Polapril

General characteristics. Structure:

Active agent: ramiprit 2,5 mg

Other ingredients: starch prezhelatinizirovanny, gelatin, the water purified titanium dioxide (E171), ferrous oxide black (E172), indigo carmine (E132), ferrous oxide yellow (E172).

Active agent: ramiprit 5 mg

Other ingredients: starch prezhelatinizirovanny, gelatin, the water purified titanium dioxide (E171), ferrous oxide black (E172), indigo carmine (E132), ferrous oxide yellow (E172).

Active agent: ramiprit 10 mg

Other ingredients: starch prezhelatinizirovanny, gelatin, the water purified titanium dioxide (E171), ferrous oxide black (E172), indigo carmine (E132), ferrous oxide yellow (E172).

Pharmacological properties:

Pharmacodynamics. Ramiprilat — an active metabolite of a ramipril, inhibits enzyme to a dipeptidilkarboksipeptidaz of I (synonyms: APF; kininaza of II). In a blood plasma and fabrics this enzyme catalyzes transformation of angiotensin I to active vasoconstrictive agent (vasoconstrictor) angiotensin II, and also disintegration of an active vazodilatator of bradikinin. Decrease in formation of angiotensin II and inhibition of disintegration of bradikinin leads to expansion of blood vessels. As angiotensin II also stimulates release of Aldosteronum, owing to action of a ramiprilat secretion of Aldosteronum decreases. Growth of activity of bradikinin, obviously, defines cardiotyre-tread and endotelioprotektorny effects. It is not established as far as it influences development of certain side effects (for example the irritating cough). APF inhibitors are effective even at patients with hypertensia who have a concentration of a renin in a blood plasma low. The average response to monotherapy by APF inhibitor at patients of negroid race (usually in population with hypertensia and low concentration of a renin) was lower in comparison with representatives of other races.
Reception of a ramipril causes noticeable decrease in resistance of peripheral arteries. Generally the renal plazmotok and a glomerular filtration rate significantly do not change.
Introduction of a ramipril to patients with hypertensia leads to decrease in the ABP in a prone position and standing, without the compensatory growth of ChSS.
At most of patients the anti-hypertensive effect after oral administration of a single dose is shown in 1–2 h. The maximum effect of a single dose is, as a rule, reached in 3–6 h and usually lasts 24 h.
The maximum anti-hypertensive effect at long use of a ramipril is noted in 3–4 weeks. At long therapy it remains for 2 years.
In response to the sharp termination of reception of a ramipril the bystry and expressed growth of the ABP is not noted.
At patients with clinical displays of heart failure which treatment was begun in 3–10 days after an acute myocardial infarction ramiprit reduced risk of mortality by 27% in comparison with placebo.
At patients with not diabetic or diabetic explicit nephropathy ramiprit reduces the speed of progressing of a renal failure and approach of a final stage of a renal failure, and thereof — the need for carrying out dialysis or transplantation of a kidney. At patients with not diabetic or diabetic initial nephropathy ramiprit reduces albumine excretion. Ramipril with the high statistical importance reduces the frequency of approach of a myocardial infarction, stroke or cardiovascular death.
Besides, ramiprit reduces the general mortality and emergence of need for carrying out revascularization, and also emergence and progressing of congestive heart failure detains. Ramipril reduces risk of development of a nephropathy in the general population and at patients with diabetes. Ramipril also significantly reduces the frequency of emergence of a microalbuminuria. Such effects were noted at patients both with hypertensia, and with a normotenziya.

Pharmacokinetics. In a liver by hydrolysis the only active metabolite of a ramipril — рамиприлат is formed. Bioavailability of a ramiprilat after oral administration of 2,5 and 5 mg of a ramipril makes about 45% in comparison with its availability later in/in introductions of the same doses.
After oral administration of 10 mg of a ramipril about 40% are removed with a stake and about 60% — with urine.
About 80-90% of metabolites in urine and bile are necessary on рамиприлат or metabolites of a ramiprilat.
During the researches on animals it is established that ramiprit gets into breast milk.
Ramipril is quickly absorbed after oral administration. Absorption of a ramipril makes not less than 56%. At reception of a ramipril together with food considerable influence on its absorption is noted.
Cmax of a ramipril is reached in 1 h after oral administration. T½ of a ramipril makes about 1 h Cmax of a ramiprilat in a blood plasma it is noted between 2 and 4 h after oral administration of a ramipril.
Decrease in concentration of a ramiprilat in plasma happens in several phases. T½ of an initial phase of distribution and elimination makes about 3 h. After that there comes the transitional phase (T½ about 15 h), and then — a final phase (T½ is about 4-5 days old).
Existence of a final phase is caused by slow dissociation of a ramiprilat from close, but saturated communication with APF.
After a single dose of a ramipril in a dose of 2,5 mg and above steady state (when plasma concentration of a ramiprilat remains to a constant) is reached already approximately in 4 days. After multiple dose effective T½ depending on a dose makes 13–17 h.
Linkng of a ramipril and ramiprilat with proteins of a blood plasma makes about 73 and 56% respectively.
At healthy faces at the age of 65–76 years the kinetics ramiprit and the ramiprilata is similar that at healthy faces of young age.
At a renal failure removal of a ramiprilat kidneys decreases, the renal clearance of a ramiprilat decreases in proportion to clearance of creatinine. It causes increase in plasma concentration of a ramiprilat which decrease much more slowly, than at persons with normal function of kidneys.
At introduction of high doses (10 mg) of drug at liver depression of function transformation of a ramipril in рамиприлат happens later, plasma concentration of a ramipril increase and removal of a ramiprilat is slowed down. As well as at healthy faces and patients with hypertensia, after oral administration of 5 mg of a ramipril of 1 times a day for 2 weeks at patients with congestive heart failure of considerable cumulation of a ramipril and ramiprilat it was not noted.

Indications to use:

AG, for the purpose of decrease in the ABP as monotherapy or in a combination with other hypotensive agents, for example diuretics and antagonists of calcium.
Congestive heart failure; also in a combination with diuretics.
Congestive heart failure for the first several days after an acute myocardial infarction.
Not diabetic or diabetic klubochkova or initial nephropathy.
Decrease in risk of a myocardial infarction, stroke or cardiovascular death at patients with the increased cardiovascular risk owing to existence of an ischemic heart disease (with or without the postponed myocardial infarction), the had stroke, a disease of peripheral vessels in the anamnesis or a diabetes mellitus with not less than 1 accessory factor of cardiovascular risk (a microalbuminuria, hypertensia, the increased general level XC, the LPVP low level XC, smoking).

Route of administration and doses:

It is applied inside.
The dosage is appointed by the doctor individually according to effect and portability of drug.
Polapril is recommended to accept every day at the same time. It is possible to apply irrespective of meal. It is necessary to swallow of capsules entirely, washing down with a large amount of water (about 0,5 glasses).
Treatment of AG
The recommended initial dose for adults — 2,5 mg of Polapril of 1 times a day.
Depending on the answer of the patient a dose it is possible to raise each 2–3 weeks by doubling.
Usual maintenance dose — 2,5–5 mg of Polapril a day.
The maximum daily dose for adults — 10 mg of Polapril.
More than 5 mg of Polapril a day can be an alternative to increase in a dose additional use, for example diuretic or the antagonist of calcium.
Treatment of congestive heart failure
The recommended initial dose for adults — 1,25 mg of Polapril of 1 times a day.
Depending on the answer of the patient a dose it is possible to raise each 1–2 weeks by doubling. If the necessary dose makes 2,5 mg of Polapril or above, it can be accepted in the form of a single dose or to divide into 2 receptions.
The maximum daily dose — 10 mg of Polapril.
Treatment after a myocardial infarction
The recommended initial dose — 5 mg of Polapril the day divided into 2 receptions on 2,5 mg; one dose is accepted in the morning, and another — in the evening. If the patient does not transfer such initial dosing, the dose of 1,25 mg 2 times a day for 2 days is recommended.
Then, depending on the answer of the patient, the dose can be raised by doubling each 1–3 days.
Further the general daily dose which at first was divided into 2 receptions can be accepted in the form of single.
The maximum daily dose — 10 mg of Polapril.
Experience of treatment of patients with heavy (degree IV on NYHA classification) heart failure right after a myocardial infarction is not enough. In case of drug use Polapril is recommended to begin therapy with the lowest effective daily dose (1,25 mg of Polapril of 1 times a day) and to carry out any its subsequent increase with extreme care.
Treatment of a diabetic or not diabetic nephropathy
The recommended initial dose for adults — 1,25 mg of Polapril of 1 times a day.
Depending on portability of drug the patient the dose can be raised to supporting which makes 5 mg of Polapril of 1 times a day.
Use of a dose higher than 5 mg of Polapril of 1 times a day during controlled clinical trials was studied insufficiently.
For the purpose of decrease in risk of a myocardial infarction, a stroke or cardiovascular death
The recommended initial dose for adults — 2,5 mg of Polapril of 1 times a day.
Depending on portability of drug the patient the dose can be raised gradually. It is recommended to double a dose in 1 week of treatment, and through 3 weeks — to raise it to a usual maintenance dose: 10 mg of Polapril of 1 times a day.
During controlled clinical trials use of a dose more than 10 mg of Polapril of 1 times a day are studied insufficiently.
Use of drug for patients with a heavy renal failure with clearance of creatinine of ≤36 ml/min. was investigated insufficiently.
Special populations of patients
Patients with an impaired renal function
If the clearance of creatinine makes 50–20 ml/min. on 1,73 sq.m of a body surface, the initial daily dose is usually applied to adults — 1,25 mg of Polapril. The maximum daily dose in this case makes 5 mg of Polapril.
Patients with noncompensated electrolytic balance of an organism, patients from the expressed AG, patients for whom hypotensive reaction can represent extra risk (for example with clinically significant stenosis of coronary or brain vessels)
Apply a reduced initial dose — 1,25 mg of Polapril a day.
Patients who accepted previously diuretics
It is desirable to stop reception of diuretics in 2–3 days or even earlier, depending on duration of effect of diuretic, prior to Polapril's reception or at least to lower a diuretic dose. The initial daily dose for adult patients who applied previously diuretics usually makes 1,25 mg of Polapril.
Patients with the broken function of a liver
Expressiveness of the response to treatment can be both increased, and reduced. Therefore use of drug for these patients should be begun under strict medical observation. The maximum daily dose for adults makes 2,5 mg of Polapril.
Elderly people
The initial dose has to be low — 1,25 mg of Polapril a day.

Features of use:

Polapril it is necessary to apply under constant observation of the doctor.
At patients who applied APF inhibitors, cases of a Quincke's disease of the person, extremities, lips, language, a glottis or throat were noted. Urgent treatment of the Quincke's disease posing a threat for life provides immediate introduction of Epinephrinum (п / to or slowly in/in), in parallel with control of an ECG and the ABP. Hospitalization, observation of the patient for at least 12-24 h — before total disappearance of symptoms is recommended.
At patients who accepted APF inhibitors, cases of a Quincke's disease of intestines were noted. There were complaints to an abdominal pain (with or without nausea or vomiting); in certain cases also the Quincke's disease of the person was noted. Symptoms of a Quincke's disease of intestines disappeared after the APF inhibitor reception termination.
There is no sufficient therapeutic experience of use of Polapril for children, patients with a heavy renal failure (clearance of creatinine <20 ml/min. on 1,73 sq.m of a body surface) and the patients who are on dialysis.
Patients with a superactivity a system renin-angiotenzinovoy
At treatment of patients with a superactivity a renin-angiotenzinovoy of system it is necessary to show extra care. Such patients have a risk of unexpected and considerable decrease in the ABP and deterioration in function of kidneys as a result of APF inhibition, especially when APF inhibitor or the accompanying diuretic are appointed for the first time or for the first time in higher dose. In an initiation of treatment or at increase in a dose it is necessary to carry out by drug careful control of the ABP until there is a threat of his sharp decrease.
Superactivity a renin-angiotenzinovoy of system can be expected, in particular:

• at patients with heavy, and especially malignant, hypertensia. In an initial phase of treatment special medical control is required;
• at patients with heavy heart failure or in case of use of other drugs, the reducing ABP. In case of heavy heart failure in an initial phase of treatment strict medical observation is necessary;
• patients with hemodynamically significant difficulty of inflow or outflow have blood from a left ventricle (for example a stenosis of an aorta or a stenosis of the mitral valve or a hypertrophic cardiomyopathy). In an initial phase of treatment strict medical observation is necessary;
• at patients with hemodynamically significant renal artery stenosis. On an initial phase of treatment strict medical observation is necessary.
There can be a need to stop the begun treatment by diuretics:

• at the patients who were previously accepting diuretics. If the termination of reception or a dose decline of diuretic is impossible, in an initial phase of treatment strict medical observation is necessary;
• at patients with threat or disturbance of electrolytic balance (as a result of insufficient consumption of liquid or salt or in connection with their loss — diarrhea, vomiting or the increased sweating, in cases when compensation of a lack of liquid and salt of an organism is insufficient).
Correction of a condition of dehydration, hypovolemia or deficit of electrolyte prior to treatment is recommended (however at patients with heart failure such corrective measures should be estimated carefully from the point of view of possible risk of a volume overload). At clinically significant states Polapril's reception can be begun or continued at simultaneous holding the relevant activities for the prevention of excessive decrease in the ABP and function of kidneys.
Patients with an abnormal liver function
Patients with an abnormal liver function can have a response to treatment by Polapril or is raised or reduced. Besides, at patients with heavy cirrhosis with hypostases and/or ascites activity the renin-angiotenzinovoy of system can be essential raised; therefore during treatment of these patients it is necessary to observe extra care.
At patients for whom considerable decrease in the ABP represents extra risk (for example patients with hemodynamically significant stenosis of coronary arteries or brain vessels) in an initial phase of treatment control is necessary strict medical;
Elderly people
Elderly people can have more expressed reaction to APF inhibitors. In an initiation of treatment assessment of function of kidneys is recommended.
It is recommended to carry out monitoring of function of kidneys, first of all in the first weeks of treatment by APF inhibitor. Especially careful control is necessary at patients with:

• heart failure;
• a renovascular disease, including a hemodynamic significant unilateral renal artery stenosis. In the last group of patients even the insignificant growth of level of creatinine in a blood plasma can testify to depression of function of kidneys;
• depression of function of kidneys;
• transplantirovanny kidney.
Monitoring of balance of electrolytes
It is recommended to exercise regular control of potassium concentration in a blood plasma. More frequent monitoring of level of potassium in plasma is necessary at patients with reduced function of kidneys.
Hematologic monitoring
It is recommended to carry out monitoring of quantity of leukocytes for the purpose of early detection of a possible leukopenia. More frequent monitoring is recommended in an initial phase of treatment of patients with an impaired renal function, with the accompanying collagenoses (a system lupus erythematosus or a scleroderma) or the patients receiving treatment by other drugs influencing gemogramma indicators.
Use during pregnancy and feeding by a breast
During pregnancy it is forbidden to accept Polapril. Thus, prior to administration of drug at women of reproductive age it is necessary to exclude possible pregnancy. During Polapril's reception women of reproductive age have to apply well-tried remedies of contraception. If the woman wants to become pregnant, it is necessary to stop use of drug and to replace it with another (except for APF inhibitors). If use of APF inhibitor cannot be cancelled, it is necessary to prevent pregnancy. In case during treatment by Polapril there occurred pregnancy, it is necessary to pass as soon as possible (under observation of the doctor) to reception of the alternative therapeutic means representing smaller risk for a fruit (excepting APF inhibitors).
Researches on animals showed that ramiprit gets into breast milk. As it is unknown whether gets ramiprit in breast milk of the person, Polapril's use during feeding by a breast contraindicated.
Children. Due to the lack of sufficient clinical experience Polapril children cannot appoint.
Ability to influence speed of response at control of vehicles or work with other mechanisms. Some side effects (for example symptoms of decrease in the ABP, in particular nausea, dizziness) can worsen attention and speed psychomotor reactions of the patient.
At emergence of side effects it is necessary to refrain from control of vehicles and work with other mechanisms.
They can arise especially in an initiation of treatment or upon transition from other drugs. After the first dose or further increase in a dose it is not recommended to manage the vehicle and to work with the mechanism for several hours.

Side effects:

Cardiovascular and nervous systems
There can seldom be easy symptoms and reactions, such as a headache, balance disturbance, tachycardia, weakness, drowsiness, dizziness or reduction in the rate of reaction.
Easy reactions and symptoms, such as peripheral hypostases, rushes of blood to the person, dizziness, a ring in ears, fatigue, nervous irritability, the suppressed mood, a tremor, concern, a vision disorder, frustration of a dream, confusion of consciousness, feeling of alarm, the passing erectile dysfunction, a heart consciousness, the increased sweating, disorders of hearing, drowsiness, disturbance of orthostatic regulation, heavy reactions, such as stenocardia, cardiac arrhythmia and a loss of consciousness are noted seldom.
Heavy hypotension arises seldom, the ischemia of a myocardium or brain, a myocardial infarction, a short-term ischemic attack, an ischemic stroke, an aggravation of disturbance of blood circulation caused by a stenosis of vessels, deterioration in clinical manifestations of a phenomenon of Reynaud or paresthesia were noted in isolated cases.

Kidneys and balance of electrolytes.
Increase in level of urea and creatinine to a blood plasma (the probability increases at additional use of diuretics) and deterioration in function of kidneys is sometimes noted, in isolated cases progressing/development of OPN can be noted.
Occasionally potassium concentration in a blood plasma can increase. In isolated cases in plasma a shelter sodium level can decrease, and also increase already existing proteinuria (in spite of the fact that APF inhibitors usually lead to decrease in a proteinuria) or to increase amount of urine (in connection with improvement of cordial activity).

Respiratory system, anaphylactic/anaphylactoid and skin reactions
Often there is a dry (unproductive) irritating cough which worsens at night and during rest (for example in a prone position) and more often arises at women and persons who do not smoke.
Seldom the nose congestion, sinusitis, bronchitis, a bronchospasm and диспноэ develops.
Infrequently the mediated Quincke's disease can be noted pharmacological (the angioedema caused by APF inhibitors arises at patients of negroid race in comparison with patients of other races more often). Heavy reactions of this kind and others not pharmacological the mediated anaphylactic/anaphylactoid reactions on ramiprit or any other components arise very seldom.
Reactions from skin or mucous membranes, such as rash, an itch or urticaria happen infrequently. In isolated cases there can be rash of makulopapuleny character, a pemphigus, an exacerbation of psoriasis, a psoriazoformny, pemfigoidny or lichenoid dieback and an enantema, a multiformny erythema, Stephens's syndrome — Johnson, a toxic epidermal necrolysis, an alopecia, онихолизис or photosensitivity.
The probability of emergence and weight of anaphylactic and anaphylactoid reactions to poison of insects at inhibition of APF increase. Believe that such effect can be noted also concerning other allergens.

GIT, liver
There can infrequently be nausea, increase in level of plasma enzymes of a liver and/or bilirubin, and also cholestatic jaundice. The glossitis, a sensation of discomfort in a stomach, pain in the field of an epigastrium, digestive disturbances, a lock, diarrhea, vomiting and increase in level of enzymes of a pancreas are occasionally noted dryness in a mouth. In isolated cases pancreatitis or injuries of a liver can develop (including an acute liver failure).

Hematologic reactions
Occasionally arises insignificant — in some cases essential — reduction of quantity of erythrocytes, leukocytes or thrombocytes and decrease in level of hemoglobin. In isolated cases the agranulocytosis, a pancytopenia and oppression of marrow are noted.
Hematologic reactions action APF inhibitors more often arise at patients with a renal failure, especially at the accompanying collagenoses (for example a system lupus erythematosus or a scleroderma), or at the patients using other drugs which can cause changes in composition of blood.
In isolated cases hemolitic anemia can develop.

Other side effects
There can infrequently be conjunctivitis, occasionally — spasms of muscles, decrease in a libido, appetite loss, disturbance of perception of a smell and taste (for example metal smack in a mouth) or partial, sometimes full, loss of feeling of taste.
In isolated cases the vasculitis, a mialgiya, an arthralgia, fever and an eosinophilia, and also growth of credits of anti-nuclear antibodies were noted.

Interaction with other medicines:

Combinations which are contraindicated
Methods of extracorporal therapy from which the contact of blood with negatively charged surfaces, such as dialysis or haemo filtering using certain membranes with high intensity of a flow (for example membranes from polyacrylonitrile) and Ldl-aferez using a sulfate dextrin results.
Combinations which are not recommended
Potassium salts, kaliysberegayushchy diuretics: it is necessary to expect increase in potassium concentration in a blood plasma. At simultaneous use of a ramipril and kaliysberegayushchy diuretics (for example Spironolactonum) or salts of potassium careful monitoring of plasma potassium concentration is necessary.
It is necessary to apply with care
Anti-hypertensive medicines (for example diuretics) and other drugs are capable to reduce the ABP (for example nitrates, tricyclic antidepressants, anesthetics): it is possible to expect strengthening of hypotensive effect of a ramipril. It is regularly recommended to control plasma concentration of sodium at the patients who are at the same time accepting diuretics.
Vasoconstrictive sympathomimetics: can weaken effect of decrease in the ABP Polapril. It is recommended to control the ABP especially carefully. Allopyrinolum, immunodepressants, GKS, procaineamide, cytostatics and other medicines which are capable to cause changes in a gemogramma: can increase probability of emergence of hematologic reactions at simultaneous use with ramiprily.
Lithium salts. Lithium excretion under the influence of APF inhibitors can decrease. It is capable to lead to increase in concentration of lithium in a blood plasma and to increase in toxicity of lithium. In this regard it is necessary to control concentration of lithium in a blood plasma.
Antidiabetic means (for example insulin and derivatives of sulphonylurea). APF inhibitors can increase effect of insulin. In some cases it is capable to lead to development of a hypoglycemia in patients who at the same time apply antidiabetic means. In an initiation of treatment especially careful monitoring of level of glucose in blood is recommended.
Meal significantly does not influence absorption of a ramipril.
It is necessary to take into account
NPVP (for example indometacin and acetylsalicylic acid). Easing of effect of decrease in the ABP under the influence of Polapril is possible. Besides, the concomitant use of APF and NPVP inhibitors can lead to growth of risk of depression of function of kidneys and increases in level of potassium in a blood plasma.
Heparin. Increase in potassium concentration in a blood plasma is possible.
Alcohol. Polapril can strengthen effect of alcohol.
Salt. The increased consumption of salt can weaken anti-hypertensive action of Polapril.
Method of specific desensitization. Owing to inhibition of APF the probability of emergence and weight of anaphylactic and anaphylactoid reactions to poison of insects increases. It is supposed that such effect can be also noted and concerning other allergens.

Contraindications:

Hypersensitivity to a ramipril, other APF inhibitors or components of drug; a Quincke's disease in the anamnesis (hereditary/idiopathic or caused by the previous therapy by APF inhibitors or antagonists of receptors of angiotensin ІІ); renal artery stenosis (bilateral or stenosis of an artery of the only kidney); hypotensive or hemodynamically unstable states; primary hyper aldosteronism; pregnancy period; feeding period breast; children's age.
It is necessary to avoid Polapril's use or other APF inhibitors in a combination with methods of extracorporal therapy which can cause engagement of blood with negatively charged surfaces as at the same time there is a risk of development of heavy anaphylactoid reaction that can sometimes lead to development of a heavy acute anaphylaxis.
Thus, at Polapril's reception it is impossible to carry out the procedure of dialysis or haemo filtering using polyacrylonitrile, sodium-2-metilsulfonatnykh membranes with high ultrafiltrational activity (for example AN 69) and the procedure of an aferez of LPNP using a sulfate dextran.

Overdose:

Intoxication symptoms. The overdose can be the cause of excessive expansion of peripheral vessels (with the expressed hypotension, shock), bradikardy, disturbance of balance of electrolytes and a renal failure.
Treatment of intoxication. Primary detoxication, for example by a gastric lavage, use of adsorbents, Natrium thiosulfuricum (whenever possible, for the first 30 min.). In case of developing of hypotension, except the measures directed to recovery of volume of liquid and salt balance it is necessary to apply agonists α1-адренергических receptors (for example Norepinephrinum, a dopamine) or angiotensin II (Angiotensinamidum) which, as a rule, is available only in separate exploratory laboratories.
There are no data on efficiency of an artificial diuresis, change of reaction of urine, haemo filtering or dialysis from the point of view of acceleration of elimination of a ramipril or a ramiprilat. Nevertheless the possibility of carrying out dialysis or haemo filtering is considered.

Storage conditions:

In the dry place protected from light at a temperature up to 25 °C.

Issue conditions:

According to the recipe

Packaging:

Капс. it is firm. 2,5 mg blister, No. 14, No. 28.
Капс. it is firm. 5 mg blister, No. 14, No. 28.
Капс. it is firm. 10 mg blister, No. 14, No. 28.