical intervention (including stomatology) it is necessary to warn the surgeon/anaesthesiologist about use of APF inhibitors.

Reduction of a dose depending on KK can be required by patients with a renal failure (see the section "Route of Administration and Doses"). At a renal failure, and also at heavy chronic heart failure it is necessary to control function of kidneys in the first weeks of therapy.

Simultaneous use of kaliysberegayushchy diuretics can cause increase in level of potassium in blood serum, especially in patients with a renal failure. Therefore if simultaneous use of these drugs is shown, in an initiation of treatment the drug Inkhibeys® their dose should be reduced, carefully controlling potassium concentration in blood serum and function of kidneys.

During therapy the Quincke's disease can arise APF inhibitors.

The hemodialysis through high-flowing membranes from a poliakrilnitritmetallilsulfat (for example, AN69), haemo filtering or LPNP-aferez can be caused in the patients accepting APF inhibitors, including tsilazaprit, an anaphylaxis or anaphylactoid reactions, including life-threatening shock. The mechanism of this phenomenon is precisely unknown. Above-mentioned procedures at these patients should be avoided.

Anaphylactic reactions can arise at the patients passing desensitization using aspen or apitoxin and receiving at the same time APF inhibitor. For this reason administration of drug of Inkhibeys® needs to be stopped prior to desensitization. Besides, in this situation Inkhibeys® cannot replace with beta adrenoblockers.

Use of APF inhibitors for patients with a diabetes mellitus can exponentiate hypoglycemic effect of hypoglycemic means for intake.

Administration of drug of Inkhibeys® is not recommended to patients with a hereditary lactose intolerance, with deficit of lactase or glyukozo-galaktozny malabsorption.

Influence on ability to driving of vehicles and work with cars and mechanisms
It is necessary to be careful during the driving of motor transport and occupation other potentially dangerous types of activity in connection with possible developing of dizziness.

Side effects:

Usually Inkhibeys® is well transferred. In most cases by-effects it is passing, easy or moderate severity also is not demanded by the treatment terminations. The most frequent side reactions – Sukhoi cough, skin rash, the expressed decrease in the ABP, dizziness, weakness, a headache, nausea, dyspepsia and other gastrointestinal disturbances (gastritis, dryness in a mouth, a lock).

From the alimentary system: as well as when using other APF inhibitors, at treatment the drug Inkhibeys® described separate cases of pancreatitis, sometimes with a lethal outcome.

From a liver and biliary tract: isolated cases of cholestatic hepatitis with or without necrosis, and also an abnormal liver function, such as increase in activity of "hepatic" transaminases, bilirubin, an alkaline phosphatase, gamma глутамилтрансферазы were observed.

Allergic reactions: as well as at treatment other APF inhibitors, described cases of a Quincke's disease, though rare. At spread of hypostasis on a face, lips, language, the voice device and/or a throat, Inkhibeys® it is necessary to cancel and to immediately appoint the corresponding treatment.

From cardiovascular system: patients have separate messages on symptomatic arterial hypotension during treatment by APF inhibitors, especially, with the hyponatremia and a hypovolemia caused by vomiting, diarrhea, the previous treatment by diuretics, an electrolyte-deficient diet or dialysis. It was reported about the cases of a myocardial infarction and stroke which are perhaps connected with considerable falling of the ABP at patients with coronary heart disease or cerebrovascular diseases. Also tachycardia, heartbeat, a stethalgia were noted.

From integuments and a hypodermic fatty tissue: skin rash (including, a multiformny erythema and a toxic epidermal necrolysis); reactions of a photosensitization, alopecia and other skin manifestations of hypersensitivity reactions.

From urinogenital system: at patients with heavy chronic heart failure, a stenosis of renal arteries or a renal failure isolated cases of an acute renal failure were observed.

From bodies of a hemopoiesis: a neutropenia and an agranulocytosis (especially at patients with a renal failure and general diseases of connecting fabric, such as system lupus erythematosus and scleroderma), thrombocytopenia and anemia.

Laboratory indicators: seldom - small, mostly reversible, increase in content of creatinine and urea in blood serum (such changes happen, generally at patients to a stenosis of renal arteries or to a renal failure, however sometimes they are observed also at patients with normal function of kidneys, especially at those patients who at the same time receive diuretics).

Reduction of concentration of hemoglobin, hematocrit and/or leukocytes was sometimes observed, however relationship of cause and effect of these changes is not established with administration of drug of Inkhibeys®.

Interaction with other medicines:

APF inhibitors should not be applied along with lithium as APF inhibitors reduce renal excretion of lithium owing to what toxicity of the last increases.

If Inkhibeys® is applied in a combination with other anti-hypertensive means, the additive action can be observed and the risk of development of arterial hypotension increases.

Use with the medicines causing oppression of a marrowy hemopoiesis increases risk of development of a neutropenia and/or agranulocytosis.

Use along with digoxin, nitrates, furosemide, thiazide diuretics, anticoagulants of a coumarinic row and blockers of H2 - histamine receptors did not lead to increase in concentration of digoxin in a blood plasma, and also other clinically significant or pharmacokinetic interactions were not noted.

The combined use of kaliysberegayushchy diuretics with the drug Inkhibeys® can lead to increase in level of potassium in blood serum, especially at patients with a renal failure (see the section "Special Instructions").

Drug Inkhibeys® use, as well as other APF inhibitors, together with non-steroidal anti-inflammatory drugs (NPVP) can weaken hypotensive effect of drug. It is not observed at the patients receiving Inkhibeys® before purpose of NPVP.

Insulin and hypoglycemic means for intake – risk of development of a hypoglycemia.

Contraindications:

Hypersensitivity to a tsilazapril or other APF inhibitors, a hereditary lactose intolerance, deficit of lactase, glyukozo-galaktozny malabsorption, a Quincke's disease in the anamnesis (including the hereditary, idiopathic, and also Quincke's disease caused by use of other APF inhibitors), a porphyria, pregnancy, the feeding period a breast, a hemodialysis through high-flowing membranes from a poliakrilnitritmetallilsulfat (for example, AN69), haemo filtering or LPNP-aferez.

With care: a chronic renal failure (a proteinuria more than 1 g a day), a heavy circulatory unefficiency, diseases of connecting fabric (including a system lupus erythematosus, a scleroderma), arterial hypotension, a mitral stenosis, an aortal stenosis, coronary heart disease, oppression of a marrowy hemopoiesis, a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney, a state after transplantation of kidneys, at the patients who are on a hemodialysis, a diabetes mellitus, gout, a hyperuricemia, a diet with salt restriction, the cirrhosis, states which are followed by decrease in the volume of the circulating blood (VCB) (including diarrhea, vomiting), a chronic obstructive pulmonary disease.

At children up to 18 years efficiency and safety of use of the drug Inkhibeys® is not established.

Pregnancy and period of feeding by a breast
Though clinical data on use of the drug Inkhibeys® for pregnant women are absent, use of other APF inhibitors for this group of patients was connected with cases of an oligoamnios, a pre-natal arrest of development of a fruit, arterial hypotension at newborns, an anury and a dysplasia of renal tubules.
Besides, reception of APF inhibitors in the first trimester of pregnancy was associated with the increased risk of development in a fruit of defects of cardiovascular system (defect of interatrial and/or interventricular partitions, a stenosis of a pulmonary artery, not fusion of Botalov Canal), the central nervous system (a nanocephalia, spina bifida) and malformations of kidneys. Therefore pregnant women have to be informed on potential risk for a fruit and should not use for treatment the drug Inkhibeys® (see the section "Contraindications").

During treatment by drug it is necessary to cancel breastfeeding (there are no data on penetration of a tsilazapril into breast milk).

Overdose:

Data on overdose of drug at patients are very small. At the healthy volunteers accepting single doses to 160 mg, undesirable action on the ABP was not noted.

Symptoms: the expressed decrease in the ABP, a hyperpotassemia, a hyponatremia and a renal failure with a metabolic acidosis.

Treatment: absorbent carbon (in the first 2 hours after overdose), a gastric lavage to give to the patient horizontal position with the raised legs, for increase in the volume of the circulating blood (VCB) - intravenous administration of 0.9% of solution of sodium of chloride or other plasma substituting solution, control of the ABP. If necessary perhaps partial removal of a tsilazaprilat by means of a hemodialysis. Also at inefficiency of symptomatic therapy, use of specific therapy by angiotensin-II is possible.

Storage conditions:

List B.
At a temperature not above 25 °C, in the place, unavailable to children.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 1 mg, 2.5 mg, 5 mg
On 7 tablets in the blister from a film of OPA/Al/PVC and aluminum foil.
On 4 blisters together with the application instruction place in a cardboard pack.
Tablets, film coated, 2.5 mg (packaging on CJSC MAKIZ-FARMA)

On 15, 30, 50 or 100 tablets in bottles of brown glass with the screwed polyethylene cover with control of the first opening. The free space in a bottle is filled with hygroscopic medical cotton. Each bottle together with the application instruction is placed in a cardboard pack.