Diokor

General characteristics. Structure:

Active ingredients: 80 mg of a valsartan and 12,5 mg of Hydrochlorthiazidum (Diokor 80) or 160 mg of a valsartan and 12,5 mg of Hydrochlorthiazidum (Diokor 160);                                                                                                                    

Excipients: cellulose microcrystallic, potato starch, starch corn, sodium lauryl sulfate, talc, croscarmellose sodium, silicon dioxide colloid anhydrous, magnesium stearate, a covering for drawing a cover (Opadry II White – Diokor 80; Opadry II Orange – Diokor 160).

Pharmacological properties:

Pharmacodynamics. Diokor — anti-hypertensive drug which part are the antagonist of receptors of angiotensin II and thiazide diuretic.
Renin-angiotensin-aldosteronovoy of system is active hormone the angiotensin II which is formed of angiotensin I with the participation of APF. Angiotensin II contacts the specific receptors located on cellular membranes in various fabrics. It possesses a wide range of the physiological effects including, first of all, both the direct, and mediated participation in regulation of arterial pressure. Being powerful vasoconstrictive substance, angiotensin II causes the direct pressor answer. Besides, it stimulates secretion of Aldosteronum and promotes a sodium delay.

Valsartan is the active and specific antagonist of receptors of angiotensin II intended for intake. It affects selectively the AT1 subtype receptors responsible for the known effects of angiotensin II. The increased serumal levels of angiotensin II owing to blockade of AT1-receptors valsartany can stimulate free AT2-receptors that counterbalances effect of AT1-receptors. валсартан does not show any expressed agonistic activity concerning AT1 subtype receptors. Affinity of a valsartan to receptors of the AT1 subtype is about 20 000 times higher, than to AT2 subtype receptors.

Valsartan does not inhibit the APF (a kininaz of II) turning angiotensin I into angiotensin II and destroying bradykinin. Do not note any side effects caused by bradikinin. In clinical trials in which comparison of a valsartan with APF inhibitor was carried out the frequency of development of dry cough was authentically lower at the patients treated valsartany than at the patients applying APF inhibitor. Valsartan does not enter interaction and does not block the receptors of other hormones or ion channels which are important for regulation of functions of cardiovascular system.
At treatment of patients by Diokor with arterial hypertension note the lowering of arterial pressure which is not followed by pulse rate change.
After intake of a single dose of drug at most of patients the beginning of anti-hypertensive action is noted within 2 hours, and the maximum lowering of arterial pressure is reached within 4 - 6 hours. After  administration of drug anti-hypertensive action remains more than 24 hours. At repeated purposes of drug the maximum lowering of arterial pressure, regardless of the accepted dose, is usually reached within  2 - 4 weeks and supported at the reached level during long therapy. At a combination with Hydrochlorthiazidum the reliable additional lowering of arterial pressure is reached.
Point of application of effect of thiazide diuretics is the bast layer of distal twisting renal tubules where receptors, highly sensitive to effect of diuretics, are located and where there is a suppression of transport of ions of sodium and chlorine. The mechanism of effect of thiazide diuretics is connected with suppression of the pump Na+Cl-that occurs due to the competition for places of transport of Cl-. As a result of it excretion of ions of sodium and chlorine raises approximately to the same extent. As a result of diuretic action reduction of volume of the circulating blood is observed owing to what raise activity of a renin, secretion of Aldosteronum, removal with urine of potassium and, therefore, decrease in potassium concentration in blood serum. The interrelation between a renin and Aldosteronum is mediated by angiotensin II therefore use of the antagonist of receptors of angiotensin II will reduce the potassium losses connected using thiazide diuretic.

Pharmacokinetics. After administration of drug inside absorption of a valsartan and Hydrochlorthiazidum happens quickly, however extent of absorption varies over a wide range. The average size of bioavailability of drug makes 23%.
In the range of the studied doses the kinetics of a valsartan has linear character. At repeated use of drug of changes of kinetic indicators did not note. At administration of drug once a day cumulation insignificant.
Valsartan substantially (for 94 - 97%) contacts serum proteins, is preferential with albumine. Equilibrium volume of distribution low (about 17 l). Removal of a valsartan with a stake makes 70% (from the size of the dose accepted inside). With urine about 30% are removed, it is preferential in not changed look.
At purpose of a valsartan with food, the area under a curve "concentration time" (AUC) decreases by 48% though, since about the 8th hour after administration of drug of concentration of a valsartan in a blood plasma, both in case of its reception on an empty stomach, and in case of reception with food, identical. AUC reduction nevertheless is not followed by clinically significant decrease in therapeutic effect.

Hydrochlorthiazidum. After intake absorption of Hydrochlorthiazidum happens quickly (tmax – about 2 hours). The drug pharmacokinetics in phases of distribution and removal is described in general by the bieksponentsialny descending curve; the elimination half-life of a final phase makes 6 - 15 hours.
The average size AUC increases in the therapeutic range of doses in direct ratio to increase in a dose. At repeated appointments the pharmacokinetics of a hydrochlorothiazide does not change; at appointment once a day cumulation is not considerable.
At intake bioavailability of a hydrochlorothiazide makes 60 - 80%. Removal happens to urine: more than 95% of a dose in not changed look and about 4% - in the form of a hydrolyzate 2-amino-4-chloro-m-benzenedisulfonamida.
At co-administration of Hydrochlorthiazidum with food noted both increase, and decrease in its system bioavailability (in comparison with the corresponding indicator at reception on an empty stomach). Range of these changes is not big and clinically we do not mean.

Валсартан / Hydrochlorthiazidum. At simultaneous use with valsartany system bioavailability of Hydrochlorthiazidum decreases approximately by 30%. Simultaneous use of Hydrochlorthiazidum has no significant effect on kinetics of a valsartan. Noted interaction does not exert impact on efficiency of the combined use of a valsartan and Hydrochlorthiazidum. In controlled clinical trials the clear anti-hypertensive effect of this combination which exceeded effect of each of components separately, and also effect of placebo was revealed.

Indications to use:

Arterial hypertension at patients for whom  monotherapy is inefficient.

Route of administration and doses:

The recommended drug dose — on 1 tablet once a day daily. In clinical conditions the tablets containing 80 mg of a valsartan and 12,5 mg of Hydrochlorthiazidum or in case of inefficiency of dosing - the tablets containing     160 mg of a valsartan and 12,5 mg of Hydrochlorthiazidum can be applied. The maximum anti-hypertensive effect is reached for 2 - 4 weeks.

For patients with insignificant and moderate renal failures (clearance of creatinine> of 30 ml/min.) it is not necessary to regulate a dose. For patients with an insignificant and moderate liver failure of not biliary origin and without cholestasia it is not necessary to regulate a dose.
Duration of treatment is established by the doctor individually.

Features of use:

Use during pregnancy or feeding by a breast.
Considering the mechanism of action of antagonists of angiotensin II, it is impossible to exclude risk for a fruit at Diokor's use in pregnancy reiod. It is not known whether Diokor in breast milk is allocated. Therefore Diokor it is not necessary to apply during pregnancy and feeding by a breast. If pregnancy is revealed during treatment by Diokor, drug should be cancelled as soon as possible.

Children.
Safety and efficiency of use of Diokor for children are not established yet therefore drug is not used in pediatric practice.

These combinations containing the fixed doses of components (валсартан + Hydrochlorthiazidum) should be applied as therapy of the second row of the choice. At the same time it is necessary to consider a possibility of certain changes of a condition of patients.
Changes of balance of electrolytes. It is necessary to be careful at simultaneous use of Diokor with potassium salts, kaliysberegayushchy diuretics, kaliysoderzhashchy substitutes of edible salt, and also with medicines which can cause increase in potassium concentration in blood (for example, heparin).
There are messages on development of a hypopotassemia at treatment by thiazide diuretics. Frequent control of potassium concentration in blood is recommended.
At use of thiazide diuretics the hyponatremia and a gipokhloremichesky alkalosis can develop. Tiazida cause increase in excretion with magnesium urine that can lead to a hypomagnesiemia.

Deficit in an organism of sodium and/or the volume of the circulating blood (VCB). At patients with the expressed deficit in an organism of sodium and/or OTsK as, for example, the diuretics applying high doses, in rare instances in an initiation of treatment arterial hypotension with clinical manifestations can arise Diokor. Therefore before an initiation of treatment Diokor it is necessary to carry out correction of content of sodium in an organism and/or OTsK, for example, by a diuretic dose decline.

In case of development of hypotension of the patient it is necessary to transfer to horizontal position and if necessary to carry out intravenous infusion of normal saline solution. After stabilization of arterial pressure treatment by Diokor can be continued.

Renal artery stenosis. Safety of use of Diokor for patients with a unilateral or bilateral renal artery stenosis or a stenosis of an artery of the only kidney is not established.

System lupus erythematosus. There are messages that thiazide diuretics can cause an aggravation of a system lupus erythematosus.

Other metabolic disturbances. Thiazide diuretics can cause change of tolerance to glucose, and also increase in concentration of cholesterol, triglycerides and uric acid in blood serum.

Ability to influence speed of response at control of motor transport or work with other mechanisms.
At Diokor's use as well as other anti-hypertensive means, it is recommended to be careful at control of vehicles and work with exact mechanisms.

Side effects:

Undesirable effects had in general slight and passing character.

With a frequency of 1% such undesirable effects as a headache, dizziness, a nasopharyngitis, feeling of fatigue, cough, diarrhea, a dorsodynia were observed. 

With a frequency less than 1% such undesirable effects as abdominal pain, concern, an arthralgia, an adynamy, bronchitis, an acute bronchitis, a stethalgia, dizziness, dyspepsia, an asthma, dryness in a mouth, impotence, a gastroenteritis, the raised potovydeleniye, a gipoesteziya, a hypopotassemia, hypotension, sleeplessness, myotonia, a muscle strain, nausea, a nose congestion, neck pain, hypostasis, peripheral hypostasis, average otitis, extremity pain, the accelerated heartbeat, paresthesia, pharyngolaryngeal pain, a pollakiuria, temperature increase, sinusitis, a solivost, sprain, tachycardia, a sonitus, вертиго were observed. It is unknown whether had these effects relationship of cause and effect using drug. Data of post-market researches showed isolated cases of a Quincke's disease, rash, itch and other reactions of a hypersensitivity/allergy, including a serum disease і vasculites. There are messages also on separate cases of a renal failure and a myalgia. The fluid lungs cases with granulotsitarny infiltration and deposition of IgG in alveolar membranes connected using Hydrochlorthiazidum were also recorded. Not cardiogenic fluid lungs can be mediated immunological by idiosyncratic reaction to Hydrochlorthiazidum that meets seldom.
Results of laboratory researches. At some patients who received Diokor potassium concentration in serum decreases more than by 20% in comparison with patients who accepted placebo.
Increase in levels of creatinine and urea nitrogen of blood (BUN) approximately in 5 and 2 times respectively at patients who were treated  by Diokor, in comparison with patients who accepted placebo was sometimes observed.
The neutropenia was observed in 4 strike less often at patients who were treated by Diokor, in comparison with patients who accepted placebo.

Valsartan. Other collateral effkta which were observed in clinical trials of monotherapy valsartany irrespective of their relationship of cause and effect with the studied drug, met frequency less than 1%: decrease libido, acute renal failure, isolated cases of increase in indicators of function of a liver.

Hydrochlorthiazidum. Hydrochlorthiazidum  is widely applied for many years, and doses, above than that which is Diokor's part are more often applied. When performing monotherapy by thiazide diuretics, including Hydrochlorthiazidum, a number of side effects is possible.

Changes of electrolytes and metabolism see in the section "Features of Use".
From other possible side effects were observed: often - a small tortoiseshell and other types of rash, appetite loss, moderately expressed nausea and vomiting, postural hypotension which expressiveness increases at alcohol intake, use of anesthetics or sedatives, impotence; seldom - a photosensitization, disorders of digestive tract, a lock, diarrhea, a cholestasia or jaundice, cardiac arrhythmia, a headache, dizziness, frustration of a dream, a depression, paresthesias, vision disorders, thrombocytopenia, sometimes with a purpura; very seldom - the necrotizing vasculitis and a toxic epidermal necrolysis, skin reactions reminding a system lupus erythematosus, an aggravation of skin manifestations of manifestations of a system lupus erythematosus, pancreatitis, a leukopenia, an agranulocytosis, a depression bone a vegetable pulp, hemolitic anemia, reactions of hypersensitivity, disturbance from respiratory system including a pneumonitis and a fluid lungs.

Interaction with other medicines:

Strengthening of anti-hypertensive effect at combined use of Diokor with other anti-hypertensive drugs is possible.

Simultaneous use with Diokor of salts of potassium, kaliysberegayushchy diuretics, kaliysoderzhashchy substitutes of edible salt or any other medicines which can cause increase in potassium concentration in blood (for example, heparin) demands observance of precautionary measures and, in particular, frequent definition of potassium concentration in blood.

At co-administration of drugs of lithium with inhibitors of the angiotensin-converting enzyme (ACE) or thiazide diuretics noted reversible increase in concentration of lithium in blood serum. Experience of simultaneous use of Diokor and drugs of lithium is absent therefore it is recommended to carry out control of concentration of lithium in blood serum.

Clinically significant interactions when performing monotherapy valsartany were not noted at use of the following medicines: Cimetidinum, warfarin, furosemide, digoxin, атенолол, indometacin, Hydrochlorthiazidum, амлодипин, Glibenclamidum.

As thiazide diuretic is Diokor's part, the following medicinal interactions are potentially possible:

- tiazida exponentiate action of kurarepodobny muscle relaxants;

- decrease in diuretic and anti-hypertensive action of a thiazide component of Diokor at simultaneous use with non-steroidal anti-inflammatory drugs is possible (for example, with derivatives of salicylic acid, indometacin); the accompanying hypovolemia can lead to development of an acute renal failure.

The risk of development of a hypopotassemia increases at simultaneous use of saluretics, corticosteroids, AKTG, Amphotericinum, karbenoksolon, penicillin G and derivatives of salicylic acid.

Thiazide diuretics can cause such undesirable effects as a hypopotassemia or a hypomagnesiemia which, in turn, increase risk of development of arrhythmia at glikozidny intoxication.

Dose adjustment of insulin or peroral sugar-lowering drug can be required.

Co-administration of thiazide diuretics can lead to the following phenomena: to increase the frequency of hypersensitivity reactions to Allopyrinolum; to increase risk of development of side effects of an amantadin; to strengthen hyper glycemic effect of diazoxide; to reduce removal by kidneys of cytotoxic drugs (for example, cyclophosphamide, a methotrexate) and to lead to potentiation of their myelosuppressive action.

Increase in bioavailability of thiazide diuretic is defined at co-administration of blockers of holinoretseptor (for example, atropine, Biperidinum) that it is connected with decrease in a physical activity of a digestive tract and delay of gastric emptying.

It was reported about cases of development of hemolitic anemia at simultaneous use of thiazide diuretic and Methyldopums.

Colestyraminum reduces absorption of thiazide diuretics.

At combined use of thiazide diuretics with vitamin D or salts of calcium potentiation of increase in concentration of calcium in blood serum is possible.

Simultaneous use of cyclosporine can increase risk of development of a hyperuricemia and emergence of the symptoms reminding an exacerbation of gout.

Contraindications:

Hypersensitivity to any of drug components; period of pregnancy and feeding by a breast; heavy abnormal liver functions, biliary cirrhosis and cholestasia; anury, heavy renal failures (clearance of creatinine <30 ml/min.); hypopotassemia, hyponatremia, hypercalcemia, hyperuricemia.

Overdose:

About cases of overdose of Diokor information is absent.
The expressed arterial hypotension can be the main manifestation of overdose. If drug was accepted recently, it is necessary to cause vomiting. At hypotension a usual method of therapy is intravenous administration of normal saline solution.
Diokor it is impossible to bring out of an organism by a hemodialysis because of considerable linkng of a valsartan with proteins of plasma though for removal from Hydrochlorthiazidum organism the hemodialysis is effective.

Storage conditions:

To store in original packaging, in the place, unavailable to children, at a temperature not over 25 ˚С.

Issue conditions:

According to the recipe

Packaging:

On 10 tablets in   blister strip packagings; on 1 or 3 planimetric packagings in a pack cardboard.