Akkupro ®

General characteristics. Structure:

International unlicensed name: hinaprit

Dosage form: tablets, film coated

Active agents: hinaprit a hydrochloride of 5,416 mg (5 mg of a hinapril are equivalent).

Excipients: magnesium carbonate of 46,584 mg, gelatin of 5,000 mg, lactoses monohydrate of 38,000 mg, кросповидон 4,000 mg, magnesium stearate of 1,000 mg, film cover: Опадрай white OY-S-7331 *, wax of grass 0,050 mg.

* Опадрай white OY-S-7331 contains: gipromelloza of 1,200 mg, hypro rod of 0,900 mg, titanium dioxide of 0,600 mg, macrogoal-400 of 0,300 mg.

1 tablet, film coated, a dosage of 10 mg contains:

Active agents: hinaprit a hydrochloride of 10,832 mg (10 mg of a hinapril are equivalent).

Excipients: magnesium carbonate of 93,168 mg, gelatin of 10,000 mg, lactoses monohydrate of 76,000 mg, кросповидон 8,000 mg, magnesium stearate of 2,000 mg, film cover: Опадрай white OY-S-7331 *, wax of grass 0,100 mg.

* Опадрай white OY-S-7331 contains: gipromelloza of 2,400 mg, hypro rod of 1,800 mg, titanium dioxide of 1,200 mg, macrogoal-400 of 0,600 mg.

1 tablet, film coated, a dosage of 20 mg contains:

Active agents: hinaprit a hydrochloride of 21,664 mg (20 mg of a hinapril are equivalent).

Excipients: magnesium carbonate of 125,000 mg, gelatin of 10,000 mg, lactoses monohydrate of 33,336 mg, кросповидон 8,000 mg, magnesium stearate of 2,000 mg, film cover: Опадрай white OY-S-7331 *, wax of grass 0,100 mg.

* Опадрай white OY-S-7331 contains: gipromelloza of 2,400 mg, hypro rod of 1,800 mg, titanium dioxide of 1,200 mg, macrogoal-400 of 0,600 mg.

1 tablet, film coated, a dosage of 40 mg contains:

Active agents: hinaprit a hydrochloride of 43,328 mg (40 mg of a hinapril are equivalent).

Excipients: magnesium carbonate of 250,000 mg, gelatin of 20,000 mg, lactoses monohydrate of 66,672 mg, кросповидон 16,000 mg, magnesium stearate of 4,000 mg, film cover: Опадрай brown Y-5-9020G *, wax of grass 0,200 mg.

* Опадрай brown Y-5-9020G contains a gipromelloza of 4,800 mg, a hypro rod of 3,600 mg, titanium dioxide of 1,368 mg, a macrogoal-400 of 1,200 mg, dye ferrous oxide of red 1,032 mg.

Description

Dosage of 5 mg: white, oval, biconvex tablets, film coated, with risky and figure "5" on both parties.

Dosage of 10 mg: white, triangular, biconvex tablets, film coated, with risky on both parties and figure "10" on one party.

Dosage of 20 mg: white, round, biconvex tablets, film coated, with risky on both parties and figure "20" on one party.

Dosage of 40 mg: red-brown, oval, biconvex tablets, film coated, with figure "40" on one party and "PD 535" on another.

Pharmacological properties:

Pharmacodynamics. APF represents the enzyme catalyzing transformation of angiotensin I into angiotensin II which has vasoconstrictive effect and raises a tone of vessels, including due to stimulation of secretion of Aldosteronum bark of adrenal glands. Hinapril competitively inhibits APF and causes decrease in angiotonic activity and secretion of Aldosteronum. Elimination of negative influence of angiotensin II on secretion of a renin on a feedback mechanism leads to increase in activity of a renin of a blood plasma. At the same time the lowering of arterial pressure (ABP) is followed by reduction of the general peripheric vascular resistance (GPVR) and resistance of renal vessels while changes of the heart rate (HR), cordial emission, a renal blood-groove, a glomerular filtration rate and filtrational fraction are insignificant or are absent.

Hinapril increases tolerance to an exercise stress. At prolonged use promotes myocardium hypertrophy involution at patients with arterial hypertension; improves blood supply of an ischemic myocardium. Strengthens a coronary and renal blood stream. Reduces aggregation of thrombocytes. The beginning of action after reception of a single dose - in 1 h, at most - in 2-4 h, duration of action depends on the size of the accepted dose (to 24 h). Clinically expressed effect develops in several weeks after the beginning of therapy.

Pharmacokinetics. Concentration of a hinapril in a blood plasma after intake reaches a maximum during 1 h, a hinaprilat – 2 h. Meal does not influence extent of absorption, but can increase time of achievement of the maximum concentration (TCmax) (greasy food can reduce absorption). Taking into account removal of a hinapril and its metabolites kidneys extent of absorption makes about 60%. Under the influence of liver enzymes hinaprit quickly it is metabolized to a hinaprilat by eliminating of radio group (the main metabolite – dibasic acid hinaprit), which is the APF powerful inhibitor.

About 38% of the dose of a hinapril accepted inside circulate in a blood plasma in the form of a hinaprilat. The elimination half-life (T1/2) of a hinapril makes about 1 h, a hinaprilat of a blood plasma – 3 h. It is removed by kidneys – 61% (56% in the form of a hinapril and a hinaprilat) and through intestines – 37%. T1/2 of a hinapril – 1-2 h, a hinaprilata - 3 h. About 97% of a hinapril and a hinaprilat circulate in a blood plasma in the look connected with proteins. Hinapril and his metabolites do not get through a blood-brain barrier.

At patients with a renal failure of T1/2 of a hinaprilat increases in process of decrease in the clearance of creatinine (CC). Removal of a hinaprilat decreases also at elderly patients (65 years are more senior) and closely correlates with renal failures, however, in general distinctions in efficiency and safety of treatment of patients of elderly and younger age are not revealed.

At patients with alcoholic cirrhosis concentration of a hinaprilat decreases due to disturbance of a deeterifikation of a hinapril.

Indications to use:

Arterial hypertension: (in monotherapy or in a combination with thiazide diuretics and beta adrenoblockers).
Chronic heart failure: (in a combination with diuretics and/or cardiac glycosides).

Route of administration and doses:

Accept inside, without chewing, regardless of meal time, washing down with water.
Arterial hypertension
Monotherapy: the recommended initial dose of the drug Akkupro® at the patients who are not receiving diuretics makes 10 mg of 1 times a day. Depending on clinical effect the dose can be raised (doubling) 20 or 40 mg/days which is usually appointed in 1 or 2 receptions to a maintenance dose. As a rule, it is necessary to change a dose bucketed in 4 weeks. Use of the drug Аккупро® 1 of times a day allows to achieve the resistant therapeutic answer from most of patients. The maximum daily dose makes 80 mg/days.

Combination with diuretics: the recommended initial dose of the drug Akkupro® at the patients continuing reception of diuretics makes 5 mg of 1 times a day; in the subsequent it is raised (as it is stated above) until the optimum therapeutic effect is reached (see the section "Interaction with Other Medicines").

Chronic heart failure

The recommended initial dose of the drug Akkupro® makes 5 mg 1 or 2 times a day.

After administration of drug the patient has to be under medical observation for the purpose of detection of symptomatic arterial hypotension. In case of good tolerance of an initial dose of the drug Akkupro®, it can be raised to 10-40 mg/days in 2 equal receptions.

Use for patients with a renal failure

Taking into account clinical and pharmacokinetic data at patients with an impaired renal function the initial dose is recommended to be selected as follows:


KK the Recommended initial dose
(ml/min.)
(mg)

more than 60
10

30-60
5

10-30
2,5 (1/2 tablets of 5 mg)


If portability of an initial dose good, then the drug Akkupro® it is possible to apply 2 times a day. A dose of the drug Akkupro® it is possible gradually, is not more often than once a week, to increase taking into account clinical, hemodynamic effects, and also function of kidneys.

Use for elderly patients

The recommended initial dose of the drug Akkupro® at elderly patients makes 10 mg of 1 times a day; in the subsequent it is raised until the optimum therapeutic effect is reached.

Features of use:

At treatment APF inhibitors described cases of a Quincke's disease in the head and a neck including at 0,1% of the patients receiving Akkupro®. At emergence of guttural whistle or a Quincke's disease of the face, language or voice folds the drug Akkupro® should be cancelled immediately. The patient needs to appoint adequate treatment and to observe before regression of symptoms of hypostasis. Antihistamines can be applied to reduction of symptoms. The Quincke's disease with involvement of a throat can lead to a lethal outcome. If the paraglossa, voice folds or a throat threatens with development of obstruction of respiratory tracts, the adequate emergency treatment including hypodermic administration of solution of Epinephrinum (adrenaline) 1:1000 (0,3-0,5 ml) is necessary.

At treatment APF inhibitors described also cases of a Quincke's disease of intestines. At patients noted an abdominal pain (with/without nausea or vomiting); in certain cases without the previous Quincke's disease of the person and normal activity of C1 esterase. The diagnosis was established by means of a computer tomography of belly area, ultrasonography or at the time of surgical intervention. Symptoms disappeared after the termination of reception of APF inhibitors. Therefore at the patients with pain in a stomach accepting APF inhibitors at establishment of the differential diagnosis it is necessary to consider a possibility of development of a Quincke's disease of intestines.

At patients at whom in the anamnesis the Quincke's disease which is not connected with APF inhibitor was observed the risk of its development at treatment can be increased by drugs of this group.

At the patients receiving APF inhibitors during performing the desensibilizing therapy by poison of Hymenoptera anaphylactoid reactions, life-threatening can develop. By temporary phase-out of APF inhibitors of these reactions it was possible to avoid, however they arose again at accidental reception of the specified drugs.

Anaphylactoid reactions can also develop at use of APF inhibitors for patients which carried out аферез lipoproteins of low density by absorption with the help a dextran of sulfate or at the patients who are on a hemodialysis with use of high-flowing membranes such as polyacrylonitrile. Therefore similar combinations should be avoided, using either other hypotensive drugs, or alternative membranes for a hemodialysis.

Symptomatic arterial hypotension seldom occurs at treatment by the drug Akkupro® at patients with uncomplicated arterial hypertension, however it can develop as a result of therapy by APF inhibitors at patients with reduced OTsK, for example, at observance of a diet with limited consumption of table salt, carrying out a hemodialysis. In case of symptomatic arterial hypotension, it is necessary to carry out symptomatic therapy (the patient should accept horizontal position and if necessary to carry out to it intravenous infusion using 0,9% of solution of sodium of chloride). Passing arterial hypotension is not a contraindication to further use of drug, however in similar cases it is necessary to lower its dose or to estimate expediency of simultaneous therapy with diuretics.

Other reasons of decrease in OTsK, such as vomiting or diarrhea, can also lead to the expressed decrease in the ABP. In similar cases patients should see a doctor.

At the patients receiving diuretics, drug Akkupro® use can also lead to development of symptomatic arterial hypotension. Such patient reasonablly temporarily to stop reception of diuretic in 2-3 days prior to treatment by the drug Akkupro®, except patients with the malignant or difficult giving in to treatment arterial hypertension. If monotherapy by the drug Akkupro® does not give necessary therapeutic effect, then treatment by diuretics should be resumed. If it is impossible to cancel diuretic, then the drug Akkupro® is used in a low initial dose.

At patients with chronic heart failure at whom the risk of the expressed arterial hypotension is increased treatment with the drug Akkupro® should be begun with the recommended dose under careful control of the doctor; patients need to be observed within the first two weeks of treatment, and also in all cases when the drug Akkupro® dose raises.

At therapy by APF inhibitors at patients with uncomplicated arterial hypertension the agranulocytosis which met at patients with an impaired renal function and diseases of connecting fabric more often in rare instances developed. At treatment by the drug Akkupro® the agranulocytosis developed seldom. At use of this drug (as well as other APF inhibitors) at patients with diseases of connecting fabric and/or a disease of kidneys it is necessary to control number of leukocytes in blood.

At susceptible patients the system renin-angiotensin-aldosteronovoy (SRAA) can lead activity suppression to a renal failure. At patients with heavy chronic heart failure at whom function of kidneys can depend on activity of RAAS, treatment with APF inhibitors, including hinaprit, can be followed by an oliguria and/or the progressing azotemia, and in rare instances, an acute renal failure and/or a lethal outcome.

At patients with chronic heart failure or arterial hypertension with a unilateral or bilateral renal artery stenosis, at treatment by APF inhibitors in certain cases observed increase in concentration of an urea nitrogen in blood and serumal creatinine. These changes practically always were reversible and disappeared after cancellation of APF inhibitor and/or diuretic. In similar cases within the first several weeks of treatment it is necessary to control function of kidneys.

The elimination half-life of a hinaprilat increases at decrease in KK. At patients with KK less than 60 ml/min. it is necessary to use the drug Akkupro® in lower initial dose. At such patients the dose of drug should be raised taking into account therapeutic effect, at regular control of function of kidneys though in clinical trials further deterioration in function of kidneys at treatment was not noted by drug.

Аккупро® in a combination with diuretics patients should apply with care with dysfunction or the progressing liver disease as little changes of water and electrolytic balance can cause development of a hepatic coma.

APF inhibitors, including hinaprit, can increase the content of potassium in blood serum.

Аккупро® can reduce the hypopotassemia caused by thiazide diuretics at simultaneous use. Use of the drug Akkupro® in a combination therapy with kaliysberegayushchy diuretics was not studied. Considering risk of further increase in content of potassium in blood serum, the combination therapy with kaliysberegayushchy diuretics should be carried out with care, under control of content of potassium in blood serum.

Sick diabetes mellitus more careful observation and dose adjustments of hypoglycemic means for intake and insulin can be required, especially during the first month of therapy by APF inhibitor, including hinaprit.

At treatment by APF inhibitors, including hinaprit, noted development of cough. In a typical case it is unproductive, resistant and passes after the therapy termination. At differential diagnosis of cough it is necessary to consider its possible communication with APF inhibitors.

Before surgical intervention (including stomatology) it is necessary to warn the surgeon/anaesthesiologist about use of APF inhibitors.

At emergence of any symptoms of an infection (for example, acute tonsillitis, fever) the patient should see a doctor as they can be manifestation of a neutropenia immediately.


Influence on ability to manage vehicles and to use a difficult technique

At use of the drug Akkupro® it is necessary to be careful at control of vehicles or performance of other work requiring special attention, especially in an initiation of treatment.

Side effects:

The undesirable phenomena at drug Akkupro® use usually are poorly expressed and passing. The headache (7,2%), dizziness (5,5%), cough (3,9%), increased fatigue (3,5%), rhinitis (3,2%), nausea and/or vomiting (2,8%) and a mialgiya (2,2%) are most often noted. It should be noted that in a typical case cough is unproductive, resistant and passes after the treatment termination.

Drug withdrawal of Akkupro® as a result of manifestation of side effects was observed in 5,3% of cases.

The list of the undesirable reactions distributed on systems of bodies and frequency of emergence (classification of World Health Organization) is included below:

very often - more than 1/10,

often - from more than 1/100 to less than 1/10,

infrequently - from more than 1/1000 to less than 1/100,

seldom - from more than 1/10000 to less than 1/1000,

very seldom - from less than 1/10000, including separate messages.


From a nervous system

Often: headache, dizziness, sleeplessness, paresthesias, increased fatigue.

Infrequently: depression, hypererethism, drowsiness, вертиго.


From a digestive tract

Often: nausea and/or vomiting, diarrhea, dyspepsia, abdominal pains.

Infrequently: xerostomia or throats, meteorism, pancreatitis *, Quincke's disease of intestines, gastrointestinal bleeding.

Seldom: hepatitis.


The general frustration and disturbances in an injection site

Infrequently: hypostases (peripheral or generalized), indisposition, viral infections.


From circulatory and lymphatic systems

Infrequently: hemolitic anemia *, тромбоцитопения*.


From cardiovascular system

Often: the expressed decrease in the ABP.

Infrequently: stenocardia, heart consciousness, tachycardia, heart failure, myocardial infarction, stroke, increase in the ABP, cardiogenic shock, postural hypotension *, syncope *, vazodilatation symptoms.


From respiratory system, bodies of a thorax and a mediastinum

Often: cough, диспноэ, pharyngitis, stethalgia.


From skin and hypodermic fabrics

Infrequently: an alopecia *, exfoliative dermatitis *, the increased sweating, a pemphigus *, photosensitivity reactions *, a skin itch, rash.


From skeletal and muscular and connecting fabric

Often: dorsodynia.

Infrequently: arthralgia.


From kidneys and urinary tract

Infrequently: infections of uric ways, acute renal failure.

From generative organs and a mammary gland

Infrequently: decrease in a potentiality.


From an organ of sight

Infrequently: sight easing.


From immune system

Infrequently: anaphylactic реакции*.

Seldom: Quincke's disease.


Others

Seldom: eosinophilic pneumonitis.


Laboratory indicators:
very seldom noted an agranulocytosis and a neutropenia though relationship of cause and effect using the drug Akkupro® is not established yet.

Hyperpotassemia: (see. "Special instructions")


Creatinine and urea nitrogen of blood: increase (more than by 1,25 times in comparison with the upper bound of norm) concentration of creatinine in blood serum and an urea nitrogen of blood was observed respectively at 2% and 2% of the patients receiving monotherapy of Akkupro®. Probability of increase in these indicators at the patients who are at the same time receiving diuretics, above than against the background of use of one drug Akkupro®. When performing further therapy, indicators often are returned to norm.

* - less frequent undesirable phenomena or noted during the post-market researches. 

Interaction with other medicines:

The tetracycline and other drugs interacting with magnesium: simultaneous use of tetracycline with hinaprily reduces tetracycline absorption approximately by 28-37% due to availability of magnesium of a carbonate as an auxiliary component of drug. At simultaneous use it is necessary to consider a possibility of similar interaction.

Lithium: at the patients who were at the same time receiving drugs of lithium and APF inhibitors observed increase in concentration of lithium in blood serum and symptoms of intoxication lithium due to sodium removal strengthening. It is necessary to use the specified drugs at the same time with care; at treatment regular definition of concentration of lithium in blood serum is shown. The concomitant use of diuretics can strengthen risk of intoxication lithium.

Diuretics: at simultaneous use of a hinapril with diuretics strengthening of anti-hypertensive action is noted (see the section "Special Instructions").

The drugs increasing potassium concentration in blood serum: if to the patient receiving hinaprit, kaliysberegayushchy diuretics are shown (for example, Spironolactonum, Triamterenum or amiloride), the drugs of potassium and substitutes of salt containing potassium, then it is necessary to apply them carefully under control of content of potassium in blood serum.

Ethanol (the drinks containing alcohol): ethanol strengthens anti-hypertensive action of a hinapril.

Hypoglycemic means for intake and insulin: therapy by APF inhibitors sometimes is followed by development of a hypoglycemia in the patients with a diabetes mellitus receiving insulin or hypoglycemic means for intake. Hinapril strengthens effect of hypoglycemic means for intake and insulin.

Other drugs: signs of clinically significant pharmacokinetic interaction of a hinapril with propranolol, a hydrochlorothiazide, digoxin or Cimetidinum are not revealed. Use of a hinapril 2 times a day significantly did not affect anticoagulating effect of warfarin at its single use (estimated on the basis of a prothrombin time).

At simultaneous repeated use of an atorvastatin in a dose of 10 mg with hinaprily in a dose of 80 mg did not lead to considerable changes in equilibrium pharmacokinetic parameters of an atorvastatin.

Hinapril increases risk of development of a leukopenia at simultaneous use with Allopyrinolum, cytostatic means, immunodepressants, procaineamide.

Hypotensive drugs, narcotic analgetics, medicines for the general anesthesia strengthen anti-hypertensive action of a hinapril.

Estrogen, non-steroidal anti-inflammatory drugs (including the selection inhibitors of cyclooxygenase-2) weaken anti-hypertensive effect of a hinapril owing to a liquid delay.

The medicines causing oppression of function of marrow increase risk of development of a neutropenia and/or agranulocytosis.

At simultaneous use of APF inhibitors and drugs of gold (sodium ауротиомалат, intravenously) the symptom complex including a hyperemia of the person, nausea, vomiting and decrease in the ABP is described.

 

 

Contraindications:

- Hypersensitivity to any component of drug.

- A Quincke's disease in the anamnesis as a result of the previous therapy by APF inhibitors, a hereditary and/or idiopathic Quincke's disease.

- Age up to 18 years.

- Pregnancy and period of a lactation.

- Deficit of lactase, lactose intolerance and syndrome of glyukozo-galaktozny malabsorption.


With care. Symptomatic arterial hypotension at the patients who were earlier accepting diuretics and keeping to a diet with restriction of consumption of table salt; heavy heart failure at patients with high risk of arterial hypotension; the states which are followed by decrease in the volume of the circulating blood (VCB) (including vomiting and diarrhea); hyperpotassemia; oppression of a marrowy hemopoiesis; aortal stenosis; insufficiency of cerebral circulation, coronary heart disease, coronary insufficiency - sharp decrease in the ABP against the background of therapy by APF inhibitors, can worsen the course of these diseases; a bilateral stenosis of renal arteries or a stenosis of an artery of the only kidney, a state after transplantation of kidneys; renal failure; at the patients who are on a hemodialysis (KK less than 10 ml/min.) (data on use of Akkupro® for such patients are not enough); autoimmune general diseases of connecting fabric (including, system lupus erythematosus, scleroderma); abnormal liver functions (especially at simultaneous use with diuretics); at simultaneous use with kaliysberegayushchy diuretics; diabetes mellitus; extensive surgical interventions and carrying out the general anesthesia.


Use at pregnancy and during breastfeeding

Use of the drug Akkupro® is contraindicated during pregnancy, at the women planning pregnancy, and also at the women of reproductive age who are not applying reliable methods of contraception.

The women of reproductive age accepting the drug Akkupro® have to use reliable methods of contraception.

When diagnosing pregnancy the drug Akkupro® should be cancelled as soon as possible.

Use of APF inhibitors during pregnancy is followed by increase in risk of development of anomalies from cardiovascular and nervous systems of a fruit. Besides, against the background of reception of APF inhibitors during pregnancy, cases of an oligoamnios, premature births, the births of children with arterial hypotension, pathology of kidneys (including an acute renal failure), a hypoplasia of bones of a skull, contractures of extremities, craniofacial uglinesses, a hypoplasia of lungs, a delay of pre-natal development, an open arterial channel, and also cases of pre-natal death of a fruit and the death of the newborn are described. Often the oligoamnios is diagnosed after the fruit was is irreversible is damaged.

Newborns who were affected by APF inhibitors vnutriutrobno should be observed for the purpose of detection of arterial hypotension, an oliguria and a hyperpotassemia. At emergence of an oliguria it is necessary to support the ABP and perfusion of kidneys.

It is not necessary to appoint the drug Akkupro® during breastfeeding.

Overdose:

Symptoms: the expressed decrease in the ABP, dizziness, weakness, vision disorders.

Treatment: symptomatic. The patient should accept horizontal position, performing intravenous infusion using 0,9% of solution of sodium of chloride is reasonable (for the purpose of increase in OTsK).

The hemodialysis and peritoneal dialysis are not effective.

Storage conditions:

At a temperature not above 25 °C. To store in the place, unavailable to children. Period of validity-3 years. Not to use after the period of validity specified on packaging. 

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 5 mg:

10 tablets in the blister from aluminum - PAS/aluminium/PVC of a foil, 3 blisters together with the application instruction in a cardboard pack.

Tablets, film coated, 10 mg:

10 tablets in the blister from aluminum - PAS/aluminium/PVC of a foil, 3 blisters together with the application instruction in a cardboard pack.

Tablets, film coated, 20 mg:

10 tablets in the blister from aluminum - PAS/aluminium/PVC of a foil, 3 blisters together with the application instruction in a cardboard pack.

Tablets. film coated, 40 mg:

6 tablets in the blister from aluminum - PAS/aluminium/PVC of a foil, 5 blisters together with the application instruction in a cardboard pack.