Diswagger

General characteristics. Structure:

Active agents: амлодипин 5 mg; валсартан 80 mg

Active agents: амлодипин 5 mg; валсартан 160 mg.

Pharmacological properties:

Pharmacodynamics. The diswagger contains two anti-hypertensive components with additional mechanisms of control of the ABP at patients from essential AG: амлодипин belongs to the class of antagonists of calcium, and валсартан — to a class of antagonists of angiotensin II. The combination of these ingredients has the additive anti-hypertensive effect, reducing the ABP more than each of components separately.
Amlodipin
Amlodipin inhibits transmembrane penetration of calcium ions into unstriated muscles of heart and vessels. The mechanism of anti-hypertensive action of an amlodipin is caused by the direct running-down impact on unstriated muscles of vessels that causes to reduction of OPSS and leads to decrease in the ABP. Experimental data confirm what амлодипин communicates in places of dihydropyridinic and not hydropyridinic bonds. Process of reduction of a cardiac muscle and unstriated muscles of vessels depends on passing of extracellular calcium to cells through specific ion channels.
After introduction of a therapeutic dose to patients from essential AG амлодипин causes a vazodilatation that leads to decrease in the ABP in prone positions and standing. Such decrease in the ABP is not followed by essential change of ChSS or levels of catecholamines in a blood plasma at long use.
The effect correlates with concentration in a blood plasma at patients of young and advanced age.
At patients with normal function of kidneys therapeutic doses of an amlodipin lead to decrease in renal vascular resistance and level of glomerular filtering, and also an effective renal flow of a blood plasma without changes of the filtered fraction or a proteinuria.
Measurements of a hemodynamics of cordial function at rest and at loading at patients with normal function of the ventricles receiving therapy amlodipiny in general showed slight increase of cardiac index without significant effect on dP/dt or on left ventricular and diastolic pressure or volume. In hemodynamic researches амлодипин did not show a negative inotropic effect at use in therapeutic doses for intact animals and people, even at simultaneous introduction with blockers of β-adrenoceptors..........
Amlodipin does not change function of a sinus and atrial node or atrioventricular conductivity at healthy animals or the person. At use of an amlodipin in a combination with blockers of β-adrenoceptors at patients with essential AG or stenocardia of changes of indicators of an ECG it is noted.
Positive clinical effects of an amlodipin at patients with chronic stable stenocardia, vasospastic stenocardia and an ischemic heart disease which are confirmed with an angiographic research were observed.
Valsartan
Valsartan is the active and specific antagonist of receptors of angiotensin II intended for intake. It affects selectively AT1 subtype receptors, rare and are responsible for effects of angiotensin II. The increased angiotensin II levels owing to blockade of AT1-receptors valsartany can stimulate free AT2-receptors that counterbalances effect of AT1-receptors. Valsartan has no partial activity of an agonist concerning AT1-receptors and has much more bigger (by ≅20 000 times) affinity to AT1-receptors, than to AT2-receptors.
Valsartan does not inhibit APF known also under the name of a kininaza II which turns angiotensin I into angiotensin II and bradikinin destroys, at the same time any side effects caused by bradikinin are noted. Valsartan does not enter interaction and does not block receptors of other hormones or ion channels which, as we know, play an important role in regulation of functions of cardiovascular system.
Use of drug for patients with AG leads to decrease in the ABP, without influencing at the same time ChSS.
At most of patients after appointment in a single dose of drug the beginning of anti-hypertensive activity is noted within 2 h, and the maximum decrease in the ABP is reached in 4–6 h.
The anti-hypertensive effect remains> 24 h after reception of a single dose. At repeated purposes of drug the maximum therapeutic effect is usually reached in 2–4 weeks and keeps at the reached level during long therapy. Sudden cancellation of a valsartan does not attract recovery of AG or other side effects.
Valsartan/amlodipin
The combination of an amlodipin besilat/valsartan with AG causes anti-hypertensive effect during about 24 h in patients. Sudden drug withdrawal does not lead to bystry increase in the ABP.
At patients at whom the ABP is adequately controlled amlodipiny at unacceptable hypostases the combination therapy can provide similar control of the ABP at reduction of hypostases.

Pharmacokinetics. Linearity. Valsartan and амлодипин show linearity of pharmacokinetics.
Amlodipin
Absorption. After intake in therapeutic doses of an amlodipin of Cmax in a blood plasma it is reached during 6–12 h. The calculated absolute bioavailability makes from 64 to 80%. Food significantly influences bioavailability of an amlodipin.
Distribution. The volume of distribution makes ≅21 l/kg. At patients of essential AG of ≅97,5% of the circulating drug contacts proteins of a blood plasma.
Metabolism. Amlodipin intensively (≅90%) is metabolized in a liver to inactive metabolites.
Removal. Removal of an amlodipin from a blood plasma two-phase, with Т½ about 30-50 h. Equilibrium level in a blood plasma is reached after constant introduction within 7–8 days. 10% of an initial amlodipin and 60% of metabolites of an amlodipin are removed with urine.
Valsartan
Absorption. After intake of Cmax of a valsartan in a blood plasma it is reached during 2–4 h. The average size of bioavailability of drug makes 23%. AUC of a valsartan has the descending multiexponential character (Т½a <1 h and Т½b ≅9 h). The food reduces exposure of AUC of a valsartan by ≅40%, and Cmax — for 50% though in 8 h after use concentration of a valsartan in a blood plasma is identical to group of the patients accepting drug on an empty stomach and group of the patients accepting drug after food. Decrease in AUC is not followed by clinically significant decrease in therapeutic effect therefore валсартан it is possible прменять irrespective of meal.
Distribution. The equilibrium volume of distribution of a valsartan in/in introductions makes later 17 l that indicates what валсартан is distributed in fabrics not intensively. Valsartan strongly contacts proteins of a blood plasma (94–97%), mainly albumine.
Metabolism. Valsartan substantially is not transformed as only 20% of a dose pass into metabolites. In a blood plasma in low concentration (<10% of AUC of a valsartan) the hydroxymetabolite which pharmacological is inactive is identified.
Removal. Valsartan is brought mainly in not changed view with a stake (≅83% of a dose) and urine (≅13% of a dose). After introduction the clearance of a valsartan in a blood plasma makes ≅2 l/h, and its renal clearance — ≅0,62 l/h (≅30% of the general clearance). Т½ a valsartana — 6 h.
Valsartan/amlodipin
After oral administration of Difors of Cmax in a blood plasma of a valsartan and an amlodipin it is reached for 3 and 6–8 h respectively. Speed and extent of absorption of Difors are equivalent to bioavailability of a valsartan and an amlodipin.
Renal failure.
The renal failure significantly does not influence pharmacokinetics of an amlodipin. There is no real correlation between a condition of function of kidneys (clearance of creatinine) and exposure (determine by AUC) at use of a valsartan for patients with renal failures of various degree. Therefore patients with easy and moderate degree of a renal failure accept a usual initial dose.
Abnormal liver function
At patients with a liver failure the clearance of an amlodipin decreases that leads to increase in AUC for ≅40–60%. At patients with easy and moderate severity of a chronic disease of a liver exposure (determined by AUC values) the valsartana on average exceeds that at healthy volunteers twice. Persons need to be careful with a disease of a liver at drug use.

Indications to use:

Essential AG at patients whose ABP does not reguliruyutsya by monodrugs.

Route of administration and doses:

Patients at whom the ABP is inadequately regulated by monodrugs of an amlodipin or valsartan can be transferred to a combination therapy by drug of Difors. The recommended dose — 1 tablet a day. It is recommended to accept Difors, washing down it with water.
The patients accepting валсартан and амлодипин separately can be transferred to Difors which contains the same doses of components.
For patients of advanced age usual doses are recommended.
The maximum daily dose — 1 tablet of Difors 80 or 1 tablet of Difors 160 or 1 tablet of Difors XL (the most admissible doses of components of drug — 10 mg on the maintenance of an amlodipin, 320 mg — on the maintenance of a valsartan).

Features of use:

Patients with deficit in an organism of sodium and/or OTsK
At patients from uncomplicated AG excessive hypotension was observed. Patients with the system activated a renin-angiotenzinovoy (with the lowered content of sodium and/or OTsK and the diuretics receiving high doses) who accept blockers angiotensin receptors, can have a symptomatic hypotension. Correction of this state before Difors's use or careful medical observation at the beginning of therapy is recommended.
When developing arterial hypotension at use of Difors the patient should give horizontal position and if it is necessary, to carry out infusion of physiological solution. To continue treatment before stabilization of the ABP.
Hyperpotassemia
It is necessary to carry out with care simultaneous treatment by the potassium additives, kaliysberegayushchy diuretics, salt substitutes containing potassium or other drugs which can increase potassium level (heparin, etc.), and also to provide regular control of level of potassium of blood.
Cancellation of blockers of β-adrenoceptors
Amlodipin is not a blocker of β-adrenoceptors and does not protect from danger of sudden cancellation of blockers of β-adrenoceptors, therefore the dose of drugs of this group needs to be reduced gradually.
Renal artery stenosis
There are no data on Difors's use for patients about one - or a bilateral renal artery stenosis.
Transplantation of a kidney
Experience of safe use of Difors for patients with recently postponed transplantation of a kidney is absent.
Abnormal liver function
Valsartan is brought mainly in not changed view with bile whereas амлодипин it is intensively metabolized in a liver. Extra care is necessary at Difors's use for patients with an abnormal liver function or obstructive disturbances of a gall bladder.
Renal failure
For patients with easy and moderate degree of a renal failure there is no need for dose adjustment of Difors. For patients with a heavy renal failure (clearance of creatinine <10 ml/min.) data on use of drug are absent therefore it is necessary to be careful.
Stenosis of an aorta and mitral valve, subaortic hypertrophic stenosis
As well as at treatment by other vazodilatator, with extra care it is necessary to use drug at patients for whom the stenosis of an aorta or the mitral valve or a subaortic hypertrophic stenosis is diagnosed.
With care it is necessary to use drug at unstable stenocardia.
Use during pregnancy or feeding by a breast
As well as any drug which directly influences renin-angiotensin-aldosteronovuyu system of Difors is not applied during pregnancy or at the women planning pregnancy.
Doctors have to warn the woman planning pregnancy about potential risk for a fruit at administration of drug. If in the course of therapy pregnancy is established, Difors's reception needs to be stopped immediately.
It is unknown, gets валсартан and/or амлодипин into breast milk therefore it is not recommended to use drug during feeding by a breast. If therapy by drug is necessary for mother, feeding by a breast should be stopped.
Children
Children are not recommended to appoint drug due to the lack of data on safety and efficiency.
Ability to influence speed of response at control of vehicles or work with other mechanisms
Researches concerning influence of drug on ability to manage vehicles and to work with potentially dangerous mechanisms were not conducted. However patients who have a dizziness or feeling of weakness after administration of drug have to abstain from control of vehicles and work with potentially dangerous mechanisms.

Side effects:

Side below-mentioned reactions are classified by bodies, systems and frequency of emergence, and the most widespread are specified the first. Classification of frequency of emergence of side reactions: very often (≥1/10); often (> 1/100, ≤1/10); sometimes (> 1/1000, ≤1/100); seldom (> 1/10 000, ≤1/1000); very seldom (<1/10 000), including single messages. For each frequency in group side reactions are located in ascending order of gravity.
Infections: often — a nasopharyngitis, grippopodobny symptoms.
From immune system: seldom — hypersensitivity.
From an organ of sight: seldom — a vision disorder.
From mentality: seldom — excitement.
From a nervous system: often — a headache; seldom — dizziness, drowsiness, postural dizziness, paresthesias.
From an acoustic organ and a labyrinth: infrequently — dizziness; seldom — a sonitus.
From heart: seldom — tachycardia; seldom — a syncope.
From vessels: seldom — orthostatic hypotension; seldom — arterial hypotension.
From respiratory system: seldom — cough, a pharyngalgia and throats.
From the alimentary system: seldom — an abdominal pain, a lock, diarrhea, nausea, dryness in a mouth.
From skin and hypodermic fabrics: infrequently — rash, an erythema; seldom — the increased sweating, urticaria, rash.
From a musculoskeletal system: seldom — a swelling of joints, a dorsodynia, an arthralgia; seldom — muscular spasms, heavy feeling.
From an urinary system: seldom — the speeded-up urination, a polyuria, increase in level of an urea nitrogen.
From reproductive system: seldom — disturbance of erectile function.
General disturbances: seldom — hypostases, a face edema, hypostasis of the lower extremities, increased fatigue, inflows, an adynamy.
The diswagger can cause the side reactions which are earlier noted for one of drug components (see the corresponding application instructions of monodrugs).

Interaction with other medicines:

Amlodipin. At monotherapy amlodipiny clinically significant medicinal interactions with the following drugs are not established: thiazide diuretics, blockers of β-adrenoceptors, APF inhibitors, nitrates of long action, sublingual nitroglycerine, digoxin, warfarin, аторвастатин, sildenafit; the combined antiacid drugs containing hydroxide aluminum gel, magnesium hydroxide, симетикон; Cimetidinum, NPVP, antibiotics, peroral gipoglikemiziruyushchy means.
Valsartan. At monotherapy valsartany clinically significant medicinal interactions with the following drugs are not established: Cimetidinum, warfarin, furosemide, digoxin, атенолол, indometacin, hydrochlorothiazide, амлодипин, Glibenclamidum.
Simultaneous use with the potassium additives, kaliysberegayushchy diuretics, salt substitutes containing potassium or other drugs which can increase potassium level (heparin, etc.) demands care. It is necessary to provide frequent control of level of content of potassium in blood.

Contraindications:

Hypersensitivity to any of drug components. Period of pregnancy and feeding by a breast.

Overdose:

So far there is no experiment on studying of overdose of Difors. Further information concerning active ingredients of drug is provided.
Symptoms. The main symptom of overdose of a valsartan is probably the expressed arterial hypotension with dizziness. The overdose of an amlodipin can lead to the accruing peripheral vazodilatation and probably to reflex tachycardia. It was reported about the considerable and potentially prolonged system hypotension, up to shock and a lethal outcome at overdose of an amlodipin.
Treatment. If drug is accepted recently, it is necessary to cause vomiting or to wash out a stomach. Absorption of an amlodipin considerably decreases at use of absorbent carbon at once or during 2 h after reception of an amlodipin.
Clinically significant hypotension caused by Difors's overdose demands active support of a condition of cardiovascular system, including frequent control of cordial and respiratory functions, raising of the lower extremities, control of OTsK and urination. For recovery of a vascular tone and the ABP vasoconstrictive drug in the absence of contraindications for its use can be used. At permanent decrease in the ABP which is a consequence of blockade of calcium channels, can be reasonable administration of calcium of a gluconate.

Storage conditions:

At a temperature not above 25 °C.

Issue conditions:

According to the recipe

Packaging:

Tab. п / captivity. cover of 5 mg + 80 mg blister, No. 10, No. 30.

Tab. п / captivity. cover of 5 mg + 160 mg blister, No. 10, No. 30.