Коапровель®

General characteristics. Structure:

Active agents: ирбесартан - 300,0 mg, a hydrochlorothiazide - 25,0 mg; excipients: lactoses monohydrate, cellulose microcrystallic, croscarmellose sodium, starch prezhelatizirovanny, magnesium stearate, silicon dioxide, dye ferrous oxide red (Е 172), dye ferrous oxide yellow (Е 172), опадрай ® pink *, wax of karnaubskiya.
* - Опадрай ® pink contains lactoses monohydrate, a gipromelloza, a macrogoal-3350, titanium dioxide (Е 171), dye ferrous oxide red (Е 172), dye ferrous oxide yellow (Е 172).

Description. Oval biconvex tablets, film coated from pink till grayish-pink color with an engraving in the form of heart on one party and number 2788
on another.

Pharmacological properties:

Pharmacodynamics. Коапровель® is a combination of the antagonist of receptors of angiotensin II - an irbesartan and thiazide diuretic - a hydrochlorothiazide. The combination of these ingredients has the additive hypotensive effect, reducing the arterial pressure (AP) in higher degree, than each of them separately.
At intake ирбесартан is powerful, active (that is not demanding for manifestation of the action of metabolic activation) the selection antagonist of receptors of angiotensin II (ATi type). It blocks all physiologically significant effects of angiotensin II which are implemented through receptors like ATi irrespective of a source or a way of synthesis of angiotensin II. The selection antagonistic action concerning receptors of angiotensin II (ATi) leads to increase in plasma concentration of a renin and angiotensin II and decrease in plasma concentration of Aldosteronum. At monotherapy irbesartany in the recommended doses at patients without predisposition to disturbances of electrolytic balance serumal concentration of potassium ions significantly does not change (see the sections "Special Instructions" and "Interactions with Other Medicines"). Irbesartan does not inhibit kininazu-P (angiotensin-converting enzyme) by means of which there is a formation of angiotensin II and destruction of bradikinin to inactive metabolites. Irbesartan does not influence concentration of uric acid in blood serum and on its allocation by kidneys.
The hydrochlorothiazide is thiazide diuretic. Thiazide diuretics influence renal mechanisms of a reabsorption of electrolytes, increasing excretion of ions of sodium and chlorine in approximately equivalent quantities. The hydrochlorothiazide reduces blood plasma volume, increases activity of a renin in a blood plasma and secretion of Aldosteronum with the subsequent increase in maintenance of potassium ions and bicarbonates in urine and decrease in maintenance of potassium ions in blood serum. Presumably, by means of blockade combined use of an irbesartan leads system renin-angiotensin-aldosteronovoy to prevention of loss of potassium ions in the blood serum caused by this diuretic. At reception of a hydrochlorothiazide inside the diuretic effect occurs within the first 2 hours, the diuresis reaches a maximum approximately in 4 hours and about 6-12 hours remain.
In the range of therapeutic doses the combination of a hydrochlorothiazide and an irbesartan has dozozavisimy additive hypotensive effect.
So at patients at whom indicators of the ABP did not reach the target objectives at monotherapy irbesartany in a dose of 300 mg addition to treatment of 12,5 mg of a hydrochlorothiazide (at reception of this combination once a day) led to additional decrease in the diastolic ABP at the time of residual effect of drugs (in 24 hours after their reception, that is before reception of the following doses) on 6,1 mm of mercury. (after a deduction of effect of placebo addition). The combination of 300 mg of an irbesartan and 12,5 mg of a hydrochlorothiazide caused the general decrease in the systolic/diastolic ABP by 13,6/11,5 mm of mercury. respectively (after a deduction of effect of placebo).
At patients at whom the ABP did not reach target values at monotherapy of 25 mg of a hydrochlorothiazide addition of an irbesartan gave additional decrease in the systolic/diastolic ABP on average by 11,1/7,2 mm of mercury. respectively (after an effect deduction at placebo addition).
Results of clinical studying indicate that patients with arterial hypertension at whom the ABP does not give in to control by means of a combination of 300 mg / 12,5 mg can react to increase in a dose of a hydrochlorothiazide in this combination to 25 mg (300 mg / 25 mg). At these patients the additional hypotensive effect was noted in the relation both the systolic, and diastolic ABP (decrease by 13,3 and 8,3 mm of mercury. respectively).
Hypotensive action of an irbesartan in a combination with a hydrochlorothiazide is shown after reception of the first dose of drug and remains within 1-2 weeks of reception with the subsequent its gradual strengthening and development of the maximum effect on 6-8 week. In researches on long-term reception of a combination ирбесартан / a hydrochlorothiazide the hypotensive effect remained within one year. At monotherapy cancellation irbesartany and a hydrochlorothiazide development of "ricochet" arterial hypertension was not observed, however special studying of existence or lack of a syndrome of "cancellation" for the drug Koaprovel® it was not carried out.
Efficiency of the drug Koaprovel® does not depend on age and a floor.
Patients of negroid race react to monotherapy irbesartany worse (as well as to all other medicines influencing renin-angiotensin-aldosteronovuyu system). At purpose of an irbesartan along with low doses of a hydrochlorothiazide (for example, 12,5 mg a day) response hypotensive reaction at patients of negroid race is close to that at representatives of other races.
Influence of a combination of an irbesartan and hydrochlorothiazide on indicators of incidence and mortality was not studied. Epidemiological researches showed that prolonged treatment by a hydrochlorothiazide reduces risk of cardiovascular mortality and incidence.

Pharmacokinetics. ирбесартан, a hydrochlorothiazide do not change pharmacokinetics of each other. As ирбесартан, and a hydrochlorothiazide at intake are the active drugs which are not needing biotransformation for manifestation of the activity.
After drug Koaprovel® intake absolute bioavailability of an irbesartan makes 60-80%, and a hydrochlorothiazide - 50-80%. Food does not influence bioavailability of drug. After intake the maximum concentration in blood serum are reached in 1,5-2 hours for an irbesartan and in 1-2,5 hours for a hydrochlorothiazide.
Communication of an irbesartan with proteins of a blood plasma makes about 96%, a hydrochlorothiazide - 68%. The volume of distribution of an irbesartan makes 53-93 l, a hydrochlorothiazide - 0,83-1,14 l/kg.
Linear dependence on a dose in the range of doses from 10 to 600 mg is characteristic of pharmacokinetic indicators of an irbesartan. After intake of the doses exceeding 600 mg weaker was observed, than dozoproportsionalny increase in pharmacokinetic indicators. The general and renal clearance is made by 157-176 and 3,0-3,5 ml/min., respectively. An elimination half-life of an irbesartan - 11-15 hours. At intake, single in days, equilibrium serumal concentration is established within 3 days after the beginning of therapy. At repeated receptions limited accumulation of an irbesartan in a blood plasma (less than 20%) is observed once a day. At women a little higher concentration of an irbesartan in blood serum decided on the raised ABP in comparison with men. However the distinctions connected with a floor in an elimination half-life and accumulation of an irbesartan were not revealed. Therefore female patients have no need for dose adjustment of an irbesartan. AUC values (the areas under a pharmacokinetic curve "concentration time") and Stakh (the maximum concentration) were also slightly higher at elderly patients (aged> than 65 years) in comparison with patients younger 65 years without essential distinctions in an elimination half-life of an irbesartan. Therefore the dose decline is not required from elderly patients. Average values of an elimination half-life of a hydrochlorothiazide are in range from 5 to 15 watch.
After intake of a 14C-irbesartan of 80-85% of radioactivity in a system blood-groove it is necessary on not changed ирбесартан. Irbesartan is metabolized in a liver by oxidation and conjugation with glucuronic acid. The main metabolite circulating in a system blood-groove is the irbesartana a glucuronide (about 6%). The researches in vitro demonstrate to what ирбесартан is exposed to oxidation mainly by means of P450 cytochrome isoenzyme: SUR2S9. Irbesartan and his metabolites are removed with bile and kidneys. After intake or intravenous administration of a 14C-irbesartan of 20% of radioactivity it is found in urine and traces - in Calais. Less than 2% of not changed irbesartan are allocated with kidneys. The hydrochlorothiazide is not metabolized, but quickly removed through kidneys. At least, 61% of the dose accepted inside are removed in not changed look within 24 hours. The hydrochlorothiazide gets through a placental barrier and is allocated in breast milk, but does not pass through a blood-brain barrier.
Renal failure: at patients with a renal failure or being on a hemodialysis pharmacokinetic parameters of an irbesartan change slightly. Irbesartan does not leave from an organism when carrying out a hemodialysis. It was reported that at patients with the clearance of creatinine (CC) less than 20 ml/min. were observed increase in its elimination half-life till 21 o'clock. Liver failure: at patients with easy (a functional class A or 5-6 points on classification of Chayld-Pyyu) and moderately expressed (a functional class B or 7-9 points on classification of Chayld-Pyyu) a liver failure pharmacokinetic parameters of an irbesartan change slightly. At patients with a severe form of a liver failure (a functional class C or more than 9 points on classification of Chayld-Pyyu) pharmacokinetic researches were not conducted.

Indications to use:

Arterial hypertension (treatment of patients to which the combination therapy is shown).

Route of administration and doses:

Коапровель® is accepted inside, once a day irrespective of meal.
It is recommended to carry out selection of doses of components of this combination, using monocomponent drugs of an irbesartan and hydrochlorothiazide, and only after that to replace with their corresponding fixed combination of an irbesartan and a hydrochlorothiazide.
It is possible to appoint Коапровель® 300/25 mg the patient at whom it is not possible to reach the target objectives of the ABP at administration of drug of Коапровель® 300/12,5 mg. È«á»Ó«óѽý® 300/25 mg are the maximum daily dose therefore simultaneous use of the doses exceeding 300 mg of an irbesartan and 25 mg of a hydrochlorothiazide once a day is not recommended.
In case of impossibility of achievement of the target objective of the ABP at use of the drug Коапровель® 300/25 of mg, other antihypertensives (beta adrenoblockers, blockers of "slow" calcium channels of the prolonged action) can be added to it.
Renal failure
As the hydrochlorothiazide is a part of drug, Koaprovel® is not recommended to patients with the expressed renal failures (KK less than 30 ml/min.), in this case use of "loopback" diuretics is more preferable. At a renal failure with KK more or the equal 30 ml/min. of correction of doses of the drug Koaprovel® are not required.
Liver failure
Коапровель® it is contraindicated to patients with a heavy liver failure. At a liver failure easy and moderate severity of dose adjustment of the drug Koaprovel® is not required.
Patients of advanced age
Correction a drug Koaprovel® dose is not required from patients of advanced age. SIDE EFFECT
The side effects provided below are given in a soovetstviye with the following gradation of frequency of their emergence: very often (> 1/10), it is frequent (> 1/100, <1/10); sometimes (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000) (including separate messages).
Combination ирбесартан / hydrochlorothiazide
In placebo - controlled researches at patients with arterial hypertension, the general frequency of by-effects in groups ирбесартана / a hydrochlorothiazide and placebo did not differ. The termination of therapy because of any clinical or laboratory by-effect was less frequent at the patients accepting combinations of an irbesartan and a hydrochlorothiazide than at the accepting placebos. Frequency of by-effects did not depend on a sex, age, race or doses (within the recommended range of doses). In placebo - controlled researches in which various doses (from 37,5mg/6,25mg to 300mg/25mg ирбесартана / a hydrochlorothiazide) received 898 patients with arterial hypertension, the listed below side effects were noted.
From the central nervous system Often: dizziness. Sometimes: orthostatic dizziness. From a cardiovascular sitema
Sometimes: excessive decrease in the ABP; peripheral hypostases, in particular hypostases of the lower extremities; to a syncope; tachycardia; "inflows" of blood to face skin.
From digestive tract
Often: nausea/vomiting.
Sometimes: diarrhea.
From kidneys and urinary system
Often: disturbances of an urination.
From reproductive system and mammary glands
Sometimes: disturbance of a libido, sexual dysfunction.
General disturbances
Often: feeling of fatigue.
From laboratory indicators:
At the patients receiving treatment ирбесартаном / a hydrochlorothiazide noted changes of laboratory indicators which seldom reached a threshold of the clinical importance.
Often: increase in an urea nitrogen, creatinine and a kreatinfosfokinaza in a blood plasma.
Sometimes: decrease in serumal concentration of potassium ions and sodium.
Besides, from the moment of emergence of a combination of an irbesartan and a hydrochlorothiazide in the market the listed below side effects were also noted.
From immune system
Seldom: allergic reactions, such as Quincke's disease, skin rash, small tortoiseshell.
From a metabolism
Very seldom: hyperpotassemia.
From the central nervous system
Sometimes: headache.
From an acoustic organ
Very seldom: a ring in ears.
From respiratory system
Very seldom: cough.
From digestive tract
Very seldom: change of flavoring feelings, dyspepsia, dryness in a mouth.
From gepatobiliarny system
Very seldom: abnormal liver functions, hepatitis.
From skeletal and muscular system, a connecting and bone tissue
Very seldom: mialgiya, arthralgia.
From kidneys and urinary tract
Very seldom: a renal failure, including separate cases of development of a renal failure in patients of risk group (see sections of "Contraindication", "With Care", "Special Instructions").
Additional information on side effects of separate active components of drug Koaprovel
At Koaprovel's reception in addition to above-mentioned side effects emergence of other listed below side effects about which it was reported for each active agent of this combination separately earlier is possible.
For an irbesartan
General disturbances Sometimes: stethalgias.
For a hydrochlorothiazide (without indication of frequency of emergence) Hematologic disturbances
Aplastic anemia, marrow depression, hemolitic anemia, leukopenia, neutropenia/agranulocytosis, thrombocytopenia.
Mental disturbances
Depression, sleep disorders.
Disturbances from the central nervous system Dizziness, paresthesias, concern. Vision disorders
Passing vagueness of sight, xanthopsia. Disturbances from cardiovascular system of Arrhythmia, postural hypotension. Disturbances from respiratory system
Respiratory distress syndrome (including a pneumonitis and hypostasis of a lung).
Disturbances from gepatobiliarny system
Jaundice (intra hepatic cholestatic jaundice).
Disturbances from integuments and a hypodermic fatty tissue
Anaphylactic reactions, toxic epidermal necrolysis, necrotizing angiitis (vasculitis, skin vasculitis), volchanochnopodobny syndrome, weighting of manifestations or activation of a system lupus erythematosus, photosensitivity reaction, skin rash, small tortoiseshell.
From a musculoskeletal system:
Spasms of muscles, weakness.
From kidneys and urinary tract
Intersticial nephrite, renal failure.
General disturbances
Fever.
From laboratory indicators
Disturbances of electrolytic balance (including a hypopotassemia and a hyponatremia, see the section "Special Instructions"), a glucosuria, a hyperglycemia, a hyperuricemia, increase in level of cholesterol and triglycerides.
The side effects of a hydrochlorothiazide depending on a dose (in particular disturbances of electrolytic balance) can amplify at increase in a dose of a hydrochlorothiazide.

Features of use:

Arterial hypotension - decrease in the volume of the circulating blood (VCB).
Occasionally Koaprovel® can cause arterial hypotension in patients with the raised ABP without the accompanying accessory factors of risk of development of arterial hypotension. Development of the arterial hypotension proceeding with symptomatology can be expected at patients with reduced OTsK or a hyponatremia, owing to intensive diuretic care, a diet with restriction of table salt, diarrhea or vomiting. Such states have to be corrected prior to therapy by the drug Koaprovel® (see sections of "Contraindication" and "Route of Administration and Doses").
Unilateral or bilateral stenosis of renal arteries, renovascular hypertensia. At these states there is an increased risk factor of development of heavy arterial hypotension and renal failure in patients with a stenosis of one or two renal arteries at use of APF inhibitors or antagonists of receptors of angiotensin II. Though in case of the drug Koaprovel® so far such side effects were not observed, completely it is impossible to exclude a possibility of their development.
Renal failure and transplantation of a kidney. When Koaprovel® is applied at patients with an impaired renal function, periodic control of levels of potassium, creatinine and uric acid in blood serum is recommended. There is no experience concerning use of the drug Koaprovel® for patients after transplantation of a kidney. Коапровель® it should not be applied at patients with a severe form of a renal failure (KK less than 30 ml/min.). At patients with an impaired renal function thiazide diuretics can provoke strengthening of an azotemia.
Stenosis of the mouth of an aorta and stenosis of the mitral valve, subaortic hypertrophic stenosis. Extra care at appointment of vazodilatator as such patient is necessary, including Koaprovel®.
Primary hyper aldosteronism. Use of the drug Koaprovel® is inexpedient as such patients usually do not react to the antihypertensives influencing renin-angiotensin-aldosteronovuyu system.
Metabolic and endocrine effects. Therapy by thiazide diuretics, can reduce tolerance to glucose. At patients with a diabetes mellitus increase in doses of insulin or hypoglycemic means for intake can be required. Therapy by thiazide diuretics can cause manifestation latentno of the proceeding diabetes mellitus. At therapy by thiazide diuretics at some patients the hyperuricemia or an aggravation of a course of gout can be observed.
Disturbance of electrolytic balance. Tiazida, including a hydrochlorothiazide, can cause disturbance of water and electrolytic balance (a hypopotassemia, a hyponatremia and a gipokhloremichesky alkalosis). Though at use of thiazide diuretics development of a hypopotassemia, parallel therapy irbesartany is possible can reduce the hypopotassemia caused by diuretic. The risk of a hypopotassemia increases at patients who at the same time receive glucocorticosteroids or adrenocorticotropic hormone. On the contrary, thanks to the irbesartan which is a part of the drug Koaprovel® the hyperpotassemia, especially in the presence of a renal failure and/or heart failure or a diabetes mellitus can take place. Regular control of level of potassium in blood serum at patients of risk group is recommended. Kaliysberegayushchy diuretics, potassium additives or kaliysoderzhashchy solezamenitel have to be appointed with care together with the drug Koaprovel® (see the section "Interactions with Other Medicines"). There is no confirmation that ирбесартан can reduce or prevent the hyponatremia caused by diuretics. Deficit of chlorides usually happens insignificant and does not demand treatment. Tiazida can reduce removal of calcium through kidneys and cause insignificant increases in level of calcium in blood serum on condition of lack of disturbances in calcium exchange. Noted hypercalcemia can be a sign latentno of the proceeding hyperparathyreosis. Reception of tiazid has to be stopped before carrying out a research of function of epithelial bodies. It was shown that tiazida increase removal of ions of magnesium kidneys that can lead to a hypomagnesiemia.
Anti-doping test. The hydrochlorothiazide can yield false positive result when carrying out a drug test.
Development of allergic reactions to a hydrochlorothiazide is more probable at patients with the burdened allergological anamnesis or patients with bronchial asthma. At use of thiazide diuretics the aggravation of a system lupus erythematosus was noted.
Influence on ability of control of vehicles and mechanisms
Influence of the drug Koaprovel® on ability of control of vehicles and mechanisms was not studied, but on the basis of its pharmakodinamichesky properties it is improbable that Koaprovel® will influence this ability. During control of vehicles or mechanisms it is necessary to take into account that in rare instances at its reception dizziness and increased fatigue can be observed.

Side effects:

The side effects provided below are given in a soovetstviye with the following gradation of frequency of their emergence: very often (> 1/10), it is frequent (> 1/100, <1/10); infrequently (> 1/1000, <1/100); seldom (> 1/10000, <1/1000); very seldom (<1/10000) (including separate messages), unknown frequency (it is not possible to determine the frequency of emergence of side effect by the available data). Combination ирбесартан / hydrochlorothiazide
In clinical trials safety of a combination of an irbesartan and hydrochlorothiazide was estimated at about 2750 patients, including 1540 patients with arterial hypertension receiving this treatment within 6 months and more than 970 patients receiving it within one year and more. The patients receiving Koaprovel® had usually moderately expressed side effects and passing, and their frequency was not connected with the size of the accepted dose (within the recommended range of doses). Frequency of emergence of side effects also did not depend on age, sex and race.
In placebo - controlled researches at patients with arterial hypertension, the general frequency of by-effects in groups ирбесартана / a hydrochlorothiazide and placebo did not differ. The termination of therapy because of any clinical or laboratory by-effect was less frequent at the patients accepting combinations of an irbesartan and a hydrochlorothiazide than at the accepting placebos.
In spontaneous messages on side effects and in placebo - controlled
researches, in which various doses (from 6,25 mg / 37,5 mg to 25 mg / ЗООмг
hydrochlorothiazide / ирбесартана) 898 patients with arterial hypertension received,
the listed below side effects were noted.
From a nervous system
Often: dizziness.
Infrequently: orthostatic dizziness.
Very seldom: вертиго.
Unknown frequency: headache.
From a cardiovascular sitema
Infrequently: excessive decrease in the ABP; peripheral hypostases, in particular hypostases of the lower extremities; to a syncope; tachycardia; "inflows" of blood to face skin. From digestive tract Often: nausea/vomiting.
Infrequently: diarrhea, dryness of a mucous membrane of an oral cavity. Unknown frequency: dyspepsia, dysgeusia (food faddism). From kidneys and urinary tract it is frequent: change of frequency of an urination.
Unknown frequency: a renal failure, including separate cases of development
renal failure at patients of risk group (see sections of "Contraindication",
"With care", "Special instructions").
From generative organs and a mammary gland
Infrequently: disturbance of a libido, sexual dysfunction.
General disturbances
Often: increased fatigue.
From laboratory indicators
At the patients receiving treatment by a hydrochlorothiazide / ирбесартаном noted changes of laboratory indicators which seldom reached a threshold of the clinical importance.
Often: increase in an urea nitrogen, creatinine and a kreatinfosfokinaza in a blood plasma. Infrequently: decrease in serumal concentration of potassium ions and sodium. From immune system
Unknown frequency: allergic reactions, such as Quincke's disease, skin rash, small tortoiseshell.
From exchange food substance Unknown frequency: hyperpotassemia. From an acoustic organ and labyrinth disturbances Very seldom: a ring in ears.
From respiratory system, bodies of a thorax and a mediastinum
Unknown frequency: cough.
From a liver and biliary tract
Unknown frequency: abnormal liver functions, hepatitis.
From skeletal and muscular and connecting fabric
Unknown chatota: mialgiya, arthralgia.
Additional information on side effects of separate active agents of the drug Koaprovel®
At administration of drug of Koaprovel® in addition to the above-mentioned collateral
to effects emergence of other listed below side effects about which it was reported for each active agent of this combination separately earlier is possible.
For an irbesartan
General disturbances
Infrequently: stethalgias.
For a hydrochlorothiazide (without indication of frequency of emergence) Disturbances from blood and lymphatic system
Aplastic anemia, oppression of a marrowy hemopoiesis, hemolitic, anemia, leukopenia, neutropenia/agranulocytosis, thrombocytopenia.
Disturbances of mentality
Depression, sleep disorders.
Disturbances from a nervous ssitema
Vertigo, paresthesia, concern, feeling of "ease" in the head. Disturbances from body a zrekniya the Passing vagueness of sight, a xanthopsia. Disturbances from cardiovascular system of Arrhythmia, postural hypotension.
Disturbances from respiratory system, bodies of a thorax and a mediastinum the Respiratory distress a syndrome (including a pneumonitis and hypostasis of a lung). Disturbances from a gastrointestinal rakt
Anorexia, irritation of a mucous membrane of a stomach, diarrhea, lock. Disturbances from a liver and biliary tract Jaundice (intra hepatic cholestatic jaundice). Disturbances from skin and hypodermic fabrics
Anaphylactic reactions, toxic epidermal necrolysis, necrotizing
angiitis (vasculitis, skin vasculitis), skin volchanochnopodobny reactions, weighting
manifestations   or   aggravation   of a current   of a skin      lupus erythematosus,   reaction
photosensitivity, skin rash, small tortoiseshell.
From skeletal and muscular and connecting fabric
Muscular spasms.
From kidneys and urinary tract
Intersticial nephrite, renal failure.
General disturbances
Fever, weakness.
From laboratory indicators
Disturbances of water and electrolytic balance (including a hypopotassemia, a hypomagnesiemia and a hyponatremia, (see the section "Special Instructions"), a glucosuria, a hyperglycemia, a hyperuricemia, increase in concentration of cholesterol and triglycerides in blood. The side effects of a hydrochlorothiazide depending on a dose (in particular disturbances of water and electrolytic balance) can amplify at increase in a dose of a hydrochlorothiazide.

Interaction with other medicines:

The hypotensive effect of the drug Koaprovel® can be strengthened by simultaneous use of other antihypertensives, especially ganglioblokator and blockers of beta adrenoceptors, diazoxide. Irbesartan and a hydrochlorothiazide (at doses to 300 mg irbesartana/25 hydrochlorothiazide mg) were safely applied in combination with other antihypertensives, including blockers of "slow" calcium channels and beta adrenoblockers. Preliminary therapy by diuretics in high doses can lead to a hypovolemia and the increased risk of development of arterial hypotension (see the section "Special Instructions").
Slity
Diuretics reduce renal clearance of lithium and increase risk of development of toxic effects of lithium. Besides, at a combination of drugs of lithium to inhibitors of an angiotensin-converting enzyme (APF) increase in plasma concentration of lithium was also observed. So far similar effects at reception of an irbesartan were observed extremely seldom. In case of administration of drug of Koaprovel® the risk of toxic effect of lithium can be increased. Use of a combination of the drug Koaprovel® with drugs of lithium is not recommended. If this combination after all is necessary, then it is necessary to monitorirovat serumal concentration of lithium.
With the medicines influencing potassium level in blood
Removal of potassium at reception of a hydrochlorothiazide decreases thanks to kaliysberegayushchy effect of an irbesartan. However this effect of a hydrochlorothiazide can be strengthened by other medicines causing loss of potassium and a hypopotassemia (for example, diuretics, laxatives, Amphotericinum In, karbenoksolony,  sodium salt   of penicillin G,  derivatives  of salicylic acid). On the contrary, based on experience of use of other medicines which reduce activity of the renin angiotensin system, the accompanying use of the kaliysberegayushchy diuretics, potassium additives, kaliysoderzhashchy solezamenitel or other medicines capable to increase potassium levels in blood serum (for example, sodium salt of heparin) can lead to increase in potassium concentration in blood serum. Patients of risk group are recommended to carry out adequate control of level of potassium in blood serum.
With cardiac glycosides, antiaritmika
At combined use with the drug Koaprovel®, in case of the emergence of a hypopotassemia and a hypomagnesiemia caused by the thiazide diuretic which is its part danger of developing of arrhythmias including posing hazard to life increases. At use of such combinations carrying out regular control of level of potassium in blood serum is required (see the section "Special Instructions").
With non-steroidal anti-inflammatory drugs (NPVP)
At simultaneous use of antagonists of receptors of angiotensin II and non-steroidal anti-inflammatory drugs (for example, the selection inhibitors of cyclooxygenase-2 (TsOG-2), acetylsalicylic acid (more than 3 g/days) and non-selective NPVP) easing of hypotensive effect of the drug Koaprovel® due to decrease in efficiency of a hydrochlorothiazide is possible.
As well as in a case with APF inhibitors, combined use of antagonists of receptors of angiotensin II and NPVP can increase risk of disturbance of renal function, including a possibility of development of an acute renal failure and lead to increase in potassium ions in blood serum, especially at patients with already impaired renal function. At purpose of this combination it is necessary to observe precautionary measures, especially at elderly patients. During a combination therapy patients should not be dehydrated by antagonists of receptors of angiotensin II and NPVP and at them it is necessary to control indicators of function of kidneys.
Additional information on interaction with other medicines for an irbesartan
The pharmacokinetics of an irbesartan at its combination to a hydrochlorothiazide and nifedipine does not change. Irbesartan is generally metabolized by means of an isoenzyme of CYP2C9 and, to a lesser extent, - by a glyukuronirovaniye. Considerable pharmacokinetic and pharmakodinamichesky interactions at combined use of an irbesartan with the warfarin, drug which is exposed to metabolism by means of CYP2C9 were not observed. Effects of inductors of an isoenzyme of SUR2S9, such as rifampicin, on pharmacokinetics of an irbesartan were not estimated. The pharmacokinetics of digoxin and a simvastatin did not change at combined use with irbesartany.
Additional information on interaction with other medicines for a hydrochlorothiazide
With ethanol, barbiturates or drugs
Strengthening of the orthostatic hypotension caused by thiazide diuretics by them can be observed.
With hypoglycemic means for intake, insulin
Increase in a dose of hypoglycemic means as the hydrochlorothiazide can increase glucose level in blood can be required (see the section "Special Instructions"). With Colestyraminum or kolestipoly
Absorption of a hydrochlorothiazide in the presence of the anion-exchange pitches decreases. It is necessary to divide on time reception of these drugs not less than for 4 hours.
With glucocorticosteroids, adrenocorticotropic hormone
   Perhaps more expressed  disturbance of electrolytic  balance   , in particular, increases danger of emergence of a hypopotassemia.
With catecholamines (for example, with Norepinephrinum)
The effect of these means can be weakened under the influence of thiazide diuretics. With not depolarizing muscle relaxants (tubocurarine)
The effect of not depolarizing muscle relaxants can be strengthened by a hydrochlorothiazide. With antigouty means
At a concomitant use of the drug Koaprovel® and antigouty means increase in doses of antigouty drugs because of a possibility of increase serumal concentration of uric acid can be required at reception of a hydrochlorothiazide. At the same time increase in doses of a probenetsid or Sulfinpyrazonum can be required. Increase in risk of development of allergic reactions to Allopyrinolum.
With calcium salts
Thiazide diuretics can increase calcium level in blood serum. If the calcic additives or drugs influencing calcium level (for example have to be appointed, at therapy by vitamin D), then control of level of calcium in blood serum and carrying out the corresponding correction of a dosage of drugs of calcium is necessary.
With beta adrenoblockers and diazoxide
Thiazide diuretics increase risk of development of their hyper glycemic effects.
With anticholinergics (for example, atropine, Biperidinum)
Increase in bioavailability of diuretics of a thiazide row due to delay of motility of digestive tract.
With amantadiny
Tiazida can increase risk of emergence of its side effects. With cyclophosphamide, a methotrexate
Tiazida can reduce allocation by kidneys of these cytotoxic means and strengthen their myelosuppressive effects.

Contraindications:

Pregnancy (see the section "Pregnancy and Period of a Lactation").
The lactation period (see the section "Pregnancy and Period of a Lactation").
Hypersensitivity to active agents, to any of excipients (see the section "Structure") or to other drugs derivative of sulfonamides (the hydrochlorothiazide is derivative sulfonamides).
Age up to 18 years (efficiency and safety are not established).
Hereditary intolerance of a galactose, insufficiency of lactase or disturbance of absorption of glucose and galactose.
Heavy renal failure (KK less than 30 ml/min.), an anury (in connection with existence in composition of drug of a hydrochlorothiazide).
Refractory hypopotassemia, hypomagnesiemia, hypercalcemia (in connection with existence in composition of drug of a hydrochlorothiazide).
Heavy liver failure (a functional class C or more than 9 points on classification of Chayld-Pyyu), biliary cirrhosis, a cholestasia (in connection with existence in composition of drug of a hydrochlorothiazide as the minimum disturbances of water and electrolytic balance at such patients can provoke a hepatic coma).
To apply with care:
at a stenosis of the aortal or mitral valve; hypertrophic subaortic stenosis (GOKMP);
at dehydration, a hyponatremia, diarrhea, vomiting, observance of a diet with restriction of consumption of table salt, treatment by diuretics (risk of development of the expressed arterial hypotension);
at a bilateral or unilateral stenosis of renal arteries, chronic heart failure of the III—IV stage on NYHA classification (as well as at use of other means influencing renin-angiotensin-aldosteronovuyu system it is impossible to exclude existence of risk of development of arterial hypotension, an oliguria and/or azotemia and the progressing acute renal failure); at coronary heart disease and/or atherosclerotic defeat of vessels of a brain (risk of strengthening of ischemia of a myocardium or brain up to development of a myocardial infarction or a stroke at excessive decrease in the ABP); at a renal failure of easy and moderate severity (KK from 60 to 30 ml/min.), a hemodialysis (risk of increase in an azotemia in connection with existence in composition of drug of a hydrochlorothiazide and development of a hyperpotassemia in connection with existence in composition of drug of an irbesartan);
after transplantation of a kidney (lack of experience of a clinical use);
at a liver failure (functional class A and B (5-6 points and 7-9
points on criteria for evaluation of classification of Chayld-Pyyu);
at a diabetes mellitus (in connection with existence in composition of drug of a hydrochlorothiazide decrease in tolerance to glucose is possible);
at the increased level of cholesterol and triglycerides in blood (in connection with existence in composition of drug of a hydrochlorothiazide as thiazide diuretics, especially in high doses, can increase the level of cholesterol and triglycerides in blood); at gout (in connection with existence in composition of drug of a hydrochlorothiazide increase in concentration of urates in blood is possible);
at a hyperpotassemia, a concomitant use of kaliysberegayushchy drugs and or the salt substitutes (risk of a hyperpotassemia) containing potassium;
at a system lupus erythematosus (in connection with existence in composition of drug of a hydrochlorothiazide the exacerbation of this disease is possible); at  a concomitant  use of other    antihypertensives  (a possibility of potentiation of their hypotensive action);
at latentno the proceeding hyperparathyreosis (in connection with existence in composition of drug of a hydrochlorothiazide as thiazide diuretics, especially in high doses, increase risk of development or strengthening of a hypercalcemia); after a sympathectomy (risk of strengthening of hypotensive effect of a hydrochlorothiazide). at a concomitant use of salts of lithium (the hydrochlorothiazide increases risk of toxic effect of lithium see the section "Interaction with Other Medicines");

Pregnancy
Administration of drug of Koaprovel® at pregnancy is contraindicated.
Irbesartan is contraindicated at pregnancy as impact on a fruit of the medicines influencing renin-angiotensin-aldosteronovuyu system can lead to damage and death of the developing fruit.
Thiazide diuretics get through a placental barrier and are found in umbilical blood. Usually use of diuretics at pregnant women is not recommended and subjects mother and a fruit to unnecessary risk, including development of jaundice in a fruit or the newborn, thrombocytopenia and perhaps other adverse reactions which are observed at adults. Especially reception of a hydrochlorothiazide in the first trimester of pregnancy is not recommended.
If the patient plans pregnancy or if during treatment the drug Koaprovel® established pregnancy, then administration of drug of Koaprovel® has to be stopped (in case of pregnancy approach, as soon as possible). In need of continuation of hypotensive therapy, the patient should appoint alternative hypotensive therapy the drugs having the established safety profile at pregnancy.
Lactation period
Коапровель® it is contraindicated to use during the entire period of feeding by a breast because of potential risk for the child. In case of the imperative need of administration of drug of Koaprovel® by mother, breastfeeding has to be stopped.

Overdose:

As the most probable manifestations of overdose of an irbesartan it is possible to expect the expressed decrease in the ABP and tachycardia; also bradycardia can take place.
The overdose of a hydrochlorothiazide is followed by decrease in content in blood of electrolytes (a hypopotassemia, a hyponatremia) and dehydration as a result of an excess diuresis. The most general signs and symptoms of overdose - nausea and drowsiness. The hypopotassemia can lead to spasms and/or strengthening of arrhythmias in case of the accompanying use of glycosides of a foxglove and antiarrhytmic means.
There is no special information on drug Koaprovel® overdose treatment. In case of overdose careful control of a condition of the patient is required, therapy has to be symptomatic and supporting. Treatment depends on time which passed from the moment of medicine reception and on weight of symptoms. The recommended measures include provoking of vomiting and/or a gastric lavage. At overdose there can be useful a use of absorbent carbon. Regular control of level of electrolytes and creatinine in blood serum has to be carried out. In case of the expressed decrease in the ABP of the patient it is necessary to lay on a back in situation with the raised lower extremities and as soon as possible to begin carrying out completion of salts and volume of the circulating blood.
Irbesartan is not brought by means of a hemodialysis.

Storage conditions:

To store at a temperature not above 30 °C. To store in the place, unavailable to children. Period of validity 3 years.
Not to accept drug after the period of validity specified on packaging.

Issue conditions:

According to the recipe

Packaging:

Tablets, film coated, 300 mg / 25 mg.
On 14 tablets in PVC / the blister Is scarlet. On 1, 2, 4, 6 or 7 blisters with the application instruction in a cardboard pack.